Objective: Efficient diagnostic pathways in advanced non-small cell lung cancer (NSCLC) are crucial for timely treatment initiation and improved outcomes. This study evaluated the impact of diagnostic delays and the role of minimally invasive techniques in biomarker assessment and survival in a real-world clinical cohort. Methods: A retrospective cohort study was conducted involving 205 patients with advanced NSCLC diagnosed between January 2020 and December 2023. Diagnostic procedures included EBUS/EUS-B, transthoracic biopsy, and surgical biopsy. The time-to-diagnostic procedure, time-to-therapy, and survival were analyzed using multivariate models. Results: The time interval to the first diagnostic procedure independently predicted mortality (HR=1.66; p=0.016). EBUS and EUS-B achieved significantly shorter diagnostic times (median 8 and 5 days, respectively) compared to transthoracic (20.5 days) and surgical (24.5 days) biopsies. These endoscopic techniques were also associated with shorter time intervals to systemic therapy initiation (p=0.011). Minimally invasive approaches provided sufficient tissue for complete morphological, immunohistochemical, and molecular profiling in most cases, with no significant differences in adequacy among procedures. Patients with actionable mutations had a 44% lower mortality risk (HR=0.56; p=0.013), while high PD-L1 expression was associated with a 56% reduction in mortality risk (HR=0.44; p=0.003). Conclusions: Minimally invasive techniques, particularly EBUS and EUS-B, shortened diagnostic delays, ensured adequate biomarker sampling, and enabled earlier initiation of systemic therapy. Since the time-to-diagnosis was independently associated with survival, these approaches may have indirectly contributed to improved outcomes. Our findings highlight the importance of streamlining diagnostic pathways and expanding access to endoscopic methods to optimize care in advanced NSCLC.

Keywords: Non-small cell lung cancer; Diagnostic pathways; EBUS; EUS-B; Molecular profiling; Survival analysis.

For patients with stage III (A or B) non-small cell lung cancer, radiation is still the standard treatment. However, long-term survival remains poor and new alternatives and therapeutic associations are being studied. Recently, chemotherapy has been in focus, with several combinations with radiation therapy and/or surgery. An update of the recently published data about the controversies on whether or not one should combine chemotherapy with radiation in locally advanced lung tumors was done. Cisplatin-based chemotherapy regimens combined with radiation are favorable, with a possible increase in survival of 3% in 2 years and 2% in 5 years. Neither the best drug combination nor the ideal association regimen have been defined yet. The indication of a combined treatment must be based on patient's clinical conditions and on a balance between quality of life, toxicity, and cost of chemotherapy.

Keywords: Lung neoplasms. Radiation therapy. Chemotherapy.

Several advances have been made in the treatment of advanced non-small cell lung cancer in the last few years. Combined therapies using chemotherapy have improved survival of patients with locally advanced disease (stage III) when compared to either radiation or surgery. New chemotherapeutic agents, used alone or combined, have also made a strong impact with metastatic disease (stage IV). Ongoing randomized trials will certainly define new treatment standards and hopefully improve the outcome of patients with non-small cell lung cancer.

Keywords: Locally advanced. Non-small cell lung cancer.

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

Objective: To evaluate the effect of chemotherapy on the physical condition of patients with advanced lung cancer. Methods: We evaluated 50 patients with non-small cell lung cancer (in stages IIIB and IV) and Eastern Cooperative Oncology Group (ECOG) performance status scale scores between zero and two. All patients underwent chemotherapy using paclitaxel and platinum derivatives and were evaluated at three time points (prechemotherapy, postchemotherapy and six months after starting the treatment), at which the ECOG scale, the body mass index (BMI) and the six-minute walk distance (6MWD) were assessed. Results: Of the 50 patients included in the study, 14 died, 5 were excluded due to the worsening of their performance status, and 31 completed the six-month follow-up. There was no statistically significant difference between the time points of assessment for BMI (prechemotherapy vs. postchemotherapy, p = 1.00; and prechemotherapy vs. six months later, p = 0.218) or for 6MWD. Performance status improved, and this was especially due to the increase in the number of asymptomatic patients after the six-month follow-up (p = 0.031). Conclusions: Chemotherapy had a beneficial effect on the performance status of the patients. No significant changes in BMI or 6MWD were found during the study period, which might suggest the maintenance of the physical condition of the patients.

Keywords: Drug therapy; Lung neoplasms; Exercise tolerance.

