KIF15 missense variant is associated with the early onset of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has an unknown aetiology and limited treatment options. A recent meta-analysis identified three novel causal variants in the TERT, SPDL1, and KIF15 genes. This observational study aimed to investigate whether the aforementioned variants cause clinical phenotypes in a well-characterised IPF cohort. METHODS: The study consisted of 138 patients with IPF who were diagnosed and treated at the Helsinki University Hospital and genotyped in the FinnGen FinnIPF study. Data on > 25 clinical parameters were collected by two pulmonologists who were blinded to the genetic data for patients with TERT loss of function and missense variants, SPDL1 and KIF15 missense variants, and a MUC5B variant commonly present in patients with IPF, or no variants were separately analysed. RESULTS: The KIF15 missense variant is associated with the early onset of the disease, leading to progression to early-age transplantation or death. In patients with the KIF15 variant, the median age at diagnosis was 54.0 years (36.5-69.5 years) compared with 72.0 years (65.8-75.3 years) in the other patients (P = 0.023). The proportion of KIF15 variant carriers was 9- or 3.6-fold higher in patients aged < 55 or 65 years, respectively. The variants for TERT and MUC5B had similar effects on the patient's clinical course, as previously described. No distinct phenotypes were observed in patients with the SPDL1 variant. CONCLUSIONS: Our study indicated the potential of KIF15 to be used in the genetic diagnostics of IPF. Further studies are needed to elucidate the biological mechanisms of KIF15 in IPF.

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.

Malignant pleural mesothelioma in Finland: regional and gender variation.

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.

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.

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

Activin-A and activin-B, members of the TGF-ß superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth.

Upregulation of activin-B and follistatin in pulmonary fibrosis - a translational study using human biopsies and a specific inhibitor in mouse fibrosis models.

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.

Novel therapeutic approaches for pleural mesothelioma identified by functional ex vivo drug sensitivity testing.

OBJECTIVES: Pleural mesothelioma (PM) is an aggressive malignancy with limited treatment options. The first-line therapy has remained unchanged for two decades and consists of pemetrexed in combination with cisplatin. Immune-checkpoint inhibitors (nivolumab plus ipilimumab) have high response rates, resulting in recent updates in treatment recommendations by the U.S. Food and Drug Administration. However, the overall benefits of combination treatment are modest, suggesting that other targeted therapy options should be investigated. MATERIALS AND METHODS: We employed high-throughput drug sensitivity and resistance testing on five established PM cell lines using 527 cancer drugs in a 2D setting. Drugs of the greatest potential (n = 19) were selected for further testing in primary cell models derived from pleural effusions of seven PM patients. RESULTS: All established and primary patient-derived PM cell models were sensitive to the mTOR inhibitor AZD8055. Furthermore, another mTOR inhibitor (temsirolimus) showed efficacy in most of the primary patient-derived cells, although a less robust effect was observed when compared with the established cell lines. Most of the established cell lines and all patient-derived primary cells exhibited sensitivity to the PI3K/mTOR/DNA-PK inhibitor LY3023414. The Chk1 inhibitor prexasertib showed activity in 4/5 (80%) of the established cell lines and in 2/7 (29%) of the patient-derived primary cell lines. The BET family inhibitor JQ1 showed activity in four patient-derived cell models and in one established cell line. CONCLUSION: mTOR and Chk1 pathways had promising results with established mesothelioma cell lines in an ex vivo setting. In patient-derived primary cells, drugs targeting mTOR pathway in particular showed efficacy. These findings may inform novel treatment strategies for PM.

Dyspnea Associates With a Widely Impaired Quality of Life in Idiopathic Pulmonary Fibrosis Patients: A Longitudinal Study Using 15D.

