Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma

BackgroundPleural 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. MethodsWe 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. ResultsWe 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). ConclusionHigh-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.Peer reviewe

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.Peer reviewe

Response to letter on use of functional imaging by 11C-metomidate PET for primary aldosteronism subtyping

Non peer reviewe

Comparison of standard methods for evaluating the metal concentrations in bio ash

Abstract The current growth strategy and environmental legislation of the European Union both aim to increase the amount of renewable energy and to improve the use of waste streams. These policies mean there will be an increasing need to utilise bio ash. Currently, Finland and Denmark are the only European countries with specific national legislation concerning bio ash use. Sweden has recommendations concerning the use of bio ash fertilisers. Besides having different limit values for harmful elements and nutrients in ash fertilisers, all these countries have different digestion methods that are allowed for element content determinations. This study compared the results of the five digestion methods (aqua regia, nitric acid, nitric/hydrochloric acids, nitric/hydrochloric/hydrogen fluoride acids, and lithium tetraborate fusion) established by Nordic authorities. Two Finnish peat-wood fly ash samples were studied. Our results indicate that the choice of digestion methods produces a significant difference in the obtained heavy metal or nutrient concentration of bio ash, especially regarding the potassium concentration

Characterisation of used traction sand for utilization aspects in earth construction based on the requirements of Finnish environmental legislation

Abstract Finland launched a new Government Decree, the so-called MARA-regulation, on the utilization of certain wastes in earth construction on 1.1.2018. This statutory regulation sets limit values for the solubility of heavy metals (Sb, As, Ba, Cd, Cr, Cu, Pb, Mo, Ni, Se, Zn, V, Hg), chloride, sulphate, fluoride and dissolved organic carbon, as well as for organic substance (petroleum hydrocarbons, benzene, naphthalene, TEX (toluene, ethylbenzene and xylene), PAH-, phenolic- and PCB-compounds). In this case study, the concentrations of these harmful substances in the used traction sand collected in the city of Kemi, Northern Finland, were lower than their limit values set in the MARA-regulation. Therefore, this residue is a potential material to be used at earth construction sites such as in roads and roadways, in field and embankment structures, as well as in floor structures of industrial or storage buildings. However, if the used traction sand is to be utilized for these kinds of civil engineering purposes, an environmental permit is still needed because this material is not yet included in the scope of the MARA-regulation. This paper also gives an overview of the relevant Finnish environmental legislation on the utilization of wastes as an earth construction material