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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.

Malignant pleural mesothelioma (MPM) has a rich stromal component containing mesenchymal fibroblasts. However, the properties and interplay of MPM tumor cells and their surrounding stromal fibroblasts are poorly characterized. Our objective was to spatially profile known mesenchymal markers in both tumor cells and associated fibroblasts and correlate their expression with patient survival. The primary study cohort consisted of 74 MPM patients, including 16 patients who survived at least 60 months. We analyzed location-specific tissue expression of seven fibroblast markers in clinical samples using multiplexed fluorescence immunohistochemistry (mfIHC) and digital image analysis. Effect on survival was assessed using Cox regression analyses. The outcome measurement was all-cause mortality. Univariate analysis revealed that high expression of secreted protein acidic and cysteine rich (SPARC) and fibroblast activation protein in stromal cells was associated with shorter survival. Importantly, high expression of platelet-derived growth factor receptor beta (PDGFRB) in tumor cells, but not in stromal cells, was associated with shorter survival (hazard ratio [HR] = 1.02, p

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.

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.

A large number of fibroblast foci (FF) predict mortality in idiopathic pulmonary fibrosis (IPF). Other prognostic histological markers have not been identified. Artificial intelligence (AI) offers a possibility to quantitate possible prognostic histological features in IPF. We aimed to test the use of AI in IPF lung tissue samples by quantitating FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with a deep convolutional neural network (CNN). Lung tissue samples of 71 patients with IPF from the FinnishIPF registry were analyzed by an AI model developed in the Aiforia® platform. The model was trained to detect tissue, air spaces, FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with 20 samples. For survival analysis, cut-point values for high and low values of histological parameters were determined with maximally selected rank statistics. Survival was analyzed using the Kaplan-Meier method. A large area of FF predicted poor prognosis in IPF (p = 0.01). High numbers of interstitial mononuclear inflammatory cells and intra-alveolar macrophages were associated with prolonged survival (p = 0.01 and p = 0.01, respectively). Of lung function values, low diffusing capacity for carbon monoxide was connected to a high density of FF (p = 0.03) and a high forced vital capacity of predicted was associated with a high intra-alveolar macrophage density (p = 0.03). The deep CNN detected histological features that are difficult to quantitate manually. Interstitial mononuclear inflammation and intra-alveolar macrophages were novel prognostic histological biomarkers in IPF. Evaluating histological features with AI provides novel information on the prognostic estimation of IPF.

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.

Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, where the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. In order to study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival over five years (long-term survivals [LTS]) and compared the findings with 84 tumors from a reference group with average survival (RG). We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34,90%) and a tubulopapillary growth pattern (n = 30,70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49,61%) and solid growth pattern (n = 59,70%) were more frequent in RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (p

Background: Malignant pleural mesothelioma (MPM) is a rare occupational cancer with a poor prognosis. Even with a multimodality treatment approach, the treatment outcomes remain unsatisfactory. The use of asbestos has been banned in most developed countries, but MPM continues to be a significant occupational disease also in these countries. Aim of this study is to identify modern epidemiology and assess equality in care.Methods: Our study cohort consists of 1010 patients diagnosed with MPM in Finland during 2000-2012. The data were collected from the Finnish Cancer Registry, the National Workers' Compensation Center Registry and the National Registry of Causes of Death, Statistics Finland.Results: Women were diagnosed a mean of 4.5 years later than males (p=.001), but survival did not differ (overall median survival 9.7 months). A workers' compensation claim was more common in males (OR 11.0 [95% CI 7.5-16.2]) and in regions with a major asbestos industry (OR 1.7 [95% CI 1.3-2.2]). One-year and three-year survivals did not differ regionally. Patients without chemotherapy treatment had an inferior survival (RR 1.8 [95% CI 1.5-2.0]). The initial survival benefit gained with pemetrexed was diluted at 51 months.Conclusions: MPM is a disease with a poor prognosis, although chemotherapy appears to improve survival time. Significant gender and regional variation exists among patients, with notable differences in diagnostic and treatment practices. Long-term outcomes with pemetrexed remain indeterminate.Impact: Emphasize centralized consult services for the diagnosis, treatment and support that patients receive for MPM, facilitating equal outcomes and compensation.