Background: Open lung biopsy is regarded as the gold standard for the diagnosis of diffuse pulmonary infiltrates. Objective: To determine the diagnostic yield, therapeutic changes, complications and mortality attributed to open lung biopsy in patients with diffuse pulmonary infiltrates and on mechanical ventilation. Method: We reviewed, retrospectively, the charts of 24 patients, ranging from 26 to 89 years of age, admitted to the intensive care units of two private hospitals and submitted to open lung biopsy. Results: Diagnostic positivity was found in 100% of patients, resulting in an alteration in the treatment regimen in 75%. Postoperative complications occurred in five patients (20.8%). There were no biopsy-related deaths, although global mortality was 45.8%. Conclusion: Open lung biopsy is a safe and high yield procedure for diagnosing diffuse pulmonary infiltrate in patients on mechanical ventilation. Despite the fact that no mortality impact factor has been assigned to such patients, data in the literature regarding prognosis must be taken into consideration.

Keywords: Biopsy. Respiratory insufficiency. Respiration artificial.

Objective: Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. Most patients are diagnosed at an advanced stage, palliative chemotherapy therefore being the only treatment option. This study was aimed at evaluating the health-related quality of life (HRQoL) of advanced-stage NSCLC patients receiving palliative chemotherapy with carboplatin and paclitaxel. Methods: This was a multiple case study of advanced-stage NSCLC outpatients receiving chemotherapy at a public hospital in Rio de Janeiro, Brazil. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire was used in conjunction with its supplemental lung cancer-specific module in order to assess HRQoL. Results: Physical and cognitive functioning scale scores differed significantly among chemotherapy cycles, indicating improved and worsened HRQoL, respectively. The differences regarding the scores for pain, loss of appetite, chest pain, and arm/shoulder pain indicated improved HRQoL. Conclusions: Chemotherapy was found to improve certain aspects of HRQoL in patients with advanced-stage NSCLC.

Keywords: Carcinoma, non-small-cell lung; Quality of life; Palliative care; Carboplatin; Paclitaxel.

Objective: To investigate the diagnostic value of α-enolase (ENO1) and serum ENO1 autoantibody levels in lung cancer. Methods: Immunohistochemistry staining and ELISA were performed to detect ENO1 expression in lung tissue and serum ENO1 autoantibody levels, respectively. Results: The expression of ENO1 was higher in lung cancer tissues than in benign lung disease tissues (p < 0.001). The proportion of lung cancer samples expressing ENO1 was not significantly different among the various pathological classification groups. The proportion of samples expressing ENO1 was higher in lung cancer patients in stages I/II than in those in stages III/IV (χ2 = 5.445; p = 0.018). The expression of ENO1 in lung cancer tissues was not associated with age, gender, or smoking history. Serum ENO1 antibody levels were significantly higher in the lung cancer group than in the benign lung disease and control groups (p < 0.001). The differences among the pathological classification groups were not statistically significant. Serum ENO1 antibody levels were also in lung cancer patients in stages I/II than in those in stages III/IV (p < 0.01). Serum ENO1 antibody levels were not associated with age, gender, or smoking history in lung cancer patients. The ROC curve representing the diagnosis of lung cancer based on ENO1 antibody levels had an area under the curve of 0.806. Conclusions: Our results suggest that high levels of ENO1 are associated with the clinical stage of lung cancer and that ENO1 expression and its serum autoantibody levels show diagnostic value in lung cancer.

Keywords: Phosphopyruvate hydratase/analysis; Enzyme-linked immunosorbent assay; Immunohistochemistry; Lung neoplasms.

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: Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting. Methods: This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting. Results: The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity. Conclusions: These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.

Keywords: Lung neoplasms; Chemotherapy, adjuvant; Cisplatin/toxicity; Vinorelbine/toxicity.

Objective: Preoperative functional evaluation is central to optimizing the identification of patients with non-small cell lung cancer (NSCLC) who are candidates for surgery. The minute ventilation/carbon dioxide output (VE/VCO2) slope has proven to be a predictor of surgical complications and mortality. Pulmonary rehabilitation programs (PRPs) could influence short-term outcomes in patients with COPD undergoing lung resection. Our objective was to evaluate the effects of a PRP on the VE/VCO2 slope in a cohort of patients with COPD undergoing lung resection for NSCLC. Methods: We retrospectively evaluated 25 consecutive patients with COPD participating in a three-week high-intensity PRP prior to undergoing lung surgery for NSCLC, between December of 2015 and January of 2017. Patients underwent complete functional assessment, including spirometry, DLCO measurement, and cardiopulmonary exercise testing. Results: There were no significant differences between the mean pre- and post-PRP values (% of predicted) for FEV1 (61.5 ± 22.0% vs. 62.0 ± 21.1%) and DLCO (67.2 ± 18.1% vs. 67.5 ± 13.2%). Conversely, there were significant improvements in the mean peak oxygen uptake (from 14.7 ± 2.5 to 18.2 ± 2.7 mL/kg per min; p < 0.001) and VE/VCO2 slope (from 32.0 ± 2.8 to 30.1 ± 4.0; p < 0.01). Conclusions: Our results indicate that a high-intensity PRP can improve ventilatory efficiency in patients with COPD undergoing lung resection for NSCLC. Further comprehensive prospective studies are required to corroborate these preliminary results.

