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// Fabian Dominik Mairinger 1 , Claudia Vollbrecht 2, 3, 4 , Elena Flom 1 , Daniel Christian Christoph 5 , Kurt-Werner Schmid 1 , Jens Kollmeier 6 , Helmut Hans Popper 7 , Thomas Mairinger 8 and Robert Fred Henry Walter 1, 9 1 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Institute of Pathology, Division of Molecular Pathology, Charite, Berlin, Germany 3 German Cancer Consortium (DKTK), Germany 4 German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 6 Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany 7 Department of Pathology, Division of Molecular Lung- and Pleurapathology, Medical University of Graz, Graz, Austria 8 Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany 9 Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Correspondence to: Fabian Dominik Mairinger, email: fabian.mairinger@uk-essen.de Keywords: pleural mesothelioma, pemetrexed, thymidylate synthethase, folylpolyglutamate synthase, personalized therapy Received: October 12, 2016 Accepted: March 01, 2017 Published: March 21, 2017 ABSTRACT Background: Malignant pleural mesothelioma (MPM) is a rare tumor linked to a dismal prognosis. Even the most effective chemotherapeutical regime of pemetrexed combined with cisplatin leads to a remission-rate of only about 40%. The reasons for the rather poor efficacy remain largely unknown. Results: Phenotypes were significantly associated with progression (p=0.0279) and remission (p=0.0262). Cox-regression revealed significant associations between SLC19A1 / TYMS -ratio (p=0.0076) as well as FPGS / TYMS -ratio (p=0.0026) and OS. For differentiation by risk-groups, COXPH identified a strong correlation (p=0.0008). Methods: 56 MPM specimens from patients treated with pemetrexed were used for qPCR analysis. Phenotypes and risk groups were defined by their expression levels of members of the folic acid metabolism and correlated to survival and objective response. Conclusion: Our results indicate that the balance between folic acid uptake, activation and metabolism plays a crucial role in response to pemetrexed-based chemotherapy and the prognosis of MPM patients. Implementing this marker profile in MPM stratification may help to individualize MPM-therapy more efficiently.

// Robert Fred Henry Walter 1, 2, * , Fabian Dominik Mairinger 2, 3, * , Robert Werner 4 , Claudia Vollbrecht 3 , Thomas Hager 2 , Kurt Werner Schmid 2 , Jeremias Wohlschlaeger 2, 5 , Daniel Christian Christoph 6 1 Ruhrlandklinik Essen, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 3 Institute of Pathology, Division of Molecular Pathology, Charite, Berlin, Germany 4 Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany 5 Institute of Pathology, Ev.-Luth. Diakonissenkrankenhaus Flensburg, Flensburg, Germany 6 Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany * These authors have contributed equally to this work Correspondence to: Robert Fred Henry Walter, e-mail: robert.walter@ruhrlandklinik.uk-essen.de Keywords: lung cancer, neuroendocrine pulmonary tumors, folic acid metabolism, DNA repair, NanoString nCounter Received: January 29, 2016 Accepted: January 30, 2016 Published: February 26, 2016 ABSTRACT Purpose: 25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking. Experimental Design: Sixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism ( ATIC , DHFR , FOLR1 , FPGS , GART , GGT1 , SLC19A1 , TYMS ) and DNA-repair ( ERCC1 , MLH1 , MSH2 , MSH6 , XRCC1 ). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair. Results: Expression of FOLR1 , FPGS , MLH1 and TYMS (each p

// Robert Fred Henry Walter 1,2 , Robert Werner 2 , Saskia Ting 2 , Claudia Vollbrecht 3 , Dirk Theegarten 2 , Daniel Christian Christoph 4 , Kurt Werner Schmid 2 , Jeremias Wohlschlaeger 2 and Fabian Dominik Mairinger 2 1 Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 3 Institute of Pathology, University Hospital Cologne, Cologne, Germany 4 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Correspondence to: Robert Fred Henry Walter, email: // Keywords : small-cell lung cancer, large-cell neuroendocrine lung cancer, carcinoids, apoptosis, NanoString nCounter Received : March 11, 2015 Accepted : April 15, 2015 Published : May 04, 2015 Abstract Background: Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. Materials and Methods: Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. Results: ASCL1 , BCL2 , CASP8 , CCNE1 , CDK1 , CDK2 , CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2 , CDKN1B , CDKN2A and PNN expression was significantly different with higher expression in SCLC. Conclusion: Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC.

