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ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE INTERNATIONAL MESOTHELIOMA INTEREST GROUP Follow us on Twitter @iMig_meso for updates during the Conference! ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Table of contents PLENARY SESSIONS Please note that the iMig 2016 Abstract Book only includes Peer Reviewed Abstracts and excludes any abstracts from Invited Speakers. 3 PL01: ORIGINS OF MESOTHELIOMA MONDAY, MAY 2, 2016 08:25 – 10:25 PL02: PREDICTING THE OUTCOME MONDAY, MAY 2, 2016 11:15 – 12:45 PL03: THE KNIFE OR THE NEEDLE? TUESDAY, MAY 3, 2016 09:00 – 10:30 [NO PEER REVIEW ABSTRACTS] PL04: FROM GENETICS TO THERAPY TUESDAY, MAY 3, 2016 11:15 – 12:45 6 PL05: WHAT IS IN THE LOCKER NOW? WEDNESDAY, MAY 4, 2016 09:00 – 10:30 8 PL06: THE “IMMUNE WAR” ON MESOTHELIOMA WEDNESDAY, MAY 4, 2016 11:15 – 12:45 MINI SYMPOSIUM 3 4 11 12 MS01: MARF INTERNATIONAL MESO UK MINI SYMPOSIUM MONDAY, MAY 2, 2016 14:15 – 15:45 MS02: CELL DEATH MECHANISMS MONDAY, MAY 2, 2016 14:15 – 15:45 MS03: IMAGING AND ENDPOINT EVALUATION MONDAY, MAY 2, 2016 14:15 – 15:45 17 MS04: CELL AND VACCINE BASED THERAPY MONDAY, MAY 2, 2016 14:15 – 15:45 22 MS05: OPTIMUM DIAGNOSTIC PATHWAY FOR SUSPECTED MESOTHELIOMA MONDAY, MAY 2, 2016 16:30 – 18:00 27 MS06: ASBESTOS CONTROL MONDAY, MAY 2, 2016 16:30 – 18:00 32 MS07: BAP1 AND GENETICS MONDAY, MAY 2, 2016 16:30 – 18:00 36 12 MS08: PATHOLOGY MONDAY, MAY 2, 2016 16:30 – 18:00 39 MS09: SURGERY (TECHNICAL ASPECTS) TUESDAY, MAY 3, 2016 14:15 – 15:45 44 MS10: NOVEL TARGETS ENTERING IN THE CLINIC TUESDAY, MAY 3, 2016 14:15 – 15:45 46 MS11: CRITICAL SIGNALING PATHWAY TUESDAY, MAY 3, 2016 14:15 – 15:45 50 MS12: TREATMENT ADVANCES IN PERITONEAL MESOTHELIOMA / PALLIATIVE CARE FOR ALL MESOTHELIOMA TUESDAY, MAY 3, 2016 14:15 – 15:45 55 MS13: GENOMICS AND DRUG SENSITIVITY TUESDAY, MAY 3, 2016 16:30 – 18:00 57 MS14: RADIOTHERAPY TUESDAY, MAY 3, 2016 16:30 – 18:00 60 MS15: MULTIMODALITY TUESDAY, MAY 3, 2016 16:30 – 18:00 64 MS16: NOVEL IMMUNE STRATEGIES TUESDAY, MAY 3, 2016 16:30 – 18:00 68 14 POSTER SESSIONS 73 PP01: POSTER MIXER AND POSTER DISCUSSION SESSION 1 MONDAY, MAY 2, 2016 18:00 – 19:30 73 PP02: POSTER MIXER AND POSTER DISCUSSION SESSION 2 TUESDAY, MAY 3, 2016 18:00 – 19:30 117 AUTHOR INDEX 159 iMig2016.ORG 2 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PLENARY SESSIONS PL01: ORIGINS OF MESOTHELIOMA MONDAY, MAY 2, 2016 08:25 – 10:25 PL01.04: PLEURAL MESOTHELIOMA AND ASBESTOS EXPOSURE: A CASE-CONTROL STUDY WITH QUANTITATIVE RISK ASSESSMENT Daniela Ferrante1, Dario Mirabelli2, Sara Tunesi3 , Benedetto Terracini2, Corrado Magnani4 CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Eastern Piedmont, Novara, ITALY, 2Center for Cancer Epidemiology and Prevention, City of Health and Science Hospital; Human Genetics Foundation, HuGeF, Turin, ITALY,3CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Eastern Piedmont; Center for Cancer Epidemiology and Prevention, City of Health and Science Hospital, Turin, ITALY, 4CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Eastern Piedmont; Human Genetics Foundation, HuGeF, Turin, ITALY 1 Objectives: The area of Casale Monferrato (NW Italy, population around 100,000) showed an extremely high incidence of malignant mesothelioma (MM) caused by the “Eternit” plant, the most important asbestos cement plant in Italy active in the town of Casale Monferrato for 80 years. During 1990-2010, the annual incidence rate of definite pleural MM (excluding diagnoses of “probable” and “possible” MM) was 27.3 (per 100,000) among men and 15 (per 100,000) among women, about 10 times higher than the corresponding Italian rate. Several studies have estimated the effect of asbestos exposure in this population considering the risk of MM separately for occupational, environmental and domestic exposure. The purpose of the present population-based case-control study was to quantify the association between MM and asbestos cumulative exposure using individual assessment of all sources of exposure. Methods: The study included the incident cases of pleural malignant mesothelioma diagnosed from 1/1/2001 to 30/6/2006 to residents in the area. Cases were detected in the hospitals of the area. The controls were a random sample of residents matched to cases by sex and date of birth. Cases and controls were interviewed with a standardized questionnaire including sections on demographic characteristics, lifelong occupational and residential histories, selected leisure time activities and characteristics of the home environment possibly relevant for asbestos exposure. Two hundred cases and 348 controls were included in the study. Asbestos exposure was assessed by an experienced rater and cumulative exposure was computed considering all sources of exposure. The data analysis was based on unconditional logistic regression adjusting all models for gender, age at diagnosis and type of interview (subjects vs with proxy). Results: A highly statistically significant trend in the risk of pleural malignant mesothelioma was observed with increasing total (occupational and non occupational) cumulative exposure. ORs increased from 4.4 (CI 95% 1.7 to 11.3) for cumulative exposure <1 f/mL-years to 62.1 (CI 95% 22.2 to 173.2) for cumulative exposures above 10 f/mL-years when both occupational and non-occupational exposures were considered. Among 84 cases and 201 controls never occupationally exposed, corresponding ORs were 3.8 (CI 95% 1.3 to 11.1) and 23.3 (CI 95% 2.9 to 186.9) (reference: residents only exposed to background levels of asbestos). Having a family member occupationally exposed to asbestos doubles the risk of MM (38 cases and 35 controls; OR=2.2; CI95% 1.2-4.0). Having a garden or courtyard paved with asbestos cement tailings, an asbestos cement roof or buildings near home were also associated with a significant increase in the OR (152 cases and 221 controls; OR=1.9 CI95%1.2-3.0). Conclusion: This study underlines that, in addition to occupational exposures, environmental and familial/domestic exposures to asbestos also contribute to the occurrence of MM in the population of Casale Monferrato. Continuing epidemiological surveillance and investigation into the specific routes and circumstances of exposures contributing to MM occurrence in this population is, therefore, important. Keywords: pleura, asbestos, environmental asbestos exposure, cumulative exposure PL01.06: LONG-FIBRE CARBON NANOTUBES INDUCE PLEURAL MESOTHELIOMA VIA SILENCING AND/OR LOSS OF KEY TUMOUR SUPPRESSOR GENES Tatyana Chernova1, Fiona A. Murphy1, Sara Galavotti1, XiaoMing Sun1, Ian R. Powley1, Stefano Grosso1, Anja Schinwald2, David Dinsdale1, John Le Quesne1, Jonathan Bennett3 , Apostolos Nakas3 , Peter Greaves4 , Craig A. Poland5, Ken Donaldson2, Martin Bushell1, Anne E. Willis1, Marion Macfarlane1 MRC Toxicology Unit, Leicester, UNITED KINGDOM, 2Centre For Inflammation Research, MRC/University of Edinburgh, Edinburgh, UNITED KINGDOM, 3Glenfield Hospital, UHL NHS Trust, Leicester, UNITED KINGDOM, 4Department of Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 5Institute of Occupational Medicine, Edinburgh, UNITED KINGDOM 1 Objectives: Exposure to asbestos fibres causes pathological changes in the pleural cavity including malignant mesothelioma. Length-dependent retention of asbestos fibres in the pleural cavity is crucial for disease development. Chronic inflammation induced by pathogenic asbestos fibres plays a key role in carcinogenesis and epigenetic events, rather than driver mutations, are considered to be major causative factors. Manufactured carbon nanotubes (CNT) are similar to asbestos in terms of their high aspect ratio and thus may pose an asbestos-like inhalation hazard, however the molecular mechanisms underlying their carcinogenic potential have not been sufficiently explored. Methods: Using a model of direct injection into the pleural cavity we compared the molecular changes which occur at the iMig2016.ORG 3 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP mesothelium after exposure to short and long asbestos fibres and short and long CNT over 1 year following injection. Results: We show a common pro-oncogenic activity of long CNT and long asbestos throughout disease progression. The common key molecular events encompass changes in gene expression and signaling pathway activation, oxidative DNA damage, increased mitosis and proliferation. Instillation of long CNT into the pleural cavity of mice induces chronic inflammation and pro-oncogenic changes leading to development of mesothelioma with deletion of p19/Arf and silencing of p16/ Ink4a and NF2. Epigenetic changes induced by pathogenic fibres occur at the pre-neoplastic stage of disease and may play a key role in progression of pleural inflammatory lesions to malignant mesothelioma. Conclusion: Together these data demonstrate that exposure to long CNT induces development of pleural mesothelioma replicating the pathogenesis of human disease and highlights commonality in the hazard mechanism of long pathogenic fibres at the molecular level. Crucially, our findings reinforce concerns that long CNT may pose an asbestos-like hazard, leading to malignant mesothelioma. enhances the expression of genes encoding cell-cycle promoting proteins including CCDN1 and FOXM1 and connective tissue growth factor (CTGF), the latter of which was associated with extracellular matrix