PAI-1 level differences in malignant plural effusion, parapneumonic pleuritis, and cardiac hydrothorax

Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.Background and Objectives: Plasminogen activator inhibitor-1 (PAI-1) is a fibrinolytic system enzyme whose role in various fibrinolytic processes is currently unknown. In clinical manifestations of pleural liquids of diverse etiology, various levels of fibrinolytic activity can be observed—parapneumonic processes tend to loculate in fibrin septa, while malignant pleural effusion (MPE) does not. The purpose of this study was to determine possible differences in PAI-1 levels in pleural effusions of varied etiology. Material and Methods: PAI-1 level in pleural effusion and serum was determined in 144 patients with pleural effusions of various etiology (cardiac hydrothorax—42 patients (29.2%), MPE—67 patients (46.5%), parapneumonic pleuritis—27 (18.8%), tuberculous pleuritis—6 patients (4.1%), pancreatogenic pleuritis—1 patient (0.7%) and pulmonary artery thromboembolism with pleuritis—1 patient (0.7%)). Results: The median PAI-1 level (ng/mL) was the highest in the parapneumonic pleuritis group both in the effusion and the serum, with values of 291 (213–499) ng/mL and 204 (151–412) ng/mL, respectively, resulting in a statistically significant difference (p < 0.001) from the cardiac hydrothorax and MPE groups. However, there was no statistically significant difference between PAI-1 levels in the pleural effusion and serum in the cardiac hydrothorax and MPE groups. Conclusion: The PAI-1 level in MPE and cardiac hydrothorax was statistically significantly lower than in parapneumonic pleuritis.publishersversionPeer reviewe

LC-MS/MS method for simultaneous quantification of the first-line anti-tuberculosis drugs and six primary metabolites in patient plasma : Implications for therapeutic drug monitoring

Funding Information: This study was funded by the Latvian Council of Science. Project No: lzp-2020/1-0050. Publisher Copyright: © 2021 The AuthorsThe pharmacokinetic profiling of drug substances and corresponding metabolites in the biological matrix is one of the most informative tools for the treatment efficacy assessment. Therefore, to satisfy the need for comprehensive monitoring of anti-tuberculosis drugs in human plasma, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of first-line anti-tuberculosis drugs (ethambutol, isoniazid, pyrazinamide, and rifampicin) along with their six primary metabolites. Simple single-step protein precipitation with methanol was chosen as the most convenient sample pre-treatment method. Chromatographic separation of the ten analyte mixture was achieved within 10 minutes on a reverse-phase C8 column using mobile phase gradient mode. The multiple reaction monitoring mode (MRM) was used for analyte detection and quantification in patient samples. The chosen quantification ranges fully covered expected plasma concentrations. The method exhibited acceptable selectivity; the within- and between-run accuracy ranged from 87.2 to 113.6%, but within- and between-run precision was between 1.6 and 14.9% (at the LLOQ level CV < 20%). Although the response of the isonicotinic acid varied depending on the matrix source (CV 21.8%), validation results proved that such inconsistency does not affect the accuracy and precision of results. If stored at room temperature plasma samples should be processed within 4 h after collection, temporary storage at −20 °C up to 24 h is acceptable due to stability issues of analytes. The developed method was applied for the patient sample analysis (n = 34) receiving anti-tuberculosis treatment with the first-line drugs.publishersversionPeer reviewe

Diagnostic value of tumour markers CA-125 and CEA in the diagnostics of malignant pleural fluids

Copyright: Copyright 2016 Elsevier B.V., All rights reserved.The significance of carbohydrate (cancer) antigen 125 (Ca-125) and carcinoembryonic antigen (CEA) tumour markers levels in differential diagnostics of malignant and benign pleural effusion was studied. Within this prospective study, 121 patients with fluids of various aetiology in the pleural cavity were analysed. Malignant pleural effusion was detected in 55 patients, parapneumonic effusion in 28 patients, transudative effusion of cardiac origin in 31 patients, pancreatitis in one patient and tuberculous pleurisy in five patients. The highest accuracy in diagnosis of malignancy was observed for Ca-125 and CEA levels in the pleural fluid: 75.2% at cut-off value ≥1452 U/mL and 76.9% at cut-off value ≥6.58 ng/mL, respectively. We conclude that the level of tumour markers in pleural fluid has additional diagnostic significance in the differential diagnosis of malignant and benign pleural effusions.publishersversionPeer reviewe

Protocol for the EARCO Registry : a pan-European observational study in patients with α1-antitrypsin deficiency

Rationale and objectives Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD. Study design and population The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level <11 µM (50 mg·dL−1) and/or a proteinase inhibitor genotype ZZ, SZ or compound heterozygotes or homozygotes of other rare deficient variants. Assessments at baseline and during the yearly follow-up visits include lung function testing (spirometry, body plethysmography and diffusing capacity of the lung), exercise capacity, blood tests and questionnaires (symptoms, quality of life and physical activity). To ensure correct data collection, there will be designated investigator staff to document the data in the case report form. All data will be reviewed by the EARCO database manager. Summary The EARCO Registry aims to understand the natural history and prognosis of AATD better with the goal to create and validate prognostic tools to support medical decision-making

Phenotypes of COPD patients with a smoking history in Central and Eastern Europe: The POPE Study