// Fabian D. Mairinger 1, * , Jan Schmeller 1, * , Sabrina Borchert 1 , Michael Wessolly 1 , Elena Mairinger 1 , Jens Kollmeier 2 , Thomas Hager 1 , Thomas Mairinger 3 , Daniel C. Christoph 4, 5 , Robert F.H. Walter 1, 6 , Wilfried E.E. Eberhardt 4, 6 , Till Plones 7 , Jeremias Wohlschlaeger 1, 8 , Bharat Jasani 9 , Kurt Werner Schmid 1 and Agnes Bankfalvi 1 1 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany 3 Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany 4 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 5 Department of Internistic Oncology, Kliniken Essen Mitte, Essen, Germany 6 Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 7 Department of Thoracic Surgery and Thoracical Endoscopy, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 8 Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany 9 Department of Pathology, Targos Molecular Pathology GmbH, Kassel, Germany * These authors have contributed equally to this work Correspondence to: Fabian D. Mairinger, email: fabian.mairinger@uk-essen.de Keywords: malignant pleural mesothelioma; metallothionein; overall survival; prognostic biomarker; platin-based chemotherapy; Pathology Received: August 18, 2017 Accepted: March 11, 2018 Published: April 27, 2018 ABSTRACT Background: Malignant pleural mesothelioma (MPM) is a biologically highly aggressive tumor arising from the pleura with a dismal prognosis. Cisplatin is the drug of choice for the treatment of MPM, and carboplatin seems to have comparable efficacy. Nevertheless, cisplatin treatment results in a response rate of merely 14% and a median survival of less than seven months. Due to their role in many cellular processes, methallothioneins (MTs) have been widely studied in various cancers. The known heavy metal detoxifying effect of MT-I and MT-II may be the reason for heavy metal drug resistance of various cancers including MPM. Methods: 105 patients were retrospectively analyzed immunohistochemically for their MT expression levels. Survival analysis was done by Cox-regression, and statistical significance determined using likelihood ratio, Wald test and Score (logrank) tests. Results: Cox-regression analyses were done in a linear and logarithmic scale revealing a significant association between expression of MT and shortened overall survival (OS) in a linear (p=0.0009) and logarithmic scale (p=0.0003). Reduced progression free survival (PFS) was also observed for MT expressing tumors (linear: p=0.0134, log: p=0.0152). Conclusion: Since both, overall survival and progression-free survival are negatively correlated with detectable MT expression in MPM, our results indicate a possible resistance to platin-based chemotherapy associated with MT expression upregulation, found exclusively in progressive MPM samples. Initial cell culture studies suggest promoter DNA hypomethylation and expression of miRNA-566 a direct regulator of copper transporter SLC31A1 and a putative regulator of MT1A and MT2A gene expression, to be responsible for the drug resistance.

// Robert Fred Henry Walter 1, 2 , Claudia Vollbrecht 3, 4 , Robert Werner 2 , Jeremias Wohlschlaeger 2 , Daniel Christian Christoph 5 , Kurt Werner Schmid 2 , Fabian Dominik Mairinger 2, 4 1 Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 3 Institute of Pathology, University Hospital Cologne, Koln, Germany 4 Institute of Pathology, Division of Molecular Pathology, Charite, Berlin, Germany 5 Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Correspondence to: Fabian Dominik Mairinger, e-mail: fabian_mairinger@hotmail.com Keywords: MDM2, microRNA, pleural mesothelioma, NanoString nCounter Received: September 04, 2015 Accepted: February 02, 2016 Published: February 24, 2016 ABSTRACT Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour first-line treated with a combination of cisplatin and pemetrexed. MDM2 and P14/ARF (CDKN2A) are upstream regulators of TP53 and may contribute to its inactivation. In the present study, we now aimed to define the impact of miRNA expression on this mechanism. Material and Methods: 24 formalin-fixed paraffin-embedded (FFPE) tumour specimens were used for miRNA expression analysis of the 800 most important miRNAs using the nCounter technique (NanoString). Significantly deregulated miRNAs were identified before a KEGG-pathway analysis was performed. Results: 17 miRNAs regulating TP53 , 18 miRNAs regulating MDM2 , and 11 miRNAs directly regulating CDKN2A are significantly downregulated in MDM2-expressing mesotheliomas. TP53 is downregulated in MDM2-negative tumours through miRNAs with a miSVR prediction score of 11.67, RB1 with a prediction score of 8.02, MDM2 with a prediction score of 4.50 and CDKN2A with a prediction score of 1.27. Conclusion: MDM2 expression seems to impact miRNA expression levels in MPM. Especially, miRNAs involved in TP53-signaling are strongly decreased in MDM2-positive mesotheliomas. A better understanding of its tumour biology may open the chance for new therapeutic approaches and thereby augment patients’ outcome.