formation of the MM cells in vivo. To determine the biological roles of YAP on untransformed mesothelial cells, we established immortalized mesothelial cell lines (HOMC), and examined whether YAP activation induces malignant phenotypes in the cells. We found that transduction of both wild-type and constitutively active-type (S127A) YAP enhanced HOMC-cell proliferation in vitro. We also demonstrated that YAP-transduced HOMC cells showed enhanced tumorigenicity in vivo after inoculation into nude mice subcutaneously or into intrathoracic cavities. Finally, we are currently analyzing whether or not TAZ, a paralog of YAP, is also involved in the dysregulation of the YAP/TAZ target gene expressions in MM cells, and YAP/TAZ activation is a synergistic effect on MM cell proliferation and promotion. Conclusion: Our results indicate that the NF2-Hippo pathway inactivation induces YAP and TAZ activation, which confers more malignant phenotypes of mesothelial cells. Keywords: signal transduction, Hippo pathway Keywords: in vivo model, epigenetics, carbon nanotubes, mesothelioma PL02: PREDICTING THE OUTCOME MONDAY, MAY 2, 2016 11:15 – 12:45 PL01.09: CONSTITUTIVE YAP ACTIVATION INDUCES MALIGNANT PHENOTYPES OF IMMORTALIZED MESOTHELIAL CELLS Yoshitaka Sekido Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, JAPAN Objectives: Malignant mesothelioma (MM) is an aggressive tumor arising primarily from pleural or peritoneal cavities, which is caused by asbestos exposure after long latency. Three major tumor suppressor genes which are frequently mutated in MM are CDKN2A, NF2, and BAP1. NF2 encodes Merlin, a member of the Ezrin-Radixin-Moesin protein, and Merlin regulates the Hippo signaling pathway, which has been shown to play important roles in organ size control and cancer development. Inactivation of Hippo pathway is known to induce constitutive underphosphorylation/activation of YAP transcriptional coactivator. The objective of this study is to demonstrate whether YAP confers more malignant phenotypes to mesothelial cells in vitro and in vivo. Methods: Immortalized mesothelial cell lines (HOMC) were established by transduction of HPV-E6/E7 and hTERT into primary mesothelial cells. Immortalized mesothelial cells which were transduced with YAP or control vectors were injected subcutaneously or into the right thoracic cavity of nude mice. Results: Our previous studies have identified alteration or aberrant expression of the components in this cascade including LATS2, SAV1 and AJUBA, which causes constitutive activation of YAP transcriptional coactivator. We found that activated YAP PL02.03: IMPACT OF TUMOR THICKNESS ON SURVIVAL AFTER ACCELERATED HEMITHORACIC RADIATION FOLLOWED BY EXTRAPLEURAL PNEUMONECTOMY Marc De Perrot, Ronald Feld, Penelope Bradbury, Natasha Leighl, Bc John Cho Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Center, Toronto, ON, CANADA Objectives: Surgery for mesothelioma after radiation therapy (SMART) provides encouraging results in patients with malignant pleural mesothelioma of epithelial subtype. However, patient selection for this approach based on radiological parameters remains not well defined. In this analysis, we reviewed the impact of tumor thickness (TT) on long-term outcome in an attempt to find radiological criteria to select patients for this therapy. Methods: Pre-treatment CT scan was reviewed for all patients undergoing the SMART approach between 10/2008 and 11/2015. Patients undergoing chemotherapy before SMART were excluded from analysis (n=4). The thickest part of the tumor was measured on three sites along the chest wall (anterior, middle, posterior), mediastinum (upper, lower anterior, lower posterior) and diaphragm (anterior, middle, posterior) using modified RECIST criteria. TT of <1cm, 1-1.5cm and >1.5cm was then used as a cut-off. All patients were followed up until death or 11/2015. Survival was calculated from the start of radiation iMig2016.ORG 4 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP using life table analysis and statistical differences were determined by log-rank test. Results: All 70 consecutive patients (81% men, age 41-82, median 64 years) included in the SMART protocol completed radiation (25-30 Gy in 5 fractions) and surgery (extrapleural pneumonectomy) with no 30-day mortality. Two patients died after discharged from hospital for a treatment related mortality of 2.9%. The overall median survival and disease-free survival (DFS) reached 45 months and 31 months in patients with epithelial subtypes, respectively, compared to 13 months (p=0.0008) and 8 months (p=0.0002) in patients with biphasic subtypes. Among patients with epithelial subtype, the 5-year survival reached 51±13% in the absence of pT4N1-2 disease on final pathology (median survival not reached after a median follow-up of 29 months), while the median survival was 19 months in pT4N1-2 disease (p=0.006). The median DFS was 16 months in patients with epithelial pT4N1-2 disease compared to 48 months in the remaining patients with epithelial subtype (p=0.01). Age (p=0.3) and gender (p=0.2) did not impact survival and DFS. Maximal TT of <1cm, 1-1.5cm and >1.5cm on the chest wall had no impact on survival (p=0.6) and DFS (p=0.8). Maximal TT <1cm on the mediastinum was associated with better DFS (p=0.03), but had no significant impact on survival (p=0.1). In contrast, maximal TT on the diaphragm had a major impact on survival and DFS. Median survival reached 51 months when maximal TT was <1cm on the diaphragm, 24 months when maximal TT was 1-1.5cm and 12 months when maximal TT was >1.5cm (p<0.0001). All patients had recurrence within 18 months when maximal TT on the diaphragm was >1.5cm (median DFS 10 months), while the 3-year DFS reached 54±12% (median DFS, 47 months) when maximal TT was <1cm and 36±12% (median DFS, 14 months) when maximal TT was 1-1.5cm (p<0.0001). Conclusion: The outcome of patients with epithelial subtypes remains encouraging after the SMART approach, particularly in the absence of pT4N1-2 disease. Maximal TT on the diaphragm based on pre-treatment CT scan appears to be a good predictor of outcome, independently of histologic subtypes, and could potentially be used as a selection criteria for this approach. PL02.05: MUTATION PROFILES OF MALIGNANT PLEURAL MESOTHELIOMAS ACCORDING TO MOLECULAR CLASSIFICATION Lisa Quetel1, Clément Meiller1, Robin Tranchant1, Annie Renier1, Françoise Galateau-Sallé2, Marie-Christine Copin3 , Paul Hofman4 , Françoise Le Pimpec-Barthes1, Sandrine Imbeaud1, Jessica Zucman-Rossi1, Marie Claude Jaurand1, Didier Jean1 Inserm U.1162, INSERM U.1162, Paris, FRANCE, 2MESOBANK, Lyon, FRANCE, 3CHRU Lille, Lille, FRANCE, 4CHU Nice, Nice, FRANCE 1 Objectives: Development of precision medicine for Malignant Pleural Mesothelioma (MPM) needs a deep knowledge of the molecular changes associated with mesothelial carcinogenesis especially to take into account the tumor variability between patients. Recently, based on transcriptomic data, we defined a ro- bust molecular classification of MPM composed of two groups, C1 and C2, linked to histology and survival. C1 MPM exhibited more frequent BAP1 alterations. To better define the mutation profile of the C1 and C2 MPM groups, we performed targeted Next-Generation Sequencing (NGS) of candidate genes. Methods: NGS (Miseq, Illumina) was performed using 165 MPM including 60 MPM cultures and 105 frozen MPM tumors samples. Twenty-two candidate genes were selected: key altered genes in mesothelial carcinogenesis (CDKN2A, CDKN2B, NF2, BAP1, TP53 and LATS2) previously sequenced by Sanger method, genes mutated at low frequency in MPM (KRAS, HRAS, EGFR, CTNNB1…) and genes recently reported as altered in MPM (CUL1, ARID1A, ARID2, SMARCA4, SETD2…). The TERT promoter, in which we previously identified oncogenic hot-spot mutations, was also included. Genetic alterations were analyzed with a total depth of 200X. Large deletions were detected from NGS data based on coverage and confirmed by PCR on genomic DNA or by Multiplex ligation-dependent probe amplification (MLPA). Gene expression was also assessed by RT-qPCR to validate absence of transcript for genes with large deletion. Results: Data demonstrated an enrichment in C>T transitions and high frequency of large biallelic deletion in CDKN2A/ CDKN2B, NF2 and BAP1 genes. Previous genetic alterations identified by Sanger sequencing in our collection have been found. Variants inducing protein structure modification and not identified as SNP, were found in 19 genes. The mutation frequencies are consistent with literature data for previously well-characterized genes and allow to precise the frequency for the others. Genetic alterations deleterious to the function of the protein (deletion/insertion, splice-site mutation, substitutions nonsense and damaging missense predicted by SIFT and Polyphen) represent more than 60% of the non-synonymous variants, and are enriched in 10 genes. Among them, the highest alteration frequency was found in CDKN2A, CDKN2B, NF2 and BAP1 genes (over 25%) and frequencies around 5-10% were found in TP53, LATS2, and SETD2 genes. TERT promoter mutations were found at an overall rate of 18% in all MPM and 59% in sarcomatoid MPM, supporting the strong association with this histological subtype (P=0.0001), which we described in a precedent study. The highest frequency of BAP1 mutations in C1 MPM (P=0.0006) was confirmed. Moreover, an enrichment