mMRC dyspnoea scale indicates impaired quality of life and increased pain in patients with idiopathic pulmonary fibrosis

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Inorganic particulate matter in the lung tissue of idiopathic pulmonary fibrosis patients reflects population density and fine particle levels

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a dismal prognosis and an unknown etiology. Inorganic dust is a known risk factor, and air pollution seems to affect disease progression. We aimed to investigate inorganic particulate matter in IPF lung tissue samples. Using polarizing light microscopy, we examined coal dust pigment and inorganic particulate matter in 73 lung tissue samples from the FinnishIPF registry. We scored the amount of coal dust pigment and particulate matter from 0 to 5. Using energy dispersive spectrometry with a scanning electron microscope, we conducted an elemental analysis of six IPF lung tissue samples. We compared the results to the registry data, and to the population density and air quality data. To compare categorical data, we used Fisher's exact test; we estimated the survival of the patients with Kaplan-Meier curves. We found inorganic particulate matter in all samples in varying amounts. Samples from the southern regions of Finland, where population density and fine particle levels are high, more often had particulate matter scores from 3 to 5 than samples from the northern regions (31/50, 62.0% vs. 7/23, 30.4%, p = 0.02). The highest particulate matter scores of 4 and 5 (n = 15) associated with a known exposure to inorganic dust (p = 0.004). An association between particulate matter in the lung tissue of IPF patients and exposure to air pollution may exist.Peer reviewe

Label-free plasma proteomics identifies haptoglobin-related protein as candidate marker of idiopathic pulmonary fibrosis and dysregulation of complement and oxidative pathways

Idiopathic pulmonary fibrosis (IPF) is a lung parenchymal disease of unknown cause usually occurring in older adults. It is a chronic and progressive condition with poor prognosis and diagnosis is largely clinical. Currently, there exist few biomarkers that can predict patient outcome or response to therapies. Together with lack of markers, the need for novel markers for the detection and monitoring of IPF, is paramount. We have performed label-free plasma proteomics of thirty six individuals, 17 of which had confirmed IPF. Proteomics data was analyzed by volcano plot, hierarchical clustering, Partial-least square discriminant analysis (PLS-DA) and Ingenuity pathway analysis. Univariate and multivariate statistical analysis overlap identified haptoglobin-related protein as a possible marker of IPF when compared to control samples (Area under the curve 0.851, ROC-analysis). LXR/RXR activation and complement activation pathways were enriched in t-test significant proteins and oxidative regulators, complement proteins and protease inhibitors were enriched in PLS-DA significant proteins. Our pilot study points towards aberrations in complement activation and oxidative damage in IPF patients and provides haptoglobin-related protein as a new candidate biomarker of IPF.Peer reviewe

Overexpression of activin-A and -B in malignant mesothelioma - Attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth

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BAP1 germline variants in Finnish patients with malignant mesothelioma

Objectives: Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1-inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM. Materials and methods: 56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing. Results: Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p. (G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor. Conclusion: The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has >= 2 BAP1-TPDS core tumors, including BINs.Peer reviewe

Outcomes of patients with advanced idiopathic pulmonary fibrosis treated with nintedanib or pirfenidone in a real-world multicentre cohort

Background and objective Antifibrotic therapy with nintedanib or pirfenidone slows disease progression and reduces mortality in patients with idiopathic pulmonary fibrosis (IPF). However, patients with advanced IPF, as defined by forced vital capacity (FVC) < 50% and/or diffusion capacity for carbon monoxide (DLCO) < 30% of predicted, have not been included in randomized trials, and the outcomes of such patients who initiate treatment are not well understood. We determined lung function, disease progression and mortality outcomes following initiation of antifibrotic therapy in patients with advanced IPF at the time of treatment initiation compared to those with mild-moderate IPF. Methods We included 502 patients enrolled in IPF registries from four Nordic countries. Linear mixed models were used to assess change in FVC and DLCO over time. Cox proportional hazards models were used to assess transplant-free survival and progression- and transplant-free survival. Results Of 502 patients, 66 (13%) had advanced IPF. Annual change in FVC was -125 ml (95% CI -163, -87) among patients with mild-moderate IPF, and +28 ml (95% CI -96, +152) among those with advanced IPF. Advanced IPF at treatment initiation was associated with poorer transplant-free survival (hazard ratio [HR] 2.39 [95% CI 1.66, 3.43]) and progression- and transplant-free survival (HR 1.60 [95% CI 1.15, 2.23]). Conclusion In a broadly representative IPF population, patients with advanced IPF at the initiation of antifibrotic therapy did not have greater lung function decline over time compared with those with mild-moderate IPF, but had substantially higher mortality. Prospective studies are needed to determine the effect of antifibrotic therapy in patients with advanced IPF.Peer reviewe

