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.

Mucoepidermoid carcinoma is an uncommon neoplasm of the tracheobronchial tree, of unknown etiology. Its preferred endobronchial location often results in respiratory symptoms such as obstruction of the airways and lung diseases of slow recovery. They usually are slow growing tumors although they may present an aggressive behavior with local invasion and lymph node metastases depending on their histopathologic characteristics. The mainstay therapy is complete surgical resection either by means of lobectomy or by lung sparing procedures such as bronchotomy and bronchoplasty. Prognosis depends upon the degree of cellular differentiation of the tumors. The authors report a case of this rare neoplasia and describe the clinical and radiographic characteristics, and the surgical treatment.

In cases of recent asthma in which clinical control with the usual treatment (corticosteroids and bronchodilator) is unsatisfactory, it is important to consider other diagnoses, such as congestive heart failure, gastroesophageal reflux or other forms of airway obstruction. We report the case of a female patient with mucoepidermoid carcinoma of the trachea mimicking asthma. The patient presented cough and wheezing, as well as abnormal spirometry results with an obstructive pattern that was responsive to bronchodilators. One year later, the patient presented clinical and spirometric worsening. The chest X-ray revealed no abnormalities. A CT scan showed a vegetative lesion obstructing the tracheal lumen and located 1 cm from the carina. Fiberoptic bronchoscopy showed a finding similar to a bronchial carcinoid tumor. The anatomopathological diagnosis made after surgical resection was low-grade mucoepidermoid carcinoma, without lymph node involvement. Although the flow-volume curve was not suggestive of upper airway obstruction, the spirometry performed after the surgery showed a significant reduction in the degree of obstruction and greater reversibility after bronchodilator use. There was no evidence of recurrence of the disease or of the symptoms after a two-year follow-up period.

Keywords: Bronchial hyperreactivity; Carcinoma, mucoepidermoid; Trachea; Asthma; Lung diseases, obstructive.

Pancoast syndrome consists of signs and symptoms resulting from a tumor affecting the pulmonary apex and adjacent structures. The process is typically caused by a neoplasm. The majority of cases of Pancoast syndrome are caused by bronchogenic carcinoma. The most commonly found histologic subtypes are adenocarcinoma and epidermoid carcinoma. There have been very few reports of small cell lung carcinoma in the genesis of Pancoast syndrome. We describe the case of a patient with Pancoast syndrome caused by small cell lung carcinoma and discuss the aspects related to the diagnosis and treatment.

Keywords: Pancoast syndrome; Small cell lung carcinoma; Lung neoplasms.

Objective: The emergence of tuberculosis/HIV co-infection and the increase in the number of cases of infection with nontuberculous mycobacteria (NTM) require rapid laboratory test results in the isolation and identification of mycobacteria. The objective of this study was to evaluate the identification of mycobacteria by means of gene probes in comparison with that obtained using classical biochemical methods. Methods: Between 2002 and 2004, 178 mycobacterial cultures, all testing positive for acid-fast bacilli, were analyzed. Samples were obtained from clinical specimens of patients with respiratory symptoms or with clinical suspicion of pulmonary tuberculosis/mycobacteriosis who were treated in the greater metropolitan area of Santos. Results: The gene probe identified 137 samples (77%) as Mycobacterium tuberculosis complex and 41 (23%) as NTM. Discordant results between the methods (3%) were obtained only in the year of implementation (2002). When comparing the methods, the sensitivity, specificity, positive predictive value and negative predictive value of the gene probe method were 98%, 93%, 98% and 93%, respectively. Conclusions: Despite the cost, the identification of mycobacteria using the molecular technique is faster: maximum 3 h vs. 28-30 days for classical methods. The use of gene probes is a validated molecular technique. It is fast, easy to use and readily available on the market. It has high specificity and sensitivity, which justifies its implementation and routine use in referral laboratories, since it facilitates the diagnosis providing agile clinical interventions.

Keywords: Mycobacterium tuberculosis; Tuberculosis/diagnosis; Mycobacterium/classification; DNA probes.

Recurrent pneumonia is characterized by frequent infection and infiltrates in one or more lung lobes. The localized form of the disease is caused by intraluminal obstruction, extrinsic compression or structural abnormalities. The pattern, frequency and severity of the infections, together with a thorough review of all chest X-rays, inform the diagnosis. Herein, we report a case of recurrent pneumonia due to endobronchial obstruction by mucoepidermoid carcinoma.