in SETD2 (histone methyltransferase) mutations and a significant association with ARID1A (member of the SWI/SNF chromatin remodeling family) mutations, mainly consisting in non-deleterious substitutions, were identified. Conversely, relevant mutations in TP53 gene were significantly associated with C2 MPM (P =0.02). Conclusion: The NGS gene candidate approach precise the genetic landscape of C1 and C2 MPM main tumor groups. C1 MPM are characterized by mutations in genes involved in chromatin organization. Interestingly, mutations in TP53, which is linked with tumor aggressiveness, are found mainly in the MPM of the C2 group, gathering patients with the worse prognosis. Keywords: Tumor molecular classification, Genetic alterations, Next Generation Sequencing (NGS) iMig2016.ORG 5 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PL04.03: PHASE 1 STUDY OF TAZEMETOSTAT (EPZ-6438), AN INHIBITOR OF EZH2, IN PATIENTS WITH NON-HODGKIN LYMPHOMA AND SOLID TUMORS occurring in >10% of pts were: asthenia, anorexia, thrombocytopenia, nausea, constipation, diarrhea, vomiting and muscle spasms. Four pts had grade ≥3 treatment related AE’s: thrombocytopenia, neutropenia, hypertension, and transaminase elevation. The recommended phase 2 dose was determined to be 800 mg BID. Of 16 response-evaluable NHL pts, objective responses (CRs, PRs) were observed in 56% (5/10 DLBCL, 3/5 FL and 1/1 MZL). Four NHL pts remained on study for >1 year. Of the ST pts, all 6 who experienced tumor reduction had either INI1- or SMARCA4-negative tumors as of 31-Aug. 2015. This includes a CR that is ongoing through 65 weeks (MRT), PRs (MRT, ES, MRT of ovary) and stable disease >24 weeks (ES, MRT of ovary). Vincent Ribrag1, Antoine Italiano2, Jean-Charles Soria1, Jean-Marie Michot1, Anna Schmidt2, Sophie Postel-Vinay1, Fontanet Bijou3 , Jean-Michele Coindre2, Maud Toulmonde2, Christophe Massard1, Stephen J. Blakemore4 , Alice Mcdonald4 , Scott Ribich4 , Blythe Thomson4 , Heike Keilhack4 , Maria Roche4 , John Larus4, Peter T. Ho4 Conclusion: Tazemetostat demonstrates a safety profile favorable for chronic dosing and objective responses in pts with relapsed or refractory B-cell NHL including DLBCL, FL and MZL and in subjects with advanced STs consisting of MRT, ES, and MRT of ovary. Phase 2 trials in B-cell NHL and INI1- or SMARCA4-negative tumors are enrolling. A phase 2 trial in pts with BAP1-mutated mesothelioma is planned. PL04: FROM GENETICS TO THERAPY TUESDAY, MAY 3, 2016 11:15 – 12:45 Institut Gustave Roussy, Villejuif, FRANCE, 2Institut Bergonie, Bordeaux, FRANCE, 3French Blood Institute, Bordeaux, FRANCE, 4Epizyme Inc., Cambridge, MA, UNITED STATES OF AMERICA 1 Objectives: The histone methyl transferase EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and responsible for methylation of lysine 27 of histone H3 (H3K27), which results in chromatin remodeling and repressed transcription when trimethylated. Aberrant EZH2 activity has been implicated as an oncogenic driver in non-Hodgkin lymphoma (NHL). The SWI/SNF complex also remodels chromatin, activates transcription and acts in opposition to PRC2. Oncogenesis from mutation and/or loss of the SWI/SNF subunit INI1 in cancers such as malignant rhabdoid tumor (MRT) is sensitive to EZH2 inhibition. Tazemetostat is a potent, selective small molecule inhibitor of EZH2 in phase 2 clinical development. EZH2 inhibition may have therapeutic potential in BAP1 mutated mesothelioma (Levine, Nat Med 2015). Methods: This phase 1 open-label first-in-human study evaluated the safety, tolerability, and preliminary efficacy of tazemetostat administered orally as a monotherapy twice a day (BID). Eligible patients (pts) had either a relapsed/refractory B-cell NHL or solid tumors (ST). Archival tumor tissue from NHL pts was analyzed for EZH2 hot spot mutations by either amplicon-based next generation sequencing [NGS] or cobas® EZH2 Mutation Test [in development]. In addition, cell-of-origin in Diffuse Large B-cell Lymphoma (DLBCL) pts was determined by immunohistochemistry using the Hans algorithm. For tumors that were INI1-negative, central confirmation of diagnostic pathology and INI1 loss was performed. Tazemetostat was administered to subjects in 5 dose cohorts (100 mg, 200 mg, 400 mg, 800 mg and 1600 mg) and in 2 clinical pharmacology sub-study cohorts. Tumor response assessments were performed every 8 weeks and graded according to Cheson/IWG criteria or RECIST as appropriate. Results: As of 7-Nov. 2015, 58 pts were enrolled to this trial including 21 NHL pts, (14 DLBCL, 6 follicular lymphoma [FL] and 1 marginal zone lymphoma [MZL]). Of the 37 ST pts, 8 had INI1-negative tumors (MRT [5], epithelioid sarcoma (ES) [3]) and 3 had SMARCA4-negative tumors (MRT of ovary [2], thoracic sarcoma [1]). Adverse events (AE) regardless of attribution Keywords: EZH2, Phase 1, Lymphoma, INI1 PL04.05: DIFFERENTIAL RESPONSE OF MALIGNANT PLEURAL MESOTHELIOMA CELLS TO YAP TARGETED THERAPY ACCORDING TO MOLECULAR CLASSIFICATION Robin Tranchant1, Annie Renier1, Lisa Quetel1, Leanne De Koning2, Françoise Le Pimpec-Barthes1, Jessica Zucman-Rossi1, Marie Claude Jaurand1, Didier Jean1 Inserm U.1162, INSERM U.1162, Paris, FRANCE, 2Rppa Platform, Institut Curie, Paris, FRANCE 1 Objectives: Novel target therapies require better knowledge of molecular and clinico-biological heterogeneity of tumors. To better characterize MPM heterogeneity, we recently identified a robust MPM transcriptomic classification defining two groups (C1 and C2). Epithelioid MPM, the most frequent histologic subtype, was found in both tumor groups, with a worse survival prognosis in the C2 group. These groups differ by their mutation profile and by specifically deregulated pathways such as epithelial-mesenchymal transition (EMT) and TGFβ pathway. The aim of the work was to determine if the effect of a panel of ten specific molecular inhibitors induced a differential response in the 2 groups. Both inhibitors of epigenetic regulation and signaling pathways involved in mesothelial carcinogenesis were investigated. Methods: A panel of 18 MPM primary cultured cells classified in C1 or C2 and characterized for genetic alteration in genes involved in mesothelial carcinogenesis. Cell viability was determined by the MTS assay after treatment with a gradient concentration of ten inhibitors for 48 hours (Table 1). Gene expression was measured by quantitative RT-PCR, and protein phosphorylation and expression by Reverse Phase Protein Array. iMig2016.ORG 6 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Results: The mTOR/PI3K/Akt pathway inhibitor (PF_04691502), YAP/TEAD association inhibitor (Verteporfin) and the histone deacetylase inhibitor (Vorinostat) were the most effective to reduce MPM viability (Table 1). MPM of the C1 molecular group were more sensitive to Verteporfin treatment than MPM of the C2 group (P=0.01 – Figure 1). YAP activity is known to be regulated by Hippo pathway, but no significant relationship between Verteporfin sensitivity and the mutations status of two members of Hippo pathway, NF2 and LATS2, was observed. A decrease in YAP phosphorylation (P=0.04) and an overexpression of YAP target genes (CTGF and CYR61, P<0.01) were observed in C2 MPM in comparison with C1 MPM, indicating a higher co-transcriptional activity of YAP in C2 MPM. CTGF mRNA expression was predictive of Verteporfin sensitivity. Verteporfin induced a downregulation of YAP target genes (CTGF and CYR61), but also of target genes of TGFβ pathway (MMP2 andSERPINE1). Conclusion: MPM sensibility to Verteporfin was dependent of YAP activity and could be predicted by CTGF gene expression. Our data suggest that YAP deregulation is stronger in C2 group and is not only associated with Hippo inactivation. YAP targeting by Verteporfin may be a promising strategy for MPM patient treatment, especially for MPM of the C1 molecular group. Keywords: Tumor molecular classification, Genomics, Drug sensitivity, Hippo pathway iMig2016.ORG 7 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PL04.06: NOVEL SYNERGISTIC CELL THERAPIES FOR THE TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA Keywords: chemotherapy, MSCTRAIL, mesothelioma, Cell Therapy Beth Sage, Krishna Kolluri, Zhenqiang Yuan, Neelam Kumar, Adam Giangreco, Sam Janes PL05: WHAT IS IN THE LOCKER NOW? WEDNESDAY, MAY 4, 2016 09:00 – 10:30 Ucl Respiratory, University College London, London, UNITED KINGDOM Objectives: Malignant pleural mesothelioma (MPM) is an aggressive fatal cancer with no effective treatments. Mesenchymal stem cells (MSCs) migrate and incorporate into tumour stroma making them good vehicles for the delivery of anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells without affecting healthy tissues and is known to target the extrinsic apoptotic pathway. However, some cancer cells are resistant to TRAIL due to expression of proteins that block this pathway. Current chemotherapeutics target the proteins that inhibit the extrinsic apoptotic pathway suggesting that MSCTRAIL could be used in conjunction with those agents to increase the therapeutic effect. This study aimed to test whether MSCs modified to express TRAIL (MSCTRAIL) alone or in conjunction with Vorinostat (cFLIP inhibitor), LCL161 (IAP inhibitor), SNS032 (cFLIP & MCL1 inhibitor) and Obatoclax BCL2 family inhibitor) could be a successful treatment for MPM. Methods: Human MSCs were transduced with a lentiviral vector containing TRAIL. The biological activity of MSCTRAIL was determined using co-culture experiments where DiI stained MPM cells were incubated in a 4:1 ratio with MSCTRAIL cells with or without chemotherapy or rTRAIL for 24 hours. Apoptosis and cell death were determined using Annexin V and DAPI staining on flow cytometry. To test the effect of MSCTRAIL in vivo a bioluminescent tumour model was established. MPM cells were transduced with a luciferase lentivirus and injected into the pleural cavity of NOD/SCID mice to establish an orthotopic tumour model. MSCTRAIL cells were delivered via tail vein injections on days 5, 9, 12, 15 and 18 post tumour inoculation and bioluminescence was measured twice weekly. Results: MSCs were successfully transduced with TRAIL with 96% efficiency and TRAIL production was confirmed by ELISA. Ten human MPM cell lines were tested with 6 being sensitive to TRAIL and 4 resistant. In vivo delivery of MSCTRAIL to xenograft tumours from a TRAIL sensitive cell line resulted in a significant reduction in MPM tumour growth. TRAIL resistant cell lines were further tested with a combination of MSCTRAIL and 4 different chemotherapy agents and showed a significant increase in cell death. 