The histologic manifestation of idiopathic pulmonary fibrosis (IPF) is usual interstitial pneumonia (UIP), which is a good prognostic determinant of survival compared with other histologic interstitial lung disease patterns. According to the current international guidelines, the histologic features of suspected IPF/UIP are divided into 4 categories: UIP, probable UIP, possible UIP, and not UIP pattern. Four pulmonary pathologists who were blinded to clinicoradiologic information reevaluated 50 surgical lung biopsies (83.3%), 6 lung explant (10.0%), and 4 autopsy samples (6.7%) from the FinnishIPF registry (N=60) using the current diagnostic guidelines. Additional histologic features atypical for UIP were also evaluated and compared with clinicora-diologic information. The interobserver agreement of pathologists was examined by Cohen kappa (κ) coefficient; the survival of the patients was estimated with Kaplan-Meier curves. The histologic reevaluation indicated that 38 of 60 patients (63.3%) had definite UIP. Inflammation was the most common additional histologic finding (15/60, 25.0%). The interobserver agreement on histologic diagnosis ranged from slight (κ=0.044) to substantial (κ=0.779). The interobserver agreement varied extensively with regard to the presence of giant cells. The observed histologic features displayed no association with radiologic patterns or survival. Definite UIP and honeycombing findings in high-resolution computed tomography correlated with poor prognosis. A high level of interobserver variability was observed between pathologists, even in this well-defined cohort of IPF patients, which highlights the importance of multidisciplinary decision making in IPF diagnostics and stresses the need for a reassessment of the histologic criteria.

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.

Activin A has previously been associated with cancer cachexia and in vitro resistance to platinum-based chemotherapy. We studied circulating activin A concentrations as well as activin B and their antagonists' follistatin/follistatin-like 3 in presurgical patients with non-small-cell lung cancer and malignant pleural mesothelioma. We found that circulating activing A levels were elevated in malignant pleural mesothelioma and associated with cancer cachexia and poor response to platinum-based chemotherapy. Circulating activing A separated non-small-cell lung cancer from benign lung lesion. Background: Previous preclinical studies have shown that activin A is overexpressed in malignant pleural mesothelioma (MPM), associates with cancer cachexia, and is observed in in vitro resistance to platinum-based chemotherapy. We evaluated circulating activin levels and their endogenous antagonists' follistatin/follistatin-like 3 in intrathoracic tumors. Materials and Methods: Patients suspected of thoracic malignancy were recruited prior to surgery. Serum samples were collected from 21 patients with MPM, 59 patients with non-small-cell lung cancer (NSCLC), and 22 patients with benign lung lesions. Circulating activin/follistatin levels were measured using enzymelinked immunosorbent assay and compared with clinicopathologic parameters. Results: Circulating activin A levels were elevated in patients with MPM when compared with patients with NSCLC or benign lung lesion samples (P

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 FinnishlPF 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.