Background: Research on health-related quality of life (HRQoL) is crucial for developing comprehensive palliative care in idiopathic pulmonary fibrosis (IPF). Objectives: To study IPF patients' HRQoL compared with general population and its association with dyspnea in a longitudinal follow-up. Design: Assessment of IPF patients' HRQoL by a generic tool. Comparison of baseline data with the general population and a 30-month follow-up with 6 months intervals. Setting/Subjects: In total, 246 IPF patients were recruited from the Finnish nationwide real-life study, FinnishIPF. Measurements: Modified Medical Research Council (MMRC) dyspnea scale for dyspnea and the generic HRQoL tool 15D for the total and dimensional HRQoL were used. Results: At baseline, the mean 15D total score was lower (0.786, standard deviation [SD] 0.116) in IPF patients than in the general population (0.871, SD 0.043) (p < 0.001) and among the IPF patients with MMRC ≥2 compared with those with MMRC <2 (p < 0.001). In patients with MMRC ≥2, significant impairment compared with general population existed in 11 dimensions of HRQoL, such as breathing, usual activities, and sexual activity, whereas this was true in only 4 dimensions in MMRC <2 category. Mental function was not impaired in either group. During the follow-up, 15D total score decreased in both MMRC categories (p < 0.001) but stayed constantly worse in the MMRC ≥2 group. Seven and two dimensions of HRQoL significantly declined in the categories of MMRC <2 and MMRC ≥2, respectively. Conclusions: Patients with IPF, especially if dyspnea limits everyday life, suffer from widely impaired HRQoL, although self-assessed mental capability is preserved. Integrated palliative care is supported to face the multiple needs of IPF patients.

Effective intravenous delivery of adenovirus armed with TNFα and IL-2 improves anti-PD-1 checkpoint blockade in non-small cell lung cancer.

Lung cancer remains among the most difficult-to-treat malignancies and is the leading cause of cancer-related deaths worldwide. The introduction of targeted therapies and checkpoint inhibitors has improved treatment outcomes; however, most patients with advanced-stage non-small cell lung cancer (NSCLC) eventually fail these therapies. Therefore, there is a major unmet clinical need for checkpoint refractory/resistant NSCLC. Here, we tested the combination of aPD-1 and adenovirus armed with TNFα and IL-2 (Ad5-CMV-mTNFα/mIL-2) in an immunocompetent murine NSCLC model. Moreover, although local delivery has been standard for virotherapy, treatment was administered intravenously to facilitate clinical translation and putative routine use. We showed that treatment of tumor-bearing animals with aPD-1 in combination with intravenously injected armed adenovirus significantly decreased cancer growth, even in the presence of neutralizing antibodies. We observed an increased frequency of cytotoxic tumor-infiltrating lymphocytes, including tumor-specific cells. Combination treatment led to a decreased percentage of immunosuppressive tumor-associated macrophages and an improvement in dendritic cell maturation. Moreover, we observed expansion of the tumor-specific memory T cell compartment in secondary lymphoid organs in the group that received aPD-1 with the virus. However, although the non-replicative Ad5-CMV-mTNFα/mIL-2 virus allows high transgene expression in the murine model, it does not fully reflect the clinical outcome in humans. Thus, we complemented our findings using NSCLC ex vivo models fully permissive for the TNFα and IL-2- armed oncolytic adenovirus TILT-123. Overall, our data demonstrate the ability of systemically administered adenovirus armed with TNFα and IL-2 to potentiate the anti-tumor efficacy of aPD-1 and warrant further investigation in clinical trials.

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.

