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OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) accelerate the progressive impairment of lung function and general health. Together with maintenance therapy for chronic obstructive pulmonary disease (COPD), N-acetylcysteine (NAC) and natural propolis have demonstrated pharmacological properties that address crucial pathophysiological processes underlying COPD and may prevent AECOPDs. This study aims at responding to dose-dependent efficacy and safety concerns regarding a propolis-NAC combination for the reduction of COPD exacerbation rates. PATIENTS AND METHODS: This was a single-center, randomized, double-blind, phase IV trial with three treatment arms: Placebo and two active substance groups, one (AS-600) received 600 mg of NAC + 80 mg of propolis while the other (AS-1,200) received 1,200 mg of NAC + 160 mg of propolis. Following an AECOPD, frequent-exacerbation phenotype patients (n=46) were assigned a once-daily three-month therapy with the study drug and one year follow-up. The primary endpoint was the COPD exacerbation incidence rate during the follow-up period as a measure of dose-dependent efficacy of NAC-propolis combination compared to placebo. RESULTS: There was a statistically significant difference in the AECOPD incidence rate: 52.6% in patients that received placebo, 15.4% that received AS-600 and only 7.1% that received AS-1,200 (Fisher's exact test, p = 0.013). Compared to placebo, AECOPD frequency was significantly lower only in AS-1,200 (p=0.009). Compared to placebo, the relative risk for exacerbation was 0.29 in AS-600 and 0.13 in AS-1,200. No adverse events related to the treatment were reported. CONCLUSIONS: Oral combination of natural propolis with NAC confirmed formulation efficiency with a favorable safety profile. Our results need to be confirmed by larger clinical trials. [ABSTRACT FROM AUTHOR]

Background: The objective of this prospective study was to evaluate whether soluble programmed cell death1/programmed cell death-ligand 1 (PD-1/PD-L1) and serum amyloid A1 (SAA1) are potential diagnostic, predictive or prognostic biomarkers in lung cancer. Methods: Lung cancer patients (n = 115) with advanced metastatic disease, 101 with non-small cell lung cancer, NSCLC (77 EGFR wild-type NSCLC patients on chemotherapy, 15 EGFR mutation positive adenocarcinoma patients, 9 patients with mPD-L1 Expression >50% NSCLC - responders to immunotherapy), and 14 patients with small cell lung cancer (SCLC) were examined. ELISA method was used to determine sPD-L1 and SAA1 concentrations in patients' plasma. Results: Significantly higher blood concentrations of sPDL1 and SAA1 were noted in lung cancer patients compared with a healthy control group. In PD-L1+ NSCLC patients, a significantly higher sPD-L1 level was noticed compared to any other lung cancer subgroup, as well as the highest average SAA1 value compared to other subgroups. Conclusions: It seems that sPD-1/PD-L1 might be a potential biomarker, prognostic and/or predictive, particularly in patients treated with immunotherapy. Serum amyloid A1 has potential to act as a good predictor of patients' survival, as well as a biomarker of a more advanced disease, with possibly good capability to predict the course of disease measured at different time points.

Branislava Milenkovic,1,2 Sanja Dimic Janjic,2 Spasoje Popevic1,2 1Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 2Clinic for Pulmonary Diseases, Clinical Center of Serbia, Belgrade, Serbia Abstract: Emphysema is an incurable and underdiagnosed disease with obstructive ventilatory impairment of lung function. Despite decades of research, medical treatments available so far did not significantly improve the survival benefits. Different bronchoscopic methods for lung volume reduction (LVR) in emphysema were used in the past 2 decades aiming to close the airways serving the hyperinflated lung regions and to allow the gas in the more distal bullas to be absorbed. Sealants and adhesives can be natural/biological, synthetic and semisynthetic. In lung surgery, lung sealants are used to treat prolonged air leak, which is the most common complication. Sealants can also be applied in bronchoscopic lung volume reduction (BLVR) as they administer into the peripheral airways where they polymerize and act as tissue glue on the surface of the lung to seal the target area to cause durable permanent absorption atelectasis. Initial studies analyzed the efficacy of bronchoscopic instillation of a fibrinogen–thrombin complex solution in advanced emphysema. Future studies will analyze the effects of adding chondroitin sulfate and poly-l-lysine to thrombin–fibrinogen complex thus promoting fibroblast attachment, proliferation and scarring, causing bronchial fibrostenosis and preventing ventilation of the affected part of the lung. Modifications of these methods were later developed, and the efficacy of BLVR with other sealants was analyzed in clinical studies. Results from current studies using this treatment method are promising showing that it is effective in improving exercise tolerance and quality of life in patients with advanced emphysema. It seems that subjective benefits in dyspnea scores and quality of life are more marked than improvements in lung function tests. The safety profile of sealant techniques in BLVR was mostly acceptable in clinical studies. The definite conclusions about the effectiveness of sealant in BLVR could be difficult because only a small population was involved in the current studies. More randomized large controlled studies are needed in establishing the definite role of biological BLVR in the bronchoscopic treatment of emphysema. Keywords: sealant, emphysema, lung volume reduction