Keywords: Carcinoma, non-small-cell lung; Pulmonary disease, chronic obstructive/rehabilitation; Carbon dioxide/metabolism; Oxygen consumption/physiology; Risk assessment.

A significant percentage of pleural effusions remains without a diagnostic explanation. In such circumstances, the anatomical-pathological result of nonspecific chronic pleuritis should be revised. This is an important issue, not only for the pathologist, but mainly for the pneumologist, who usually makes the clinical-pathological correlation during the routine practice. Although the existence of established criteria is accepted, they are certainly subjective and make the communication by means of a common language difficult, mainly among pathologists. The authors recently studied 311 pleural biopsies with histo-pathological diagnoses of chronic nonspecific pleuritis. All specimens were reviewed and the histo-pathological parameters quantified by stereology. The patients were stratified according to the final diagnosis of their disease, including cases of chronic renal failure, vasculitis, pancreatitis, tuberculosis, cancer, and congestive cardiac failure, in this case considering the pleura as normal. This procedure allowed us to obtain a discriminating model, whose morphological subcriteria classified almost 90% of the nonspecific chronic pleuritis biopsies, according to their final clinical diagnoses, which included true nonspecific chronic pleuritis or tuberculosis pleuritis, paraneoplastic pleuritis, or even normal pleura. By adding to this model the biochemistry or differential cytology of the pleural liquid, its classificatory power reaches 99% of correctness. This study represents the result of the experience acquired over several years in the histo-pathological interpretation of pleural biopsies, based on the correlation between morphology and biochemistry and cytology of the pleural fluid.

Keywords: Biopsy, needle. Pleura/pathology. Pleura/cytology. Pleural effusion.

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.

Objective: Although Mycobacterium avium complex (MAC) lung disease has been shown to be associated with lung cancer and hematologic malignancies, there have been few studies of its relationships with other types of cancer. The aim of this study was to assess the effect that coexisting advanced extrapulmonary solid tumors have on the progression of MAC lung disease. Methods: This was a retrospective study of patients diagnosed with MAC lung disease, on the basis of the American Thoracic Society (ATS) criteria, between October of 2005 and March of 2019. The patients were divided into three groups: those with advanced-stage cancer (A-SC group); those with early-stage cancer (E-SC group); and those without cancer (control group). Progression of MAC lung disease was defined as exacerbation seen on imaging. Patient characteristics and the time to progression were compared among the three groups. Results: A total of 286 patients met the ATS diagnostic criteria for MAC lung disease, and 128 of those were excluded. Of the remaining 158 patients, 20 (7.0%) were in the A-SC group, 36 (12.6%) were in the E-SC group, and 102 (35.7%) were in the control group. The median time to progression in the A-SC, E-SC, and control groups was 432, 3,595, and 2,829 days, respectively (p < 0.01). A proportional hazards model showed that the significant predictors of MAC lung disease progression were advanced-stage cancer (hazard ratio [HR] = 6.096; 95% CI: 2.688-13.826; p < 0.01), cavitary lesions (HR = 2.750; 95% CI: 1.306-5.791; p < 0.01), and a high Nodule-Infiltration-Cavity-Ectasis score (HR = 1.046; 95% CI: 1.004-1.091; p = 0.033). Conclusions: A coexisting advanced extrapulmonary solid tumor could hasten the progression of MAC lung disease.

Keywords: Nontuberculous mycobacteria; Mycobacterium avium complex; Neoplasms; Radiography.

Objective: To present an alternative method of detecting micrometastases in lymph nodes previously testing negative for non-small cell lung cancer (NSCLC) by routine hematoxylin-eosin staining. Methods: A total of 77 hilar and mediastinal lymph nodes resected from 18 patients with NSCLC were investigated for the presence of micrometastases using a combination of microarray analysis and immunohistochemistry. Results: Micrometastases were detected by identifying cytokeratin- and chromogranin-positive cells in lymph node microarrays. Of the 18 patients initially staged as pN0 through routine hematoxylin-eosin staining, 9 (50%) were restaged as N1, and the prognoses were re-evaluated in terms of histological and clinical parameters. The comparison of the survival curves revealed that survival was higher in the patients without micrometastases than in those with micrometastases. In addition, in the multivariate analysis adjusted for age, gender, histological type, and restaging, the presence of micrometastases proved to be an independent predictor of survival. Among patients who had been previously staged as pN0, the risk of death was found to be 7-times greater for those later diagnosed with micrometastases than for those in whom no micrometastases were identified. Conclusion: The combination of microarray analysis and immunohistochemistry might represent a low-cost and less time-consuming alternative for identifying occult micrometastases and predicting prognoses in surgically resected patients with pN0 NSCLC. Larger randomized, prospective studies are needed in order to determine the accuracy of this method.

Keywords: Lung neoplasms; Microarray analysis; Chromogranin A; Survival analysis.