Activins, cytokines belonging to the transforming growth factor-β superfamily, have an important role in inflammation and fibrosis. Activin A has been suggested to participate in the pathophysiology of human idiopathic pulmonary fibrosis (IPF), but studies on the role of activin B are sparse. Canine IPF (CIPF) is an incurable interstitial lung disease occurring particularly in West Highland white terriers (WHWTs). During the disease course there are acute exacerbations (AEs) and the condition has a poor prognosis. Microscopically, AEs of CIPF are characterized by diffuse alveolar damage, which is also a key feature of acute respiratory distress syndrome (ARDS). The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with CIPF and WHWTs with CIPF and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid (BALF) from WHWTs with CIPF and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with CIPF as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with CIPF, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of CIPF and might act as a marker of alveolar epithelial damage.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a high symptom burden and poor survival that influences patients’ health-related quality of life (HRQOL). We aimed to evaluate IPF patients’ symptoms and HRQOL in a well-documented clinical cohort during their last two years of life. Methods In April 2015, we sent the Modified Medical Research Council Dyspnea Scale (MMRC), the modified Edmonton Symptom Assessment Scale (ESAS) and a self-rating HRQOL questionnaire (RAND-36) to 300 IPF patients, of which 247 (82%) responded. Thereafter, follow-up questionnaires were sent every six months for two years. Results Ninety-two patients died by August 2017. Among these patients, HRQOL was found to be considerably low already two years before death. The most prominent declines in HRQOL occurred in physical function, vitality, emotional role and social functioning (p

This study was undertaken to investigate idiopathic pulmonary fibrosis (IPF) patients' health-related quality of life (HRQoL) and symptoms in a real-life cross-sectional study. Our secondary aim was to create a simple identification method for patients with increased need for palliative care by studying the relationship between modified Medical Research Council (mMRC) dyspnoea scale, HRQoL and symptoms. We sent a self-rating HRQoL questionnaire (RAND-36) and modified Edmonton Symptom Assessment Scale (ESAS) to 300 IPF patients; 84% of the patients responded to these questionnaires. The most prevalent (>80%) symptoms were tiredness, breathlessness, cough and pain in movement. An increasing mMRC score showed a linear relationship (p, mMRC indicates impaired HRQoL and pain in IPF http://ow.ly/oRB430gIW7U

Herpesviruses could contribute to the lung epithelial injury that initiates profibrotic responses in idiopathic pulmonary fibrosis (IPF).We identified herpesviral DNA from IPF and control lung tissue using a multiplex PCR-and microarray-based method. Active herpesviral infection was detected by standard methods, and inflammatory cell subtypes were identified with specific antibodies. Patients that underwent lung transplantation were monitored for signs of herpesviral infection.A total of 11/12 IPF samples were positive for Epstein-Barr virus (EBV) and 10/12 for human herpesvirus 6B (HHV-6B) DNA. Control lung samples (n = 10) were negative for EBV DNA, whereas three samples were positive for HHV-6B. EBV-encoded RNA (EBER) was identified in nine IPF samples and localized mainly to lymphocytic aggregates. HHV-6B antigens were detected in mononuclear cells in IPF lung tissue. CD20+ B lymphocytic aggregates that were surrounded by CD3+ T cells were abundant in IPF lungs. CD23+ cells (activated B cells, EBV-transformed lymphoblasts, and dendritic cells) were observed in the aggregates. IPF patients had no signs of increased herpesviral activation after lung transplantation.Inflammatory cells are the main source of herpesviral DNA in the human IPF lung. Diagnostic tools should be actively used to elucidate whether herpesviral infection affects the pathogenesis, progression, and/or exacerbation of IPF.

Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.

Background: Activins are members of the TGF-ß superfamily of growth factors. First, we identified by expression array screening that activin-B and follistatin are upregulated in human idiopathic pulmonary fibrosis (IPF). Next, we wanted to clarify their specific role in lung fibrosis formation. Methods: We used specific antibodies for activin-A and -B subunits and follistatin to measure and localize their levels in idiopathic pulmonary fibrosis and control lung biopsies. To inhibit activin signaling, we used soluble activin type IIB receptor fused to the Fc portion of human IgG1 (sActRIIB-Fc) in two different mouse models of pulmonary fibrosis. Results: Activin-B and follistatin mRNA levels were elevated in the human IPF lung. Immunoreactivity to activin-A, -B and follistatin localized predominantly to the hyperplastic, activated alveolar epithelium, but was also seen in inflammatory cells. Mice treated with sActRIIB-Fc showed increased skeletal muscle mass and a clear reduction in alveolar cell counts in bronchoalveolar lavage fluid, but no significant antifibrotic effect in the lung was observed. Conclusions: The upregulation of activin-B and follistatin in IPF is a novel finding. Our results indicate that activin inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury. Activin-B and follistatin levels may be useful as biomarkers of IPF. peerReviewed