3 cell lines were sensitive to all chemotherapeutic agents in combination with MSCTRAIL whilst one was sensitive to SAHA, SNS032 and LCL161 with MSCTRAIL but not Obatoclax. Conclusion: MSCs can be successfully transduced with TRAIL and induce apoptosis and death of MPM cells in vitro. Intravenous delivery of MSCTRAIL causes a significant reduction in TRAIL sensitive MPM tumour growth and resistant cells can be made sensitive by the addition of agents that target different elements of the extrinsic apoptotic pathway. MSCTRAIL is a potential novel cellular therapy for this currently untreatable disease. PL05.01: PHASE II STUDY ON INTENSITY MODULATED PLEURAL RADIATION THERAPY (IMPRINT) FOR MALIGNANT PLEURAL MESOTHELIOMA: FINAL RESULTS Andreas Rimner1, Marjorie G. Zauderer2, Daniel R. Gomez3 , Prasad S. Adusumilli4 , Preeti Parhar1, Kaitlin M. Woo5, Ronglai Shen5, Michelle Ginsberg6 , David Rice7, Anne Tsao8 , Kenneth E. Rosenzweig9, Abraham J. Wu1, Ellen Yorke10, Valerie Rusch11, Lee Krug12 Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, UNITED STATES OF AMERICA, 2Medicine, Memorial Sloan Kettering Cancer Center, New York, UNITED STATES OF AMERICA, 3Radiation Oncology, MDACC, Houston, UNITED STATES OF AMERICA,4Surgery, Memorial Sloan Kettering Cancer Center, New York City, NY, UNITED STATES OF AMERICA, 5Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, UNITED STATES OF AMERICA, 6Radiology, Memorial Sloan Kettering Cancer Center, New York City, NY, UNITED STATES OF AMERICA, 7Surgery, MDACC, Houston, TX, UNITED STATES OF AMERICA, 8Md Anderson Cancer Center, The University of Texas, Houston, TX, UNITED STATES OF AMERICA, 9Radiation Oncology, Mount Sinai Medical Center, New York, NY, UNITED STATES OF AMERICA, 10Medical Physics, Memorial Sloan Kettering Cancer Center, New York City, NY, UNITED STATES OF AMERICA, 11Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA, 12Bristol Myers Squibb, New York, UNITED STATES OF AMERICA 1 Objectives: Adjuvant radiation therapy for malignant pleural mesothelioma (MPM) is particularly challenging in patients with two intact lungs after pleurectomy/decortication (P/D) or those with unresectable disease due to the risk for radiation pneumonitis (RP). Here we report the final results of a prospective phase II study to determine the safety of hemithoracic pleural IMRT as part of a multimodality lung-sparing treatment approach. Methods: Patients received up to 4 cycles of pemetrexed/platinum chemotherapy. If feasible, P/D was performed. Hemithoracic pleural IMRT was administered in 28 fractions for a total planned dose consistent with normal tissue constraints, up to 5040 cGy, as previously described (Rosenzweig et al., IJROBP 2012). The primary endpoint was the incidence of ≥grade 3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids, typically 40mg prednisone, were rapidly initiated for ≥grade 2 RP. A Simon two-stage design was used with a safety analysis after the first 9 patients. As only one patient developed ≥grade 3 RP over 4 months, the cohort was expanded to 27 evaluable patients, defined as having initiated RT. iMig2016.ORG 8 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Results: Forty-five patients were enrolled. The median age was 68 years (range 38-79). Median KPS was 90% (range 70-100%). Ten patients had sarcomatoid or biphasic and 35 had epithelioid MPM. Sixty percent had advanced stage III/IV MPM with 49% deemed unresectable. 18 patients came off study prior to receiving IMRT (9 due to disease progression, 5 due to patient refusal of surgery or RT, 2 for a change in the planned surgical procedure to extrapleural pneumonectomy, and 2 due to complications from chemotherapy). 27 patients initiated IMRT [median dose 4680cGy (range 2880 to 5040cGy)]; one patient had distant disease progression after 16 fractions; all other patients completed their radiation treatment as planned. Eight patients (30%) developed ≥grade 2 RP: 6 patients experienced grade 2 RP with symptom improvement after steroid initiation. Only 2 patients experienced grade 3 RP and were successfully weaned from oxygen after a course of steroids. Other ≥grade 2 radiation-related toxicities included fatigue (41%), nausea (41%), esophagitis (30%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed. The median progression-free and overall survival (OS) was 12.4 and 23.7 months, with a 2-year OS of 59% in resectable and 25% in unresectable patients. Conclusion: Hemithoracic pleural IMRT has an acceptable toxicity profile. Early intervention with steroids appears effective in avoiding severe toxicities of RP. Survival rates of our lung-sparing multimodality regimen were promising for this advanced patient population. This novel radiation technique will be further tested in a multicenter safety study to establish its exportability for the treatment of locally advanced MPM. Keywords: pleural IMRT, pleurectomy/decortication, trimodality therapy, radiation pneumonitis the ipsilateral, contralateral and total lung volumes, all minus GTV, were exported for analysis. The maximum RP grade (Common Terminology Criteria for Adverse Events, V4.0), onset time after treatment start, disease laterality, age, gender and smoking history were obtained from patient records. Correlation of categorical variables with Grade 2 or higher (G2+) and G3+ RP was analyzed with Fishers’ exact test. Preliminary analysis of RP correlation with mean organ dose and percent organ volume receiving dose D (VD) at selected doses was analyzed with the rank-sum test and the Cox model was used for detailed analysis of VD with D in 2 Gy increments. Results: 27 patients had G2+ RP: 13 had Grade 2, 11 Grade 3, 2 Grade 4, 1 Grade 5. Median prescription dose was 46.8 Gy (range 39.6-50.4 Gy), all in 1.8 Gy fractions. Median age was 67.6 y (42-83). There were 79 males, 24 females; 63 patients were former or current smokers, 40 were never-smokers; 44 patients had left-sided disease, 59 had right-sided. No categorical variables were significantly correlated with RP, but there was a trend (p=0.09) for RP3+ more likely for left-sided disease. The Cox model analysis revealed significant correlation (p<0.05) of RP2+ with total lung VD from 12 to 16 Gy, ipsilateral lung VD from 38-44 Gy and heart VD from 36-48 Gy. The best p-values for heart VD were an order of magnitude smaller than those for lung. The rank-sum analysis showed significant correlation of G2+ and G3+ RP with mean heart dose and of G3+ with heart V40. Conclusion: In addition to radiation dose to the lungs, radiation dose to the heart is correlated with symptomatic RP in this large cohort of MPM patients with two lungs treated with hemithoracic pleural IMRT. Heart dose should be kept as low as possible while maintaining target coverage. Continuing analysis will determine specific planning constraints. Keywords: IMRT, radiation pneumonitis, radiotherapy PL05.02: PNEUMONITIS PREDICTORS IN INTENSITY MODULATED RADIATION TREATMENT OF MESOTHELIOMA PATIENTS WITH TWO LUNGS Ellen Yorke1, Anthonia Ojo2, Andrew Jackson3 , Licheng Kuo1, Ming Yan1, Andreas Rimner2 Medical Physics, Memorial Sloan Kettering Cancer Center, New York City, NY, UNITED STATES OF AMERICA, 2Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, UNITED STATES OF AMERICA, 3Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA 1 Objectives: To determine dose-volume and clinical metrics that correlate with symptomatic radiation pneumonitis (RP) in malignant pleural mesothelioma (MPM) patients with two intact lungs uniformly treated with hemithoracic pleural intensity modulated radiation therapy (IMRT). Methods: The treatment plans of 103 consecutive MPM patients treated between 2/2005 and 3/2015 and satisfying the above criteria were recalculated with a superposition-convolution algorithm. The treatments were designed to give the highest prescription < 50.4 Gy that satisfied departmental normal tissue constraints. Dose-volume histograms for the heart and PL05.05: RANDOMIZED PHASE II STUDY OF ADJUVANT WT1 VACCINE FOR MALIGNANT PLEURAL MESOTHELIOMA (MPM) AFTER MULTIMODALITY THERAPY Marjorie G. Zauderer1, Tao Dao1, Valerie Rusch2, Michelle Ginsberg3 , Anne Tsao4 , Katherine Panageas3 , David Scheinberg3 , Lee Krug1 Medicine, Memorial Sloan Kettering Cancer Center, New York, UNITED STATES OF AMERICA, 2Surgery, Memorial Sloan Kettering Cancer Center, New York, UNITED STATES OF AMERICA, 3Memorial Sloan Kettering Cancer Center, New York, UNITED STATES OF AMERICA, 4Md Anderson Cancer Center, The University of Texas, Houston, TX, UNITED STATES OF AMERICA 1 Objectives: The WT1 gene product is highly expressed on tumor cells of numerous cancers and nominally expressed on normal adult tissues. This makes WT1 an ideal candidate for a tumor selective cancer vaccine in malignancies that express WT1, such as mesothelioma. Using four native and synthetic peptide sequences from WT1, a multivalent peptide vaccine was created to stimulate both CD4 and CD8 T cell responses. iMig2016.ORG 9 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Affinity was optimized and the peptides were combined with Montanide adjuvant and co-administered with GM-CSF injected locally. In a pilot trial including patients with previously treated MPM, the vaccine was well-tolerated and CD4/8 immune responses were generated. Subsequently, we began this randomized, double-blind, placebo-controlled, phase II study of the WT1 vaccine in patients with MPM expressing WT1 who completed multimodality therapy. Methods: After surgical resection as well as chemotherapy and/or radiation, patients were randomly assigned to receive Montanide and GM-CSF with or without the WT1 peptide vaccine. Treatment consisted of 6 subcutaneous vaccinations (Montanide, or Montanide with WT1 peptide vaccine) on weeks 0, 2, 4, 6, 8, and 10 beginning within 12 weeks after completing multimodality therapy. Injection sites were prestimulated with GM-CSF on days -2 and 0. Immune responses were evaluated by ELISPOT and T-cell proliferation assays at week 12. Patients were followed for progression with imaging every 3 months with a primary endpoint of 1-year progression-free survival (PFS). Results: 40 patients were randomized (21 on the placebo arm and 19 with the complete WT1 vaccine) from two institutions. Patient characteristics were well balanced between the arms, with a majority of men and epithelioid histology. There were no serious treatment related adverse events. Based on a pre-specified futility analysis of each arm (futility = 10 or more of the first 20 patients experience progression within 1 year), the placebo control arm was closed in May 2015; accrual was stopped and the vaccine arm was closed in November 2015. Median PFS from randomization was 11.4 months (95% CI 4.4-24.3) in the WT1 vaccine arm versus 5.7 months (95% CI 2.7-14.6) in the placebo control arm (hazard ratio 0.69, p=0.3). Similarly, median overall survival (OS) from randomization was 21.4 months (95% CI 8.5-40.4) in the WT1 vaccine arm versus 16.6 months (95% CI 7.7-24.8) in the placebo control arm (hazard ratio 0.52, p=0.14). In the subgroup with R0 resection, median OS was 39.3 months in the vaccine arm and 24.8 in the control arm (p=0.04). PFS and OS were also examined in various subgroups related to their immune response. Conclusion: This randomized, controlled phase II trial demonstrated that administration of this analog WT1 peptide vaccine in MPM was associated with a trend toward improved PFS and OS, though the trial was not originally powered to determine this effect. These results warrant additional better powered, randomized studies to define the optimal use and benefit of this vaccine in the treatment of mesothelioma. Supported by the Department of Defense, the Mesothelioma Applied Research Foundation, the National Cancer Institute, and Sellas Life Sciences Group. Keywords: Immunotherapy, WT1, adjuvant, randomized phase II PL05.06: IMPROVED QUALITY OF LIFE IN PATIENTS UNDERGOING PLEURECTOMY AND DECORTICATION FOR MALIGNANT PLEURAL MESOTHELIOMA Wickii T. Vigneswaran1, Diego Avella Patino2, Diana Kircheva2, Sydeaka Watson2, Aliya Husain3 , Hedy Kindler2, Buerkley Rose2, Amy Durkin2 Thoracic And Cardiovascular Surgery, Loyola University Medical Center, Maywood, UNITED STATES OF AMERICA, 2University of Chicago Medicine, Chicago, IL, UNITED STATES OF AMERICA, 3Department of Pathology, The University of Chicago, Chicago, IL, UNITED STATES OF AMERICA 1 Objectives: Pleurectomy and decortication (PD), a maximal cyto-reductive surgery for Malignant Pleural Mesothelioma (MPM) improves survival in selected patients, in others the survival benefit is modest. In a preliminary review we reported improvement in quality of life (QoL) following PD. We report our findings in a larger cohort of patient with longer follow-up. Methods: Patients undergoing PD were prospectively enrolled between 2010 -2015 to determine the effects of surgery on QoL. EORTC QLQ-C30 was utilized to assess the QOL at baseline, and 1, 4 -5, 7- 8, and 10-11 months (m) postoperatively. Global health, variables in functional domain and variables symptoms domains were investigated. Sub-group analysis were also performed for comparing preoperative performance status (PS, 0 vs 1&2), histology (epithelioid vs non-epithelioid and pathological tumor volume (PV, <600 ml vs >600mls). Survival was summarized using Kaplan-Meier estimates; Log-rank tests were used to compare subgroups. Results: 114 patients were enrolled. Median age: 70 years (range: 50-88). PS0: 35 (30.7%), PS1: 74 (64.9%), PS2: 5 (4.4%). Epithelioid histology: 61 (53.5%), Median volume: 575ml, ranging 100-2200ml, volume<600ml: 58 (50.9%). Overall global health worsened at the first post-operative month (p = 0.0005) returning to baseline at 3-4 months with subsequent improvement. Non epithelioid histology, PS 1&2 and PV > 600mls did not show deterioration at 1 month following PD, and remained unchanged. In functional domain, physical functioning, role functioning and social functioning deteriorated at 1 month, cognitive function was not altered whereas emotional functioning significantly improved. All measures continued to improve during the follow-up. In the symptoms domain pain, fatigue and insomnia were worse at 1 month in all groups but dyspnea was worse only in PS 0, epithelioid and in patients with tumor volume <600 ml. The overall survival was significantly better among patients with epithelioid histology (19.9m p<0.0001), PS 0 (19.1m, p=0.031), and tumor volume <600ml (19.1, p<0.001). Conclusion: Epithelioid histology, good PS, and low tumor volume correlate with good survival in MPM. Improvement in the QoL was observed after the first month and maintained at late follow-up. QoL measures however were not adversely affected by PD at any time in patients with PS 1&2, non-epithelioid histology and tumor volume >600 ml, a trend towards improvement at late follow-up was observed. The net benefit of PD justifies the procedure in majority of patients with MPM. Keywords: pleural mesothelioma, pleurectomy and decortication, quality of life iMig2016.ORG 10 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PL06: THE “IMMUNE WAR” ON MESOTHELIOMA WEDNESDAY, MAY 4, 2016 11:15 – 12:45 PL06.05: THE IMMUNE LANDSCAPE OF HUMAN MESOTHELIOMA TO PREDICT RESPONSE TO ANTIPD1 THERAPY Astero Klabatsa1, Jennifer H. Yearly2, Erin Murphy2, Terri Mcclanahan2, Andrew Kossenkov3 , Daniel Sterman4 , Evan Alley5, Leslie Litzky6 , Edmund Moon7, Steven Albelda1 Division of Pulmonary, Allergy And Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 2Merck & Co., Inc, Kenilworth, NJ, UNITED STATES OF AMERICA, 3Bioinformatics Facility, The Wistar Institute, Philadelphia, PA, UNITED STATES OF AMERICA, 44. pulmonary, Critical Care And Sleep Medicine, NYU Langone Medical Center, NY, NY, UNITED STATES OF AMERICA, 5Haematology/oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 6Pathology And Laboratory Medicine, Hospital of The University of Pennsylvania, Philadelphia, AL, UNITED STATES OF AMERICA, 7Division of Pulmonary, Allergy And Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA 1 Objectives: With the approval of anti-PD1 and anti-CTLA4 antibody therapy for lung cancer and melanoma, there is great interest in using these approaches in mesothelioma, and in fact, early trials have looked encouraging. One major issue to emerge from checkpoint inhibitory therapies is selecting those patients most likely to respond. The biomarker currently being tested is expression of PD-L1 on tumor biopsies, however, in lung cancer, the value of this marker has been controversial. Recently, a more comprehensive classification that takes into account the presence of PD-L1 and tumor infiltrating lymphocytes (TILs) has been proposed (Teng et al, Cancer Res 2015). In this scheme, tumors are divided into four groups: type I (TIL+/ PD-L1+), type 2 (TIL-/PD-L1-), type 3 (TIL-/PD-L1+), and type 4 (TIL+/PD-L1-). Type 1 would be predicted to have the best responses to anti-PD1 therapy and type 2 the worst. Methods: To study the immune landscape of mesothelioma using this scheme, we used nanostring technology to quantify mRNA expression levels of ~600 immune-related genes. We also did immunohistochemical staining for PD-L1 (scored on a 6 point scale). We studied 53 malignant mesothelioma tumors of both epithelioid (72%) and non-epithelioid (28%) histology. Results: 44% of the tumors showed high (>2 on a scale of 0-5) PD-L1 expression. The expression of high PD-L1 was greater on non-epithelioid tumors (67%) than on epithelioid tumors (29%). 