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P14/ARF-positive malignant pleural mesothelioma : ǂa ǂphenotype with distinct immune microenvironment
Federica Pezzuto, Francesca Lunardi, Luca Vedovelli, Francesco Fortarezza, Loredana Urso, Federica Grosso, Giovanni Luca Ceresoli, Izidor Kern, Gregor Vlačić, Fiorella Calabrese, 2022, original scientific article

Abstract: Introduction: The CDKN2A gene plays a central role in the pathogenesis of malignant pleural mesothelioma (MPM). The gene encodes for two tumor suppressor proteins, p16/INK4A and p14/ARF, frequently lost in MPM tumors. The exact role of p14/ARF in MPM and overall its correlation with the immune microenvironment is unknown. We aimed to determine whether there is a relationship between p14/ARF expression, tumor morphological features, and the inflammatory tumor microenvironment. Methods: Diagnostic biopsies from 76 chemo-naive MPMs were evaluated. Pathological assessments of histotype, necrosis, inflammation, grading, and mitosis were performed. We evaluated p14/ARF, PD-L1 (tumor proportion score, TPS), and Ki-67 (percentage) by immunohistochemistry. Inflammatory cell components (CD3+, CD4+, CD8+ T lymphocytes; CD20+ B-lymphocytes; CD68+ and CD163+ macrophages) were quantified as percentages of positive cells, distinguishing between intratumoral and peritumoral areas. The expression of p14/ARF was associated with several clinical and pathological characteristics. A random forest-based machine-learning algorithm (Boruta) was implemented to identify which variables were associated with p14/ARF expression. Results: p14/ARF was evaluated in 68 patients who had a sufficient number of tumor cells. Strong positivity was detected in 14 patients (21%) (11 epithelioid and 3 biphasic MPMs). At univariate analysis, p14/ARF-positive epithelioid mesotheliomas showed higher nuclear grade (G3) (p = 0.023) and higher PD-L1 expression (≥50%) (p = 0.042). The percentages of CD4 and CD163 in peritumoral areas were respectively higher and lower in p14/ARF positive tumors but did not reach statistical significance with our sample size (both p = 0.066). The Boruta algorithm confirmed the predictive value of PD-L1 percentage for p14/ARF expression in all histotypes. Conclusions: p14/ARF-positive epithelioid mesotheliomas may mark a more aggressive pathological phenotype (higher nuclear grade and PD-L1 expression). Considering the results regarding the tumor immune microenvironment, p14/ARF-negative tumors seem to have an immune microenvironment less sensitive to immune checkpoint inhibitors, being associated with low PD-L1 and CD4 expression, and high CD163 percentage. The association between p14/ARF-positive MPMs and PD-L1 expression suggests a possible interaction of the two pathways. Confirmation of our preliminary results could be important for patient selection and recruitment in future clinical trials with anticancer immunotherapy.
Keywords: lung -- cytology -- pathology, neoplasms, malignant mesothelioma, malignant pleural mesothelioma, tumor microenvironment
Published in DiRROS: 30.05.2022; Views: 109; Downloads: 77
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Dynamic contrast-enhanced MRI in malignant pleural mesothelioma : prediction of outcome based on DCE-MRI measurements in patients undergoing cytotoxic chemotherapy
Martina Vivoda Tomšič, Peter Korošec, Viljem Kovač, Sotirios Bisdas, Katarina Šurlan Popović, 2022, original scientific article

Abstract: The malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy. Methods: Thirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient's outcome. Results: Patients with higher pretreatment ET and AATH-calculated Ktrans and ve values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated Ktrans and kep values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated Ktrans was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min-1). Conclusions: In the present study, higher pre-treatment ET-calculated Ktrans values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.
Keywords: cisplatin, magnetic resonance imaging, mesothelioma
Published in DiRROS: 06.04.2022; Views: 296; Downloads: 134
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Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma : an international multicenter study
Luka Brčić, Thomas Klikovits, Zsolt Megyesfalvi, Berta Mosleh, Katharina Sinn, Richard Hritcu, Viktoria Laszlo, Tanja Čufer, Aleš Rozman, Izidor Kern, Katja Mohorčič, 2021, original scientific article

Abstract: Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM). Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome. Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [>/=1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS. Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.
Keywords: mesothelioma - anatomy and histology - analysis, 1malignant pleural mesothelioma, programmed death-ligand 1, programmed cell death 1, PD-L1
Published in DiRROS: 31.03.2021; Views: 684; Downloads: 320
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Reproducibility of malignant pleural mesothelioma histopathologic subtyping
Luka Brčić, Gregor Vlačić, Franz Quehenberger, Izidor Kern, 2018, original scientific article