Activation of transforming growth factor (TGF)-β is a key event in the progression of fibrosis in human lung tissue. Idiopathic pulmonary fibrosis (IPF) in West Highland white terriers (WHWTs) shares histopathological features of human usual interstitial pneumonia (UIP), the histopathological counterpart of IPF and non-specific interstitial pneumonia (NSIP). The aim of the present immunohistochemical study was to investigate TGF-β signalling activity and its known extracellular matrix (ECM) regulatory proteins, latent TGF-β binding protein (LTBP)-1 and fibrillin-2, in lung tissue of WHWTs with IPF and healthy WHWTs and to compare these with findings in human UIP and NSIP. P-Smad2 immunoreactivity, indicating TGF-β signalling activity, was increased in WHWTs with IPF relative to healthy WHWTs and expression was localized predominantly in the altered alveolar epithelium, as seen in both UIP and NSIP. Increased peribronchial and perivascular LTBP-1 immunoreactivity was seen in WHWTs with IPF compared with controls, possibly indicating the importance of the small airways in the canine disease. Alveolar LTPB-1 immunolabelling in diseased WHWTs was seen mainly in the altered alveolar epithelium, resembling more closely the labelling in UIP than in NSIP. Alveolar interstitial fibrillin-2 immunoreactivity, which is up-regulated in the lungs of people with UIP, was also detected in the lungs of WHWTs with IPF and people with NSIP. However, no significant difference was seen between WHWTs with IPF and control WHWTs. The results suggest that increased TGF-β signalling and expression of the ECM regulatory proteins LTBP-1 and fibrillin-2 are part of the molecular pathophysiology of canine IPF.

Activin A and B, members of the TGF-β superfamily, are regulators of differentiation, inflammation and wound healing. Dimeric activins bind to transmembrane activin type I and type II receptors and induce signaling through activation of the canonical Smad2/3 pathway as well as through activation of MAPK pathways. Depending on the tissue type activins can promote or inhibit cellular growth and/or migration. Activin A has recently been reported to have growth promoting properties in malignant mesothelioma (MM). MM is a rare and aggressive tumor originating most commonly from pleural mesothelial cells. It is asbestos exposure related malignancy that takes decades to develop. MM tumors are highly invasive and extremely resistant to conventional cancer therapy. Novel diagnostic markers and drug targets are urgently needed. We have characterized the expression of activins, follistatins and activin receptors in mesothelioma tumors and cultured mesothelioma cells. In addition, we have identified signaling pathways induced in mesothelioma cells by activin treatment. Expression of activins and receptors in mesothelioma tumors were analyzed by immunohistochemistry. Activins, follistatins and receptors in primary mesothelioma cells and in mesothelioma cell lines were analyzed at the level of mRNA and protein expression. Activation of Smad2/3 and Smad1/5/8 signaling pathways were analyzed by luciferase reporter assays and Western blotting. Activation of MAPK/JNK and MAPK/ERK pathways were analyzed by Western blotting. Immortalized but nonmalignant Met5A cells served as a control cell line. Activin A and B were strongly expressed in mesothelioma tumor tissue. Cultured primary mesothelioma cells and mesothelioma cell lines also expressed higher levels of activin A and B compared to Met5A cells. All activin receptors (ALK3, ALK4, ALK7, ACVR2A, ACVR2B) were found expressed in cultured mesothelioma cells. ACVR2A and ALK7 were significantly overexpressed in all mesothelioma cells. Majority of the mesothelioma cell lines had attenuated Smad2/3 activation upon activin stimulation. In Met5A and H28 cells there was activation of Smad2/3 as well as MAPK/JNK pathways. On the contrary, activation of MAPK/ERK pathway was detected in cells displaying attenuated Smad2/3 activation.Our results show that activin A and B are overexpressed in MM. This together with upregulation of specific activin receptors points to a role for activins in MM progression. Furthermore, we observed that mesothelioma cells have altered responses to activin stimulation, namely attenuation of canonical Smad2/3 signaling and increase in MAPK/ERK signaling. This is likely to have an impact on mesothelioma cell behavior and tumor progression. Citation Format: Jenni A. Tamminen, Mikko Rönty, Eva Sutinen, Arja Pasternack, Olli Ritvos, Marjukka Myllärniemi, Katri Koli. Overexpression of activin A and B as well as altered activation of canonical and non-canonical signaling pathways in malignant mesothelioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3449. doi:10.1158/1538-7445.AM2014-3449