Keywords: Pneumonia; Recurrent; Carcinoma, mucoepidermoid/diagnosis; Tomography, X-ray computed; Case reports

Objetivo: Determinar a utilidade, na prática rotineira, da análise da clonalidade dos linfócitos T e B nos tecidos pulmonares por reação em cadeia da polimerase no diagnóstico das doenças linfoproliferativas pulmonares. Métodos: Avaliaram-se, mediante análise imunohistoquímica e rearranjo molecular dos genes, 8 casos de pneumonia intersticial linfocítica (PIL) e 7 casos de doenças linfoproliferativas pulmonares. Resultados: Todos os 8 casos de PIL expressaram imunocoloração moderada a forte para CD3, em contraste com apenas 2 casos de linfoma e 1 caso de pseudolinfoma. Rearranjo gênico foi detectado em 4 de 8 casos de PIL, o que mudou o diagnóstico de PIL para linfoma, indicando, assim, a importância da detecção de rearranjo gênico em casos de PIL. Nesta situação, rearranjo gênico usando-se os pares de primers VH/JH e Vγ11/Jγ12 foi detectado em 3 e 1 casos de PIL, respectivamente, e não foram detectadas anormalidades gênicas usando-se as pares Dβ1/Jβ2 e Vγ101/Jγ12. Uma associação positiva foi detectada entre a intensidade de imunoexpressão CD20 e CD68 e rearranjo gênico usando-se o par de primers VH/JH. Antes do rearranjo gênico, 4 pacientes com PIL morreram rapidamente, enquanto que, após o rearranjo gênico, apenas 1 paciente com PIL morreu. Conclusões: A detecção de células B e T monoclonais por imunofenotipagem e reação em cadeia da polimerase mostrou impacto no diagnóstico de linfomas pulmonares em pacientes previamente diagnosticados com PIL. Portanto, imunofenotipagem e reação em cadeia da polimerase devem ser incluídas como métodos de 'padrão ouro' na rotina diagnósticObjetivo: Determinar a utilidade, na prática rotineira, da análise da clonalidade dos linfócitos T e B nos tecidos pulmonares por reação em cadeia da polimerase no diagnóstico das doenças linfoproliferativas pulmonares. Métodos: Avaliaram-se, mediante análise imunohistoquímica e rearranjo molecular dos genes, 8 casos de pneumonia intersticial linfocítica (PIL) e 7 casos de doenças linfoproliferativas pulmonares. Resultados: Todos os 8 casos de PIL expressaram imunocoloração moderada a forte para CD3, em contraste com apenas 2 casos de linfoma e 1 caso de pseudolinfoma. Rearranjo gênico foi detectado em 4 de 8 casos de PIL, o que mudou o diagnóstico de PIL para linfoma, indicando, assim, a importância da detecção de rearranjo gênico em casos de PIL. Nesta situação, rearranjo gênico usando-se os pares de primers VH/JH e Vγ11/Jγ12 foi detectado em 3 e 1 casos de PIL, respectivamente, e não foram detectadas anormalidades gênicas usando-se as pares Dβ1/Jβ2 e Vγ101/Jγ12. Uma associação positiva foi detectada entre a intensidade de imunoexpressão CD20 e CD68 e rearranjo gênico usando-se o par de primers VH/JH. Antes do rearranjo gênico, 4 pacientes com PIL morreram rapidamente, enquanto que, após o rearranjo gênico, apenas 1 paciente com PIL morreu. Conclusões: A detecção de células B e T monoclonais por imunofenotipagem e reação em cadeia da polimerase mostrou impacto no diagnóstico de linfomas pulmonares em pacientes previamente diagnosticados com PIL. Portanto, imunofenotipagem e reação em cadeia da polimerase devem ser incluídas como métodos de 'padrão ouro' na rotina diagnóstica.

Keywords: Linfoma; Doenças pulmonares intersticiais; Biologia molecular; Reação em cadeia da polimerase.

Objective: To analyze and compare the mutations in two different regions of the katG gene, which is responsible for isoniazid (INH) resistance. Methods: We analyzed 97 multidrug-resistant Mycobacterium tuberculosis strains isolated in cultures of sputum samples obtained from the Professor Hélio Fraga Referral Center, in Brasília, Brazil. Another 6 INH-sensitive strains did not present mutations and were included as controls. We used PCR to amplify two regions of the katG gene (GenBank accession no. U06258)-region 1, (from codon 1 to codon 119) and region 2 (from codon 267 to codon 504)-which were then sequenced in order to identify mutations. Results: Seven strains were resistant to INH and did not contain mutations in either region. Thirty strains carried mutations in region 1, which was characterized by a high number of deletions, especially at codon 4 (24 strains). Region 2 carried 83 point mutations, especially at codon 315, and there was a serine-to-threonine (AGC-to-ACC) substitution in 73 of those cases. The analysis of region 2 allowed INH resistance to be diagnosed in 81.4% of the strains. Nine strains had mutations exclusively in region 1, which allowed the proportion of INH-resistant strains identified to be increased to 90.6%. Conclusions: The number of mutations at codon 315 was high, which is consistent with cases described in Brazil and in other countries, and the analysis of region 1 resulted in a 9.2% increase in the rate at which mutations were identified.