Abstract: Context. Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis. Several studies have analyzed potential prognostic markers, but histologic type remains the single most important prognostic factor. Histologic subtypes of epithelioid MPM seem to have prognostic and therapeutic implications. Interobserver agreement in histologic pattern classification should be high. Objective. To assess interobserver and intraobserver reproducibility in histologic differentiation between the main types of MPMs, and in further subtyping of epithelioid-type mesothelioma. Design. One representative hematoxylin-eosin-stained slide was selected from the archive for each of 200 patients with MPM. They were reviewed independently by 3 pathologists and classified according to the current World Health Organization classification of pleural tumors. After the first round of evaluations, a consensus meeting was organized where problems were addressed and representative images for each histologic category were selected. Two months later, cases were reevaluated by all 3 pathologists. Results. After the first round, overall interobserver agreement for histologic subtyping of mesothelioma was fair (k, 0.36). The agreement was increased to substantial (k, 0.63) in the second round. Improvement was found in interobserver agreement for all types of MPM, and for most epithelioid subtypes. Conclusions. Moderate to substantial agreement in histologic typing and subtyping of MPM can be achieved. However, training with additional clarification of diagnostic criteria, their strict application, and help from consensus-based illustrative images is needed.
Keywords: connective and soft tissue neoplasms -- pathology, malignant pleural mesothelioma, histopathology
Published in DiRROS: 30.11.2020; Views: 5383; Downloads: 210
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Expression of FGFR1-4 in malignant pleural mesothelioma tissue and corresponding cell lines and its relationship to patient survival and FGFR inhibitor sensitivity
Gregor Vlačić, Mir Alireza Hoda, Thomas Klikovits, Katharina Sinn, Elisabeth Gschwandtner, Katja Mohorčič, Karin Schelch, Christine Pirker, Barbara Peter-Vörösmarty, Jelena Brankovic, Tanja Čufer, Aleš Rozman, Izidor Kern, 2019, original scientific article

Abstract: Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1-FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1-4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1-4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not suffcient to predict FGFR inhibitor response in MPM cell lines.
Keywords: malignant pleural mesothelioma, fibroblast growth factor receptors, azbestos, immunotherapy, chemotherapy, genomic analysis, infigratinib
Published in DiRROS: 07.10.2020; Views: 11510; Downloads: 514
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Dynamic contrast-enhanced MRI of malignant pleural mesothelioma : a comparative study of pharmacokinetic models and correlation with mRECIST criteria
Martina Vivoda Tomšič, Sotirios Bisdas, Viljem Kovač, Igor Serša, Katarina Šurlan Popović, 2019, original scientific article

Abstract: BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic malignancy that is difficult to cure. Dynamic contrast-enhanced (DCE) MRI is a functional imaging technique used to analyze tumor microvascular properties and to monitor therapy response. Purpose of this study was to compare two tracer kinetic models, the extended Tofts (ET) and the adiabatic approximation tissue homogeneity model (AATH) for analysis of DCE-MRI and examine the value of the DCE parameters to predict response to chemotherapy in patients with MPM. METHOD: This prospective, longitudinal, single tertiary radiology center study was conducted between October 2013 and July 2015. Patient underwent DCE-MRI studies at three time points: prior to therapy, during and after cisplatin-based chemotherapy. The images were analyzed using ET and AATH models. In short-term follow-up, the patients were classified as having disease control or progressive disease according to modified response evaluation criteria in solid tumors (mRECIST) criteria. Receiver operating characteristic curve analysis was used to examine specificity and sensitivity of DCE parameters for predicting response to therapy. Comparison tests were used to analyze whether derived parameters are interchangeable between the two models. RESULTS: Nineteen patients form the study population. The results indicate that the derived parameters are not interchangeable between the models. Significant correlation with response to therapy was found for AATH-calculated median pre-treatment efflux rate (kep) showing sensitivity of 83% and specificity of 100% (AUC 0.9). ET-calculated maximal pre-treatment kep showed 100% sensitivity and specificity for predicting treatment response during the early phase of the therapy and reached a favorable trend to significant prognostic value post-therapy. CONCLUSION: Both models show potential in predicting response to therapy in MPM. High pre-treatment kep values suggest MPM disease control post-chemotherapy.
Keywords: biomarker, magnetic resonance imaging, mesothelioma, perfusion, response evaluation criteria in solid tumors, prognosis
Published in DiRROS: 23.09.2020; Views: 786; Downloads: 480
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Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma
Agnes Bilecz, Paul Stockhammer, Dirk Theegarten, Izidor Kern, Marko Jakopović, Miroslav Samaržija, Thomas Klikovits, Mir Alireza Hoda, Balazs Dome, Felicitas Oberndorfer, 2020, original scientific article

Abstract: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. Methods and results: Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtype d. Nuclear grading and mitosis–necrosi s score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis – necrosis score. The mitosis–necrosis score was a robust and independent prognostic factor in our patient cohort. The prognos- tic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. Conclusions: Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches.
Keywords: epithelioid malignant pleural mesothelioma, histological subtypes
Published in DiRROS: 08.07.2020; Views: 1098; Downloads: 604
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Clinical significance of histologic subtyping of malignant pleural mesothelioma
Luka Brčić, Izidor Kern, 2020, review article

Abstract: Malignant mesothelioma (MM) is uncommon, but very aggressive tumor arising from the mesothelial cells of pleura, pericardium, peritoneum, and tunica vaginalis. Despite multimodality treatments 5-year survival is only 5% after the diagnosis. Histology and TNM staging system are still the best prognostic factors. Furthermore, histologic subtype of MM determines the clinical management of the patients. According to the 2015 WHO classification, MM is divided into diffuse, localized and well differentiated papillary mesothelioma. Major histologic subtypes of diffuse MM, namely epithelioid, biphasic and sarcomatoid, have different prognosis. However, in the last decade it has become evident that more detailed subclassification and histologic/cytological characterization of MM have prognostic and perhaps predictive implications. In this review, major histologic subtypes and cytological features of MM are presented and their relation with prognosis and predictive biomarkers is discussed.
Keywords: malignant mesothelioma, epithelioid malignant mesothelioma, biphasic malignant mesothelioma, sarcomatoid malignant mesothelioma
Published in DiRROS: 22.06.2020; Views: 1388; Downloads: 744
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