Chronic obstructive pulmonary disease (COPD) represents a major health problem in Central and Eastern European (CEE) countries; however, there are no data regarding clinical phenotypes of these patients in this region. Participation in the Phenotypes of COPD in Central and Eastern Europe (POPE) study was offered to stable patients with COPD in a real-life setting. The primary aim of this study was to assess the prevalence of phenotypes according to predefined criteria. Secondary aims included analysis of differences in symptom load, comorbidities and pharmacological treatment. 3362 patients with COPD were recruited in 10 CEE countries. 63% of the population were nonexacerbators, 20.4% frequent exacerbators with chronic bronchitis, 9.5% frequent exacerbators without chronic bronchitis and 6.9% were classified as asthma - COPD overlap. Differences in the distribution of phenotypes between countries were observed, with the highest heterogeneity observed in the nonexacerbator cohort and the lowest heterogeneity observed in the asthma - COPD cohort. There were statistically significant differences in symptom load, lung function, comorbidities and treatment between these phenotypes. The majority of patients with stable COPD in CEE are nonexacerbators; however, there are distinct differences in surrogates of disease severity and therapy between predefined COPD phenotypes. Copyright ©ERS 2017

Determinants of CAT (COPD Assessment Test) scores in a population of patients with COPD in central and Eastern Europe: The POPE study

Background: The COPD Assessment Test (CAT) has been proposed to help guide therapy in chronic obstructive pulmonary disease (COPD). It is important to understand the distribution of scores in different COPD populations and their determinants. Methods: The POPE study is an international, observational cross-sectional study of COPD subjects in 11 Central and Eastern European countries aimed at characterizing COPD phenotypes. Here we report the analysis of CAT scores with the objective of identifying their determinants, evaluating symptom load and investigating the distribution of scores among the participating countries. Additionally, we investigated the discrepancies between the CAT and modified Medical Research Council (mMRC) scores when used to classify patients according to the GOLD strategy. Results: The study included 3452 patients (69.2% men, mean forced expiratory volume in 1 s (FEV1% predicted) 52.5%). The mean CAT score was 17.5 (SD = 7.8), ranging from 15.1 in Hungary to 21.2 in Bulgaria. Multiple linear regression analysis showed six variables significantly associated with CAT scores: depression, number of previous exacerbations, 6-min walking distance, FEV1(%), mMRC and country and explained 47.2% of the variance of CAT. According to either CAT or mMRC, up to 23.9% patients would be classified in different GOLD groups. Conclusions: The CAT score may be predicted by factors related to COPD severity, depression and exercise capacity, with significant differences in the distribution of CAT scores in different countries. According to our results CAT > 10 is not equivalent to mMRC > 2 for assessing symptom burden

iPSC-derived lung and lung cancer organoid model to evaluate cisplatin encapsulated autologous iPSC-derived mesenchymal stromal cell-isolated extracellular vesicles

Abstract Background Lung cancer remains a leading cause of cancer-related mortality globally. Although recent therapeutic advancements have provided targeted treatment approaches, the development of resistance and systemic toxicity remain primary concerns. Extracellular vesicles (EVs), especially those derived from mesenchymal stromal cells (MSC), have gained attention as promising drug delivery systems, offering biocompatibility and minimal immune responses. Recognizing the limitations of conventional 2D cell culture systems in mimicking the tumor microenvironment, this study aims to describe a proof-of-principle approach for using patient-specific organoid models for both lung cancer and normal lung tissue and the feasibility of employing autologous EVs derived from induced pluripotent stem cell (iPSC)-MSC in personalized medicine approaches. Methods First, we reprogrammed healthy fibroblasts into iPSC. Next, we differentiated patient-derived iPSC into branching lung organoids (BLO) and generated patient-matched lung cancer organoids (LCO) from patient-derived tumor tissue. We show a streamlined process of MSC differentiation from iPSC and EV isolation from iPSC-MSC, encapsulated with 0.07 µg/mL of cytotoxic agent cisplatin and applied to both organoid models. Cytotoxicity of cisplatin and cisplatin-loaded EVs was recorded with LDH and CCK8 tests. Results Fibroblast-derived iPSC showed a normal karyotype, pluripotency staining, and trilineage differentiation. iPSC-derived BLO showed expression of lung markers, like TMPRSS2 and MUC5A while patient-matched LCO showed expression of Napsin and CK5. Next, we compared the effects of iPSC-MSC derived EVs loaded with cisplatin against empty EVs and cisplatin alone in lung cancer organoid and healthy lung organoid models. As expected, we found a cytotoxic effect when LCO were treated with 20 µg/mL cisplatin. Treatment of LCO and BLO with empty EVs resulted in a cytotoxic effect after 24 h. However, EVs loaded with 0.07 µg/mL cisplatin failed to induce any cytotoxic effect in both organoid models. Conclusion We report on a proof-of-principle pipeline towards using autologous or allogeneic iPSC-MSC EVs as drug delivery tests for lung cancer in future. However, due to the time and labor-intensive processes, we conclude that this pipeline might not be feasible for personalized approaches at the moment

Inhaled therapies in patients with moderate COPD in clinical practice: current thinking

COPD is a complex, heterogeneous condition. Even in the early clinical stages, COPD carries a significant burden, with breathlessness frequently leading to a reduction in exercise capacity and changes that correlate with long-term patient outcomes and mortality. Implementation of an effective management strategy is required to reduce symptoms, preserve lung function, quality of life, and exercise capacity, and prevent exacerbations. However, current clinical practice frequently differs from published guidelines on the management of COPD. This review focuses on the current scientific evidence and expert opinion on the management of moderate COPD: the symptoms arising from moderate airflow obstruction and the burden these symptoms impose, how physical activity can improve disease outcomes, the benefits of dual bronchodilation in COPD, and the limited evidence for the benefits of inhaled corticosteroids in this disease. We emphasize the importance of maximizing bronchodilation in COPD with inhaled dual-bronchodilator treatment, enhancing patient-related outcomes, and enabling the withdrawal of inhaled corticosteroids in COPD in well-defined patient groups