Background: Until now, a proper biomarker(s) to evaluate sarcoidosis activity has not been recognized. The aims of this study were to evaluate the sensitivity and specificity of the two biomarkers of sarcoidosis activity already in use (serum angiotensin converting enzyme - ACE and serum chitotriosidase) in a population of 430 sarcoidosis patients. The activities of these markers were also analyzed in a group of 264 healthy controls. Methods: Four hundred and thirty biopsy positive sarcoidosis patients were divided into groups with active and inactive disease, and groups with acute or chronic disease. In a subgroup of 55 sarcoidosis patients, activity was also assessed by F-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scanning. Both serum chitotriosidase and ACE levels showed non-normal distribution, so nonparametric tests were used in statistical analysis. Results: Serum chitotriosidase activities were almost 6 times higher in patients with active sarcoidosis than in healthy controls and inactive disease. A serum chitotriosidase value of 100 nmol/mL/h had the sensitivity of 82.5% and specificity of 70.0%. A serum ACE activity cutoff value of 32.0 U/L had the sensitivity of 66.0% and the specificity of 54%. A statistically significant correlation was obtained between the focal granulomatous activity detected on 18F-FDG PET/CT and serum chitotriosidase levels, but no such correlation was found with ACE. The levels of serum chitotriosidase activity significantly correlated with the disease duration (P< 0.0001). Also, serum chitotriosidase significantly correlated with clinical outcome status (COS) categories (p = 0.272, P = 0.001). Conclusions: Serum chitotriosidase proved to be a reliable biomarker of sarcoidosis activity and disease chronicity.

Background/Aim. Endobronchial tuberculosis (EBTB) is a specific type of pulmonary tuberculosis which often affect the tracheobronchial tree, and can be microbiologically and/or pathohistologically confirmed. The aim of the study was to determine the clinical features and diagnostic aspects of EBTB. Methods. This retrospective study was conducted at the Clinic for Lung Diseases, Clinical Center of Serbia, Belgrade, from January 1997 to December 2007. All patients with EBTB confirmed by bronchoscopy with biopsy during a study period were analysed. Data included the patient’s medical history, a physical exam, chest X-ray, mycobacterial analysis of sputum samples, endoscopic types and patohistological confirmation. Results. In the study, 57.6% of the patients were males. The most frequent symptoms were cough (71.2%), malaise (54.2%), fever (49.2%), weight loss (40.7%), and hemoptysis (13.6%). Most of the patients were diagnosed within 30 days of symptoms onset. Sputum examination showed acid-fast bacilli in 31.4% of the patients, while sputum culture for tuberculosis bacilli were positive in 55.9% of the patients. The most common radiographic localization was in the upper lung lobes (63.5%). Cavities were present in 60.4% of the patients. The most common endoscopic subtype determined by bronchoscopy were nonspecific bronchitis (39.9%) and edematous-hyperemic subtype (36.4%). Conclusion. EBTB was more frequent among men, and among people in their fifties in our country. Detailed bronchoscopic examination, correlated with clinical and laboratory findings, will improve diagnostic rate and provide timely therapy. [Projekat Ministarstva nauke Republike Srbije, br. 175046]

Recently published data indicate that vitamin D abnormalities are common in sarcoidosis patients. The purpose of this study was to compare serum vitamin 25(OH)D levels among sarcoidosis patients with different clinical courses of the disease. The study also included the first observations on cognitive functions (i.e. depression and fatigue syndrome) in relation to vitamin D deficiency in sarcoidosis patients. At the Biochemical Laboratory of the Clinical Center of Serbia, Belgrade, vitamin D25(OH)D was measured using the Elecsys® Vitamin D total test. A total of 226 patients with biopsy-positive sarcoidosis were analyzed. The average median value of serum vitamin D was 9.47 mg/L, suggesting severe deficiency. Statistically significant correlation was found in patients with chronic disease and low levels of serum vitamin 25(OH)D (Chi-Square=6.044; df=2; p=0.014). The patient group with vitamin D serum levels higher than 20 mg/L showed higher levels of the mean forced vital capacity (FVC) by 380 mL, and forced expiratory volume in one second (FEV1) by 220 mL, when compared to the patient group with lower serum vitamin D. A statistically significant role was established for serum vitamin 25(OH)D levels as the predictor of fatigue (R2=0.878; p=0.038 (b=0.216)) and depression in patients with sarcoidosis (R2=0.80; p=0.000 (b=0.391)). The insufficiency of 25(OH)D seems to be an important factor in predicting the course of chronic disease, significant lung function impairments and cognitive failures such as fatigue and depression. The fact that the majority of the analyzed sarcoidosis patients had totally deficient serum 25(OH)D levels made this finding even more notable.