Background The FinnishIPF registry is a prospective, longitudinal national registry study on the epidemiology of idiopathic pulmonary fibrosis (IPF). It was designed to describe the characteristics, management and prognosis of prevalent and incident IPF patients. The study was initiated in 2012. Methods We present here results limited to five university hospitals. Patients with IPF were screened from hospital registries using ICD-10 diagnosis codes J84.1 and J84.9. All patients who gave informed consent were included and evaluated using novel diagnostic criteria. Point prevalence on the 31 st of December in 2012 was calculated using the reported population in each university hospital city as the denominator. Results Patients with ICD-10 codes J84.1 and J84.9 yielded a heterogeneous group – on the basis of patient records assessed by pulmonologists only 20–30 % of the cases were IPF. After clinical, radiological and histological re-evaluation 111 of 123 (90 %) of patients fulfilled the clinical criteria of IPF. The estimated prevalence of IPF was 8.6 cases/100 000. 60.4 % were men. Forty four percent of the patients were never-smokers. At diagnosis, the patients’ mean age was 73.5 years and mean FVC was 80.4 % and DLCO 57.3 % of predicted. Conclusions Our results suggest that hospital registries are inaccurate for epidemiological studies unless patients are carefully re-evaluated. IPF is diagnosed in Finland at a stage when lung function is still quite well preserved. Smoking in patients with IPF was less common than in previous reports. BioMed Central open access

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with median survival from 2 to 7 years. Palliative care is an important part of patients´ care as lung transplantation is not an option for the majority of patients. The aim of this study was to describe treatment practices, decision-making and symptoms during end-of-life care of IPF patients. METHODS: We identified 59 deceased patients from a national prospective IPF cohort study (FinnishIPF) and analyzed retrospectively their health care documentation during the 6 months that preceded death. RESULTS: Hospital was the place of death for 47 patients (80 %). A majority of the patients (93 %) were hospitalized for a mean of 30 days (range 1-96 days) during the last 6 months of their life. Altogether, patients spent 15 % of their last 6 months of life in a hospital. End-of-life decisions and do not resuscitate (DNR) orders were made for 19 (32 %) and 34 (57 %) of the patients, respectively, and 22 (42 %) of these decisions were made ≤ 3 days prior to death. During the final hospital stay, antibiotics were given to 79 % and non-invasive ventilation to 36 % of patients. During the last 24 h of life, radiologic imaging or laboratory tests were taken in 19 % and 53 % of the hospitalized patients, respectively. These tests and life prolonging therapies were more common in tertiary hospitals compared to other places of death. Dyspnea (66 %) and pain (31 %) were the most common symptoms recorded. Opioids were prescribed to 71 % of the patients during the last week before death. CONCLUSIONS: The majority of IPF patients died in a hospital with ongoing life-prolonging procedures until death. The frequent use of opioids is an indicator of an intention to relieve symptoms, but end-of-life decisions were still made very late. Early integrated palliative care with advance care plan could improve the end-of-life care of dying IPF patients. BioMed Central open access