Pulmonary Asbestos Fiber Burden Is Related to Patient Survival in Malignant Pleural Mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is associated with poor prognosis and is strongly associated with occupational asbestos exposure. Given the importance of asbestos exposure in MPM pathogenesis, we retrospectively analyzed the types and concentrations of asbestos fibers within the lung tissues of patients with MPM and investigated their effects on all-cause mortality. METHODS: We formed a national data set of patients with MPM identified from the Finnish Cancer Registry and Statistics Finland. These data were merged with pulmonary asbestos fiber analysis results received from the Finnish Institute of Occupational Health. RESULTS: We identified 590 patients with MPM who underwent pulmonary asbestos fiber analysis. The median asbestos concentration within dry lung tissue was 3.20 million fibers/gram (range: 0 - 1700 million fibers/gram). Crocidolite and anthophyllite were the most prevalent asbestos fiber types detected in lung tissue. The multivariable risk of death analyses, where changes over time were accounted for, revealed that total asbestos fiber concentration was associated with increased mortality. Nevertheless, no difference in mortality was noted between different fiber types. CONCLUSIONS: Our study revealed that pulmonary fiber concentrations correlated with the manner of asbestos usage. Anthophyllite was identified as the sole fiber in a sizable proportion of cases, supporting its independent role in the pathogenesis of MPM. Our findings suggest that asbestos fiber burden, but not fiber type, may have an impact on the prognosis of MPM.

Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma.

Background: Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies. Methods: We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving ≥ 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses. Results: We observed that type M2 pro-tumorigenic macrophages (CD163+pSTAT1-HLA-DRA1-) were independently associated with shorter survival, whereas granzyme B+ cells and CD11c+ cells were independently associated with longer survival. CD11c+ cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade). Conclusion: High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.

Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics.

The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor-the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine this meta-analysis with the largest available meta-analysis of IPF, reaching 11,160 patients and 1,364,410 population controls. We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection and note an unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.

Artificial intelligence identifies inflammation and confirms fibroblast foci as prognostic tissue biomarkers in idiopathic pulmonary fibrosis.

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.

High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma.

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 < 0.001). A multivariable survival analysis adjusted for clinical parameters and stromal mfIHC markers revealed that tumor cell PDGFRB and stromal SPARC remained independently associated with survival (HR = 1.01, 95% confidence interval [CI] = 1.00-1.03 and HR = 1.05, 95% CI = 1.00-1.11, respectively). The prognostic effect of PDGFRB was validated with an artificial intelligence-based analysis method and further externally validated in another cohort of 117 MPM patients. In external validation, high tumor cell PDGFRB expression associated with shorter survival, especially in the epithelioid subtype. Our findings suggest PDGFRB and SPARC as potential markers for risk stratification and as targets for therapy.

Factor analysis identifies three separate symptom clusters in idiopathic pulmonary fibrosis.

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 (ρτ 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.

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.

Histopathological features of epithelioid malignant pleural mesotheliomas in patients with extended survival.

Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, wherein the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. To study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival more than five years (LTSs) and compared the findings with 84 tumors from a reference group (RG) with average survival. 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 the 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 < 0.001) and the presence of necrosis (P = 0.021). In univariate survival analysis, we identified the following three novel morphological features associated with survival: exophytic polypoid growth pattern, tumor density, and single mesothelium layered tubular structures. After adjustments, low nuclear grade (P < 0.001) and presence of exophytic polypoid growth (P = 0.024) were associated with prolonged survival. These results may aid in estimating DMM prognosis.

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

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.

Elevated Circulating Activin A Levels in Patients With Malignant Pleural Mesothelioma Are Related to Cancer Cachexia and Reduced Response to Platinum-based Chemotherapy.

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 enzyme-linked 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 < .0001). Also, follistatin and follistatin-like 3 levels were the highest in MPM, although with less difference compared with activin A. Receiver operating characteristic analysis for activin A for separating NSCLC from benign lung lesion showed an area under the curve of 0.856 (95% confidence interval, 0.77-0.94). Activin A levels were higher in patients with cachexia (P < .001). In patients with MPM, activin A levels correlated positively with computed tomography-based baseline tumor size (R = 0.549; P = .010) and the change in tumor size after chemotherapy (R = 0.743; P = .0006). Patients with partial response or stable disease had lower circulating activin A levels than the ones with progressive disease (P = .028). CONCLUSION: Activin A serum level could be used as a biomarker in differentiating malignant and benign lung tumors. Circulating activin A levels were elevated in MPM and associates with cancer cachexia and reduced chemotherapy response.