15% (8/53) of the tumors were type 1 (TIL+/PDL1+). This group also had the highest expression of PD1. Surprisingly, 6 of the 8 tumors in this group were non-epithelioid. 30% (16/53) tumors were type 2 (TIL-/PD-L1-), a group that would not be expected to respond to checkpoint therapy. 28% (15/53) tumors were type 3 (TIL-/PD-L1+) and 29% (14/53) were type 4 (TIL+/PD-L1-). T cell infiltration was highly linked to expression of the chemokines CXCL9, 10, 11 and CCL5. Macrophage infiltration and IFN-related genes such as IRF7, OAS2, MX1, and STAT1 seemed to be relatively similar in each group. Conclusion: These data show that the immune landscape of mesothelioma is heterogeneous. About 45% of tumors seem to have significant T cell infiltration. 15% of the tumors also have high expression of PD1 and P-DL1 and would thus be predicted to be highly responsive to anti-PD1 or anti-PD-L1 therapy. However, these data are only hypothesis-generating (as this scheme has not yet been validated) and need to be paired with clinical trial data in which the response to anti-PD1 or anti-PD-L1 therapy is determined. Keywords: classification, nanostring, checkpoint inhibitors, immune profile iMig2016.ORG 11 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MINI SYMPOSIUM MS01: MARF INTERNATIONAL MESO UK MINI SYMPOSIUM MONDAY, MAY 2, 2016 14:15 – 15:45 MS01.04: PROGRAMME FOR NURSES TO IMPROVE COMMUNICATION SKILLS IN THE CARE OF PEOPLE WITH MESOTHELIOMA IN JAPAN Yasuko S. Nagamatsu1, Helen Clayson2, Tsuyoshi Matsuda3 programme either very much agree or agree regarding overall satisfaction with the programme, comprehension and relevance. Comments from participants: Apart from the positive feed back of the program, 6 requested further program to improve communication skills including role-play. They reported that high level communication skills were important in 2 particular areas: 1) when, as routine in Japan, the diagnosis is disclosed firstly to relatives who then do not want this information to be given to the patient, and 2) when relatives demand inappropriate radical treatments when the patient has endstage disease. Conclusion: This programme to improve communication skills for nurses caring for people affected by mesothelioma was highly rated by participants. It offers a model that could apply to similar settings. Keywords: education, nursing, communication skill, mesothelioma Nursing, St. Luke’s International University, Tokyo, JAPAN, 2Centre for the Social History of Health and Healthcare, Glasgow, UNITED KINGDOM, 3Kobe University, Kobe, JAPAN 1 Objectives: Malignant Pleural Mesothelioma (MPM) causes 1400 deaths/year in Japan. Following educational programmes about mesothelioma (2 days in 2012 and 1 day in 2013) nurses reported ongoing difficulties in talking with people suffering from mesothelioma, and their relatives. To address this a 1 day communications skills programme was developed in 2014. It included 1) clinical and psychological aspects of MPM, 2) interactive lecture on communication skills including ‘breaking bad news’ ,3) videos illustrating good and bad communication skills 4) narratives of bereaved relatives and 5) group discussion. The aim of this study is to report and evaluate the programme. Methods: Recruitment: Letters of invitation to nurses were sent nationwide to heads or nursing directors of health care facilities. Ethical considerations: Ethical principles were followed: avoiding harm, voluntary participation, anonymity and protection of privacy and personal information. Participants were informed that this program included evaluation. The purpose, procedure and confidentiality of the study were explained verbally at the outset of the course and in written format. Participants were informed that nonparticipation would not disadvantage them. Data were collected from those who wished to participate and who completed the informed consent form. 1. Participants’ satisfaction form: Participants provided feedback regarding the programme by responding to the following four items: 1) satisfaction with the overall program; 2) comprehension of the content and 3) relevance of the content. The programme was evaluated using a 5-point Likert scale (5=very much agree to 1=never agree). Higher scores indicated more positive feedback for the program. 2. Comment form: This was the first educational program about communication skills in MPM therefore, it was important to capture as much feedback as possible. Participants were encouraged to provide written comments about their experience of the program in an open-ended format. Results: Participants : Twenty seven nurses had worked for for 1-35 years (mean = 15.2). Current posts were: respiratory department (8), palliative care (6), OPD (4), home visiting care (2), hospice (2) and health centre (1). Five had no experience of MPM. Participants’ satisfaction: All participants rated the MS01.05: MESOTHELIOMA PATIENTS’ AND CARERS’ CONCERNS ABOUT THEIR DIAGNOSIS, TREATMENT, AND CARE Richard Stephens1, Helen Clayson2, Heather Foot3 , Kate Hill4 , Ian Jarrold5, Katherine Cowan6 , Caroline Whiting6 ex MRC Clinical Trials Unit, London, UNITED KINGDOM, 2Centre for Social History of Health and Healthcare, University of Strathclyde and Glasgow Caledonian University, Glasgow, UNITED KINGDOM, 3(Bereaved Carer), Matlock, UNITED KINGDOM, 4Leeds Institute of Health Sciences, Leeds, UNITED KINGDOM, 5British Lung Foundation, London, UNITED KINGDOM, 6James Lind Alliance, Southampton, UNITED KINGDOM 1 Objectives: In July 2013 the UK Parliament approved measures to increase awareness of, and support research into, mesothelioma. These included a James Lind Alliance (JLA) Priority Setting Partnership (PSP), funded by the National Institute for Health Research (NIHR), which brought together patients and carers, relevant health professionals, and patient support organizations, to identify and prioritize specific interventions that could be tested in a clinical trial setting. The project involved an initial survey to identify areas where research was needed. From the 453 responses 50 unanswered research questions were generated. A second survey prioritized these questions, and the top 30 were taken to a workshop where a final prioritization was agreed. These results have been published1. However, the initial responses also identified numerous issues that fell outwith the remit of the project. The Steering Group of the JLA PSP nonetheless recognized the importance of these issues, and felt that their implementation would significantly improve the experience of mesothelioma patients (and their carers) who have to cope with this devastating disease. Methods: All the responses to the initial survey were reviewed, and those not eligible for inclusion in the original NIHR remit (i.e. a question involving an intervention that could be tested) were grouped under 4 themes proposed by an existing framework for quality of care2. iMig2016.ORG 12 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Results: Patients and carers raised concerns regarding all 4 aspects of care: 1. The medical and technical competence of health professionals (lack of compassion, knowledge and competence) – ‘‘You have mesothelioma and it will kill you within 2 years’ .. words used by my husband’s consultant without preamble’ 2. The physical and technical conditions of the care organisations (inefficient uncoordinated care, poor communication, and lengthy delays) – ‘The inconsistencies are unacceptable. Every mesothelioma patients deserves the best care and treatment. This shouldn’t depend on which hospital you attend’ 3. The degree of identity orientation in attitudes and actions of caregivers (technical complexity of the disease, and supporting patients and carers) – ‘One of my daughters (a nurse) sighed and summed it all up thus ‘we still don’t do dying very well’’ 4. The socio-cultural atmosphere of the care organization – ‘There was a distinct lack of support for us as a family when Dad was diagnosed’ Conclusion: Patients are still being diagnosed with mesothelioma in increasing numbers across the UK, and consequently new therapies and improvements in care are required for people coping with this devastating disease. This JLA PSP survey highlighted many concerns with diagnosis, treatment and care, all of which contribute to patients (and carers) feelings of abandonment, loss, bewilderment and frustration. Many of these issues have been reported previously but remain commonly experienced and unresolved3 . However, addressing these concerns, could, and should, improve the current distressing experience for patients, and help support their families and carers. 