Keywords: Isoniazid; Mutation; Tuberculosis; Drug resistance, multiple.

Objective: To identify associations between genetic polymorphisms (in the MBL2, TGF-β1 and CD14 genes) and the severity of the lung disease in patients with cystic fibrosis (CF), as well as between the presence of ΔF508 alleles and lung disease severity in such patients. Methods: This was a cross-sectional cohort study, based on clinical and laboratory data, involving 105 patients with CF treated at a university hospital in the 2005-2006 period. We included 202 healthy blood donors as controls for the determination of TGF-β1 and CD14 gene polymorphisms. Polymorphisms in the MBL2 and TGF-β1 genes at codon 10, position +869, were genotyped using the allele-specific PCR technique. The C-159T polymorphism in the CD14 gene was genotyped using PCR and enzymatic digestion. Results: Of the 105 CF patients evaluated, 67 presented with severe lung disease according to the Shwachman score. The MBL2 gene polymorphisms were not associated with disease severity in the CF patients. Analysis of the T869C polymorphism in the TGF-β1 gene showed an association only between TC heterozygotes and mild pulmonary disease. Although patients presenting the TT genotype of the C159T polymorphism in the CD14 gene predominated, there was no significant difference regarding lung disease severity. Conclusions: There was an association between the TC genotype of the T869C polymorphism (TGF-β1) and mild pulmonary disease in CF patients. In the CD14 gene, the TT genotype seems to be a risk factor for pulmonary disease but is not a modulator of severity. We found no association between being a ΔF508 homozygote and presenting severe lung disease.

Keywords: Cystic fibrosis; Polymorphism, genetic; Severity of illness index; Mannose-binding lectin; Transforming growth factor beta.

Objective: To study the effect of perillyl alcohol on the gene expression of human pulmonary adenocarcinoma cells. Methods: Pulmonary adenocarcinoma cells were incubated with perillyl alcohol in dilutions ranging from 0.03% to 0.0003% for 48 hours. Alterations were observed in the cell morphology, and cell viability was quantified using [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays. Protein synthesis of samples previously targeted with S35 was analyzed using electrophoresis on a polyacrylamide gel. Expression of the proteins p53 and p44/42 was determined using the Western blot method. Results: After 48 hours of incubation, greater numbers of morphological alterations were observed in cells treated with the 0.03% perillyl alcohol dilution than in those treated with perillyl alcohol diluted to 0.003% or further. Treatment with perillyl alcohol dilutions of 0.03%, 0.003% and 0.0003% inhibited cellular viability by 60.17% (p < 0.001), 15.62% (p < 0.001) and 11.53% (p < 0.05), respectively. The results show that 28-kDa, 42-kDa and 110-kDa proteins were induced. No statistically significant effect on p53 expression was observed. In comparison with the expression of a-tubulin, the 0.003% perillyl alcohol dilution induced an increase in p42 phosphorylation and a marked decrease in p44 phosphorylation. Conclusion: The results suggest that there are other, previously undescribed, metabolic pathways for perillyl alcohol effects in human pulmonary adenocarcinoma cells.

Keywords: Adenocarcinoma; Lung neoplasms; Monoterpenes; Cell culture; Lung/cytology

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.

Objective: The clinical, functional, radiological and genotypic descriptions of patients with an alpha-1 antitrypsin (A1AT) gene mutation in a referral center for COPD in Brazil. Methods: A cross-sectional study of patients with an A1AT gene mutation compatible with deficiency. We evaluated the A1AT dosage and genotypic, demographic, clinical, tomographic, and functional characteristics of these patients. Results: Among the 43 patients suspected of A1AT deficiency (A1ATD), the disease was confirmed by genotyping in 27 of them. The A1AT median dosage was 45 mg/dL, and 4 patients (15%) had a normal dosage. Median age was 54, 63% of the patients were male, and the respiratory symptoms started at the age of 40. The median FEV1 was 1.37L (43% predicted). Tomographic emphysema was found in 77.8% of the individuals. The emphysema was panlobular in 76% of them and 48% had lower lobe predominance. The frequency of bronchiectasis was 52% and the frequency of bronchial thickening was 81.5%. The most common genotype was Pi*ZZ in 40.7% of participants. The other genotypes found were: Pi*SZ (18.5%), PiM1Z (14.8%), Pi*M1S (7.4%), Pi*M2Z (3.7%), Pi*M1I (3.7%), Pi*ZMnichinan (3.7%), Pi*M3Plowell (3.7%), and Pi*SF (3.7%). We did not find any significant difference in age, smoking load, FEV1, or the presence of bronchiectasis between the groups with a normal and a reduced A1AT dosage, neither for 1 nor 2-allele mutation for A1ATD. Conclusions: Our patients presented a high frequency of emphysema, bronchiectasis and bronchial thickening, and early-beginning respiratory symptoms. The most frequent genotype was Pi*ZZ. Heterozygous genotypes and normal levels of A1AT also manifested significant lung disease.