Factor analysis identifies three separate symptom clusters in idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with a poor prognosis. Patients with IPF suffer from a high symptom burden, which impairs their health-related quality of life (HRQoL). Lack of research on IPF symptoms and their clustering, however, makes symptom-centred care challenging. Methods: We sent two questionnaires, RAND 36-Item Health Survey and Edmonton Symptom Assessment System, to 300 patients from the FinnishIPF registry. Of the 300 patients, 245 (82%) responded. We performed an exploratory factor analysis on the results to search for potential clustering of symptoms into factors. Results: We found three distinct symptom factors: the emotional factor (including depression, anxiety, insomnia, loss of appetite and nausea), the pain factor (pain at rest or in movement) and the respiratory symptoms factor (shortness of breath, cough, tiredness and loss of wellbeing). Correlation was strong within the factors (rho(tau) 0.78-0.85) and also evident between them. The factors correlated with the different dimensions of HRQoL: the emotional factor with mental health (correlation coefficient=-0.69) and vitality (-0.63), the pain factor with bodily pain (-0.72) and the respiratory symptoms factor with vitality (-0.69), general health (-0.64) and physical functioning (-0.62). Conclusion: We found three distinct symptom factors in IPF, of which respiratory and emotional factors showed the strongest association with decreasing HRQoL. Routine assessment of IPF patients' respiratory symptoms, mental health and pain are important as these may be linked with other symptoms and significantly impair the patient's HRQoL.Peer reviewe

Pulmonary administration of a dry powder formulation of the antifibrotic drug tilorone reduces silica-induced lung fibrosis in mice

The aim of this work was to study the antifibrotic effect of pulmonary administration of tilorone to lung fibrosis. L-leucine coated tilorone particles were prepared and their aerosolization properties were analyzed using two dry powder inhalers (Easyhaler and Twister). In addition, the biological activity and cell monolayer permeation was tested. The antifibrotic effect of tilorone delivered by oropharyngeal aspiration was studied in vivo using a silica-induced model of pulmonary fibrosis in mice in a preventive setting. When delivered from the Easyhaler in an inhalation simulator, the emitted dose and fine particle fraction were independent from the pressure applied and showed dose repeatability. However, with Twister the aerosolization was pressure-dependent indicating poor compatibility between the device and the formulation. The formulation showed more consistent permeation through a differentiated Calu-3 cell monolayer compared to pristine tilorone. Tilorone decreased the histological fibrosis score in vivo in systemic and local administration, but only systemic administration decreased the mRNA expression of type I collagen. The difference was hypothesized to result from 40-fold higher drug concentration in tissue samples in the systemic administration group. These results show that tilorone can be formulated as inhalable dry powder and has potential as an oral and inhalable antifibrotic drug.Peer reviewe

Clinical Features in Patients With Malignant Pleural Mesothelioma With 5-Year Survival and Evaluation of Original Diagnoses

Within a larger national malignant pleural mesothelioma cohort, we identified 43 patients with unusually long survival times. This study aimed to evaluate the diagnostic accuracy in this subgroup, and the diagnosis was confirmed to be correct in most cases. In addition, we searched for clinical factors related to the prolonged survival time. Introduction: Malignant pleural mesothelioma (MPM) is a fatal malignancy strongly associated with previous asbestos exposure. Overall survival remains dismal, partly owing to poor response to available treatment. The aims of this study were to evaluate diagnostic accuracy in a group of patients with MPM with an unusually long survival time and to assess the factors related to this prolonged survival. Materials and Methods: Forty-three patients with overall survival exceeding 5 years were accepted to the long-term survivor (LTS) group, and these patients were compared with 84 patients with epithelial MPM. Data were collected from various national registries and electronic medical records. In addition, all available histopathologic diagnostic samples and computed tomography studies were re-evaluated by experienced specialists. Results: Our study showed a good diagnostic accuracy, with only 1 (0.5%) patient having an incorrect MPM diagnosis. Two (0.9%) localized malignant mesotheliomas and 2 (0.9%) well-differentiated papillary mesotheliomas were also found. LTS patients were younger, more frequently female, had a better performance status at time of diagnosis, and had less evidence of prior asbestos exposure. In multivariate analysis, we showed tumor size, Eastern Cooperative Oncology Group performance status, and first-line treatment (both surgery and chemotherapy) to be associated with survival time. Conclusion: We confirmed the diagnosis of MPM in an overwhelming majority of patients in the LTS group. An epithelial subtype of MPM behaving clinically more indolently seems to exist, but further tumor and genetic characterization is needed. The prolonged survival time is most likely explained by a combination of tumor-, patient-, and treatment-related factors. (C) 2020 Elsevier Inc. All rights reserved.Peer reviewe