1 Stephens RJ et al. Lung Ca 2015, 89, 175-80 2 Wilde B et al. Scand J Caring Sci 1994, 8, 39-48 3 Clayson H et al. Hematol Oncol Clin N Am 2005, 19, 1175-90 Keywords: James Lind Alliance, Quality of Care, Patients and Carers MS01.06: ASBESTOS-RELATED DISEASE SUPPORT GROUPS: A SURVEY OF THEIR ORGANISATIONAL STRUCTURES AND ACTIVITIES Helen Clayson1, Kate M. Hill2 Centre For The Social History Of Health And Healthcare, Glasgow Caledonian University, Glasgow, UNITED KINGDOM, 2Leeds Institute of Helath Sciences, The University of Leeds, LEEDS, UNITED KINGDOM 1 day organisation and operational activity and (2) to develop a survey instrument that could be used to monitor and support group development and impact in the future. Methods: A survey form, developed by the authors in collaboration with the ASVGs Forum UK, was distributed by email in December 2015 to 14 Forum support groups. Nine responses (64%) have been received to date. The survey remains open until 31 January 2016 and it is predicted that the response rate will rise when reminders are sent out in mid-January. Results: The 9 groups were located in areas traditionally associated with substantial industrial use of asbestos. They were set up between 5 and 20 years ago (5-10 years: n=3, >10 years: n=5, 20 years: n=1) by independent health and safety organisations (n=2), trade unions (n=2), occupational health organisation (n=1), bereaved relatives (n=3) and in one case a doctor, in response to unmet needs of people with ARDs, particularly mesothelioma. All the groups provided expert advice and practical assistance with state benefits, usually in people’s homes and by telephone, sometimes on group premises and occasionally by email. All supplied details of expert solicitors. Four held regular meetings for people with ARDs at which benefits advisors, specialist nurses and sometimes solicitors were present, 3 offered medical information and 4 offered bereavement support. Six held annual educational meetings open to patients, healthcare professionals and lawyers. Three groups expressed concerns around sustainability due to insecure funding In 2015 these 9 groups supported 2460 people affected by ARDs including 963 with mesothelioma, 242 with asbestos-related lung cancer, 451 with asbestosis, 1 with laryngeal cancer and 359 bereaved relatives. Conclusion: Forum AVSGs provide essential psychosocial and practical support for a large number of people affected by ARDs, particularly in offering expert assistance with complex financial and legal matters that are a unique and additional burden in mesothelioma and asbestos-related lung cancer. Some groups also provide emotional and practical support for relatives, including in bereavement. The results reveal that a disproportionately small number of people with asbestos-related lung cancer access the groups Activity data demonstrate initiatives, eg bereavement support and education, that could benefit others affected by ARDs and those who support them. Keywords: psychosocial support, asbestos victim support groups, State benefit and civil compensation claims, mesothelioma Objectives: Mesothelioma is a devastating disease that has a high emotional impact on patients, their families and carers. Patient organisations play an important role in the supportive care of patients with asbestos-related diseases (ARDs), especially those with mesothelioma. The psychosocial sequelae and complex benefit and compensation claims associated with mesothelioma have resulted in a need that is not met by standard health and social care services. The Asbestos Victims Support Groups (AVSGs) were founded in response to this unmet need. Members of the AVSGs Forum UK adhere to a set of principles that includes specifying the nature of their relationships with lawyers. The aim of this study was (1) to provide a comprehensive picture of the way Forum AVSGs are set-up, their day-toiMig2016.ORG 13 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS02:CELL DEATH MECHANISMS MONDAY, MAY 2, 2016 14:15 – 15:45 MS02.02: SIGNALLING PATHWAYS INVOLVED IN UPREGULATION OF MCL1 IN MM; METABOLIC REPROGRAMMING PROVIDES A NOVEL APPROACH TO SENSITISE MM novel approach to selectively sensitize malignant mesothelioma cells to targeted agents such as the BH3-mimetic, ABT-737. Keywords: Metabolism, Signal transduction, Cell death, Pre-clinical models MS02.03: MONOAMINE OXYDASE A AS A POTENTIAL NEW TARGET TO TREAT MALIGNANT PLEURAL MESOTHELIOMA Xiao-Ming Sun1, Gareth J. Miles1, Ian R. Powley1, Sara Galavotti1, Tatyana Chernova1, Stefano Grosso1, Jonathan Bennett2, Apostolos Nakas2, Martin Bushell1, Anne E. Willis1, Kelvin Cain1, Marion Macfarlane1 David Roulois, Sophie Deshayes, Marc Grégoire, Christophe Blanquart MRC Toxicology Unit, Leicester, UNITED KINGDOM, 2Glenfield Hospital, UHL NHS Trust, Leicester, UNITED KINGDOM Objectives: Malignant Mesothelioma (MM) is an asbestos-related cancer and is currently resistant to the entire chemotherapeutic regime. In most tumour cells, the Warburg effect (aerobic glycolysis) not only provides building blocks for the synthesis of macromolecules, but also provides tumour cells with a survival advantage via constitutive activation of pro-survival signalling pathways. Understanding the molecular basis of this aerobic glycolysis-mediated pro-survival signalling in MM could provide important new insights to help tackle the widespread resistance of MM to the current regime of cancer chemotherapeutics. Objectives: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. Therapeutic actions are limited mainly due to late diagnosis and resistance of mesothelioma cells to treatments. Given the failure of the current therapies to improve significantly mesothelioma outcome, new strategies need to be developed. Using a transcriptomic approach, we identified monoamine oxidases (MAO) as interesting targets in mesothelioma. MAO are implicated in monoamines catabolism such as serotonin. Two isoforms of MAO have been described: MAO-A and MAO-B. In this work, we assessed the inhibition of these enzymes, alone or in combination with cisplatin, as a new therapeutic option to treat MPM. Methods: A panel of primary malignant mesothelioma (MM) cell lines, freshly-derived from patient tumours (Chernova, Sun et al, Cell Death Differ., in press) were used to assess drug sensitivity and drug resistant mechanisms. MM cells were treated with 2-deoxyglucose (2DG) to inhibit glycolysis. Apoptotic cell death was assayed by FACS, using ΔΨm or PS externalisation. Western blotting and siRNA knockdown of key proteins was carried out according to standard protocols. Oxidative phosphorylation (OCR) and glycolysis (ECAR) were measured in live cells using a Seahorse BioScience XF Analyzer. Freshly-resected 3D tumour explants, cultured ex-vivo, were used to assess the rational combination of potential therapeutic reagents in MM. Methods: This study was performed using our biocollection of MPM cell lines established from pleural effusions of mesothelioma patients. The mRNA expressions were measured using real-time PCR. In a first step, clorgyline was used to inhibit MAO-A and pargyline was used to inhibit MAO-B. Evaluation of toxicity of the treatments was performed by measuring cell viability. Apoptosis was also studied by labelling cells with annexin-V-FITC and propidium iodide, and by measuring mitochondrial potential. In a second step, clorgyline was combined with cisplatin, with primary mesothelial cells used as controls. Finally, the efficacy of the molecules was assessed on spheroids of MPM cells. Results: In this study, we have uncovered a link between aerobic glycolysis and signal transduction that appears to be responsible for increased levels of the anti-apoptotic protein, MCL-1 in MM. Signal transduction analysis revealed that 2DG-induced downregulation of MCL-1 is mediated by inhibition of Stat3-mediated MCL-1 transcription. 2DG also induced a concomitant activation of AKT, by which total MCL-1 degradation was inhibited, possibly through inactivation of GSK-3β. In combination with a specific AKT inhibitor, AZD-5363, complete clonogenic cell death was achieved in the presence of 2DG and the Bcl-2/Bcl-xL inhibitor/BH3-mimetic, ABT-737. Importantly, in MM patient freshly-resected 3D tumour explants, which retain the tumour microenvironment, 2DG/AZD-5363 -mediated downregulation of MCL-1 correlated with induction of tumour cell death. Results: Transcriptomic analysis revealed an increase of the MAO-A/MAO-B expression ratio in MPM cells compared with primary mesothelial cells. The MAO-A inhibitor clorgyline decreased MPM cell viability, whereas the MAO-B inhibitor Pargyline had no effect. The toxicity of clorgyline was related to apoptosis induction. An additive toxicity was observed on MPM cells when clorgyline was combined with cisplatin compared with drugs used alone. The toxicity of the combination was higher on MPM cells than on primary mesothelial cells. Finally, a potentiation of apoptosis induction was observed on spheroids of MPM cells treated with clorgyline and cisplatin, compared with drugs used alone. 