Background. Mounier-Kuhn syndrome or tracheobronchomegaly is a rare disorder characterized by marked dilatation of the trachea and main bronchi, bronchiectasis, and recurrent respiratory tract infections. Its clinical presentation may vary and mimick a variety of disorders. Case report. A 43-year-old female patient, non smoker, complained of intermittent mild dyspnea. Lung function tests and cardiologic findings were within normal limits. The diagnosis was established by computed tomography, which was undertaken due to recurrent lower respiratory tract infections suggestive of bronchiectasis. The transversal tracheal diameter was 2.8 cm that was the criteria for making the diagnosis. In this sporadic case, no association with other disease or condition known to cause secondary tracheobronchomegaly was established. Conclusion. Although rare in clinical practice, Mounier-Kuhn syndrome is an important differential diagnosis in cardio-pulmonary medicine due to a variety of its clinical manifestations. Nowadays, it is easy to diagnose it owing to advanced imaging techniques.

Background and Objectives : Advanced lung cancer is usually manifested by endoluminal tumor propagation, resulting in central airway obstruction. The objective of this study is to compare the high dose rate brachytherapy treatment outcomes in non-small-cell lung cancer (NSCLC) depending on the treatment planning pattern-two-dimension (2D) or three-dimension (3D) treatment planning. Materials and Methods : The study was retrospective and two groups of patients were compared in it (a group of 101 patients who underwent 2D planned high-dose-rate endobronchial brachytherapy (HDR-EBBT) in 2017/18 and a group of 83 patients who underwent 3D planned HDR-EBBT between January 2021 and June 2023). Results : In the group of 3D planned brachytherapy patients, there was a significant improvement in terms of loss of symptoms of bronchial obstruction ( p = 0.038), but no improvement in terms of ECOG PS (European Cooperative Oncology Group Performance Status) of the patient ( p = 0.847) and loss of lung atelectasis (if there was any at the beginning of the disease) ( p = 0.781). Two-year overall survival and time-to-progression periods were similar for both groups of patients ( p = 0.110 and 0.154). Fewer treatment complications were observed, and 91.4% were in 3D planned brachytherapy (BT) patients. Conclusions : Three-dimensionally planned HDR-EBBT is a suggestive, effective palliative method for the disobstruction of large airways caused by endobronchial lung tumor growth. Independent or more often combined with other types of specific oncological treatment, it certainly leads to the loss of symptoms caused by bronchial obstruction and the improvement of the quality of life of patients with advanced NSCLC. Complications of the procedure with 3D planning are less compared to 2D planned HDR-EBBT.

Background and Objectives : Treatment of advanced lung cancer (LC) has become increasingly personalized over the past decade due to an improved understanding of tumor molecular biology and antitumor immunity. The main task of a pulmonologist oncologist is to establish a tumor diagnosis and, ideally, to confirm the stage of the disease with the least invasive technique possible. Materials and Methods : The paper will summarize published reviews and original papers, as well as published clinical studies and case reports, which studied the role and compared the methods of invasive pulmonology diagnostics to obtain adequate tumor tissue samples for molecular analysis, thereby determining the most effective molecular treatments. Results : Bronchoscopy is often recommended as the initial diagnostic procedure for LC. If the tumor is endoscopically visible, the biopsy sample is susceptible to molecular testing, the same as tumor tissue samples obtained from surgical resection and mediastinoscopy. The use of new sampling methods, such as cryobiopsy for peripheral tumor lesions or cytoblock obtained by ultrasound-guided transbronchial needle aspiration (TBNA), enables obtaining adequate small biopsies and cytological samples for molecular testing, which have until recently been considered unsuitable for this type of analysis. During LC patients' treatment, resistance occurs due to changes in the mutational tumor status or pathohistological tumor type. Therefore, the repeated taking of liquid biopsies for molecular analysis or rebiopsy of tumor tissue for new pathohistological and molecular profiling has recently been mandated. Conclusions : In thoracic oncology, preference should be given to the least invasive diagnostic procedure providing a sample for histology rather than for cytology. However, there is increasing evidence that, when properly processed, cytology samples can be sufficient for both the cancer diagnosis and molecular analyses. A good knowledge of diagnostic procedures is essential for LC diagnosing and treatment in the personalized therapy era.