Keywords: Alpha-1 antitrypsin; Emphysema; Alleles.

The authors describe a case of a woman submitted to radiation therapy for breast carcinoma who presented, 40 days after the end of the treatment, fever, dry cough, dyspnea on exertion, and weight loss. Chest imaging revealed migratory opacities. The histopathological examination of transbronchial biopsy specimens showed characteristic findings of BOOP. Corticosteroid therapy resulted in dramatic clinical improvement, together with complete clearing of the pulmonary opacities on chest imaging. The authors present a brief review of the literature concerning radiation-induced lung injury, emphasizing the importance of including BOOP in the differential diagnosis in these complications. The present case, as well as the two other reports from the literature, provide further evidence for the role of irradiation injury as a cause of clinicopathological syndrome identical to idiopathic BOOP, i.e., radiation-induced BOOP.

Keywords: Bronchiolitis obliterans organizing pneumonia. BOOP. Radiation pneumonitis. Radiotherapy. Breast carcinoma.

Incidence of metastatic disease to the hypothalamic-pituitary area is low (1 to 6% in most studies), the lung and the prostate being the most common primary sites in men. Clinical presentation as panhypopituitarism is rare (0.2 to 0.8%) in patients with bronchogenic carcinoma. The authors describe a case of a man with diagnosis of squamous cell carcinoma of the lung that, during the clinical course of the disease, presented clinical and laboratorial evidence of panhypopituitarism, with an expansive sellar and supra-sellar lesion image in the CT scan of the brain.

Keywords: Panhypopituitarism. Bronchogenic carcinoma. Hypothalamic-pituitary metastases.

The usefulness of serum tumor markers in lung cancer is not well defined. Objective: The aim of this study is to examine the correlation between serum tumor markers and tumor extension and its prognostic value. Patients and method: From February 1995 to September 1997, 103 patients with non-small cell lung carcinoma were evaluated at the Department of Thoracic Surgery. Serum levels of CEA, CYFRA21.1, CA15.3, CA19.9, CA72.4, and NSE were determined before treatment. Results: The serum level of CYFRA21.1 was the most frequent elevated tumor marker (55%). Patients with advanced tumor had higher mean serum level of CEA (90.8 ng/ml), CYFRA21.1 (20.3 ng/ml) and CA15.3 (56.5%) than those with localized carcinoma, respectively 10.2 ng/ml, 12.6 ng/ml and 22.2 ng/ml. Considering all serum tumor markers evaluated in this study, only patients with elevated CEA had greater chance (5.6) of presenting with advanced non-small lung carcinoma than patients with normal CEA. Overall survival was influenced by performance status (p = 0.001), tumor extension (p = 0.006), elevated serum level of CEA (p = 0.043), more than two elevated serum tumor markers (p < 0.001), and type of treatment (p < 0.001). The prognostic value of anatomical tumor extension reached the limit of significance (p = 0.052); however, two or more elevated serum tumor markers and type of treatment had independent prognostic value (respectively, p = 0.035 and p = 0.005). Conclusion: None of these serum tumor markers had clinical value in the management of NSCLC patients.

Keywords: biological tumor markers, neoplasm staging, non-small cell lung carcinoma, prognosis

A case of a patient with Pancoast's syndrome associated with acquired immunodeficiency syndrome is reported. This association is rare and Kaposi's sarcoma and non-Hodgkin lymphoma are the most recurrent tumors in AIDS. The patient was an IV drug user and was admitted to the hospital for diagnosis of apex lung mass with signs of Pancoast's syndrome. HIV serology was positive and pathology of lung mass showed non-small cell lung cancer.

Keywords: Pancoast's syndrome. HIV. Bronchogenic carcinoma. Lung neoplasms. Acquired immunodeficiency syndrome.