1 Conclusion: Down regulation of MCL-1 levels, by inhibition of glycolysis with 2-DG or via 2-DG in combination with other well-tolerated and clinically approved therapeutics, provides a Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm U892, Nantes cedex, FRANCE Conclusion: All these data highlight MAO-A as an interesting new target to treat mesothelioma. Additional investigations on preclinical model are required to validate this hypothesis. Keywords: mesothelioma, Monoamine oxydase, cisplatin, chemotherapy iMig2016.ORG 14 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS02.04: EGFR TYROSINE KINASE INHIBITORS OVERCOME RESISTANCE TO CHEMOTHERAPY IN MALIGNANT PLEURAL MESOTHELIOMA Bernard Staumont1, Chrisostome Costa1, Fabian Vandermeers1, Sathya Neelature Sriramareddy1, Ludovic Dhont1, Céline Mascaux2, Arnaud Scherpereel3 , Bernard Duysinx4 , Renaud Louis4 , Philippe Delvenne5, Pascale Hubert5, Luc Willems1 Molecular And Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège, Liège, BELGIUM, 2Faculty Of Pharmacy, UMRS911, University of Marseille, Marseilles, FRANCE, 3Calmette Hospital, CHRU of Lille and University of Lille II, Lille, FRANCE,4Pneumology, CHU of Liège, Liège, BELGIUM, 5Laboratory of Experimental Pathology, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège, Liège, BELGIUM 1 Objectives: Malignant pleural mesothelioma (MPM) is a cancer of the pleura mainly caused by exposure to asbestos fibers. Current treatments are unsatisfactory due to intrinsic chemoresistance of the tumor. We hypothesized that chemoresistance was due to epigenetic errors and evaluated the ability of HDAC inhibitors to improve treatment efficacy. We previously showed that valproic acid (VPA) improves the first line regimen of MPM both in vitro and in vivo (Vandermeers et al, 2009, Clinical Cancer Research 15: 2818). A clinical trial also demonstrated that VPA in combination with doxorubicin increases the response rate of second line patients (Scherpereel et al, 2011, European Respiratory Journal 37:129). Methods: Transcriptomic profiling was performed by microarray analyses (Agilent). Gene expression was validated by quantitative RT-qPCR. Modulation of TGFα expression was performed by shRNA interference and transfection of a cDNA vector. Onset of apoptosis was assessed with the Annexin V assay. Results: To evaluate the mechanisms associated with the response to chemotherapy, we compared two types of MPM cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Microarray analyses and bioinformatic modeling of gene expression profiles revealed the most relevant candidate genes associated with sensitivity or resistance to this regimen. Among these, TGFa expression was associated with resistance to doxorubicin + VPA in a series of MPM cell lines. Silencing of TGFα by RNA interference in H28 cells correlated with a significant increase in apoptosis. On the other hand, overexpression of TGFα desensitized M14K cells to doxorubicin+VPA -induced apoptosis. Since TGFα interacts with the EGF receptor, we evaluated pharmacological inhibition using EGFR tyrosine kinase inhibitors (erlotinib and gefitinib) and the dual HDAC/EGFR inhibitor CUDC-101. As predicted, these TKI inhibitors improved efficacy of doxorubicin+VPA. MS02.05: TISSUE TRANSGLUTAMINASE (TG2): A POTENTIAL NOVEL TARGET FOR HUMAN MALIGNANT PLEURAL MESOTHELIOMA TREATMENT Sara Zonca1, Giulia Pinton1, Maria Felicia Soluri2, Szilvia Bakó2, Daniele Sblattero3 , Laura Moro1 1 Pharmaceutical Sciences, University of Piemonte Orientale, Novara, ITALY, 2Health Sciences, University of Piemonte Orientale, Novara, ITALY, 3Life Sciences, University of Trieste, Trieste, ITALY Objectives: Characterize the expression and function of Tissue Transglutaminase (TG2) in human malignant pleural mesothelioma (MPM) cell models. Methods: TG2 isoforms expression has been evaluated by Real time-PCR and Western Blot analyses in normal mesothelium and MPM derived cell lines grown under normoxic and hypoxic conditions. Results: We demonstrate that cells derived from biphasic MPM express higher total and surface TG2 levels than cells derived from epithelioid MPM and normal mesothelium. We firstly evidence that the full length TG2-v1 is the highest expressed TG2 isoform both in mesothelial and MPM cells; instead, only low levels of the other described variants (v2, 3, 4 and 5) are expressed. We observe a significant induction of TG2 when MPM cells are grown 48 hours as monolayer in hypoxia or packed in spheroids, where the presence of a hypoxic core is demonstrated. We describe the HIF2 dependent hypoxic induction of TG2. Importantly, while the silencing of TG2 in MPM cells in normoxia causes only a modest reduction in cell viability, its silencing in hypoxia causes a reduction by more than 80%. Furthermore, TG2 silencing results in a marked decrease in MPM spheroids volume. Conclusion: MPM is a tumor with significant areas of hypoxia; understanding of the expression and function of TG2 in the adaptation to the hypoxic environment may provide useful information for novel promising therapeutic option for MPM treatment. Keywords: tissue transglutaminase, hypoxia, Malignant pleural mesothelioma, cell viability Conclusion: Our data demonstrate that TGFα is involved in resistance of MPM to chemotherapy and that TKI inhibitors overcome resistance to second line regimen. Keywords: valproic acid, EGFR TKI, TGFalpha, chemoresistance iMig2016.ORG 15 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS02.06: AUTOPHAGY INHIBITION SENSITIZES PRIMARY MALIGNANT MESOTHELIOMA TO A DUAL PI3K/MTOR INHIBITOR Sara Galavotti1, Tatyana Chernova1, Xiao-Ming Sun1, Ian R. Powley1, Gareth J. Miles1, David Dinsdale1, Jonathan Bennett2, Apostolos Nakas2, Anne E. Willis1, Kelvin Cain1, Marion Macfarlane1 MRC Toxicology Unit, Leicester, UNITED KINGDOM, 2Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UNITED KINGDOM 1 Objectives: Malignant mesothelioma (MM) is a rare, aggressive tumour arising from the mesothelial lining cells of the pleura and commonly associated with asbestos exposure. In MM the phosphatidylinositide-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signalling pathway is constitutively active, promoting tumour growth. Inhibition of mTOR can lead to induction of autophagy and increased resistance to mTOR inhibitors, while inhibition of PI3K alone is insufficient to induce apoptosis. Importantly, a single agent dual inhibitor of PI3K/ mTOR is now feasible due to the development of pan PI3K/ mTOR inhibitors, several of which are currently undergoing clinical trials. Autophagy is an evolutionarily conserved catabolic pathway involved in the degradation of cytoplasmic macromolecules and organelles to satisfy cellular energetic and nutritional needs. Of note, autophagy has been linked to increased resistance to drug treatments, including mTOR inhibitors. Methods: We used a panel of freshly-derived primary mesothelioma cell lines (Chernova, Sun et al, Cell Death Differ., in press) and surgically-resected 3D tumour-explants cultured ex-vivo which retain the tumour microenvironment. Induction of autophagy was confirmed by electron microscopy and autophagic flux measured via western blot (LC3-II/LC3-I) and immunofluorescence/immunohistochemistry. Metabolic profiling was performed using a Seahorse Extracellular Flux Analyser. Cell death was quantified by Annexin V/PI staining or in the case of 3D tumour explants by immunostaining for cleaved PARP. Results: In primary mesothelioma cell lines, we show that dual inhibition of PI3K/mTOR induces substantial autophagy and promotes cell survival. However when autophagy is blocked we observe an increase in cell death which is caspase-independent. Since autophagy is a metabolic process, we explored whether the dual PI3K/mTOR inhibitor had any effect on cellular bioenergetics. Cells treated with the dual inhibitor indeed exhibit reduced levels of ATP and mitochondrial oxidative phosphorylation, confirming the loss of cellular energy homeostasis. Importantly, in 3D tumour-explants freshly resected from MM patients inhibition of autophagy significantly enhances sensitivity to the dual PI3K/mTOR inhibitor. Conclusion: Together, these data suggest a role for autophagy in the modulation of survival in MM and provides a rationale for targeting autophagy in MM patients. In addition, our findings reveal that inhibition of the PI3K/mTOR pathway compromises cellular energy homeostasis unveiling potential metabolic vulnerabilities in MM that could be exploited using combination therapies. MS02.07: AUTOPHAGY CORRELATES WITH PATIENT OUTCOME IN MESOTHELIOMA Carlo Follo1, Dario Barbone1, William G. Richards2, Raphael Bueno2, Courtney Broaddus1 Medicine/pulmonary, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 2Brigham and Women’s Hospital, Boston, MA, UNITED STATES OF AMERICA 1 Objectives: Autophagy, a degradation process that eliminates dysfunctional proteins and organelles and thereby provides energy and amino acids, may play an important role in cancer, although its actual role is still unclear. Understanding the role of autophagy in cancer has been limited by the inability to measure this dynamic process in formalin-fixed tissue. We considered that three-dimensional models including ex vivo tumor, such as we have developed for our research in mesothelioma, would provide valuable insights. Using these models, in which we could inhibit lysosomal proteases to measure the autophagic degradation activity, or autophagic flux, we sought a marker of autophagy that would be valid in formalin-fixed tumor and be used to assess the role of autophagy in patient outcome. Methods: Autophagy was studied in mesothelioma cell lines, as two-dimensional (2D) monolayers and three-dimensional (3D) multicellular spheroids, and in tumor from 25 chemonaive patients, both as ex vivo 3D tumor fragment spheroids (TFS) and as formalin-fixed tissue. Autophagy was evaluated as autophagic flux by detection of the accumulation of a key protein in the autophagic process (LC3) after inhibition of lysosomal proteases. Autophagy was also evaluated as autophagy initiation by detection of ATG13 puncta. ATG13 is a protein involved in the early phase of autophagy, the initiation phase. When autophagy is activated, ATG13 accumulates in structures at the forming autophagic vesicles that can be detected as puncta by immunofluorescence. Results: We found that autophagic flux in 3D, but not in 2D, correlated with ATG13 positivity. In each TFS, ATG13 positivity was similar to that of the original tumor from which the TFS was generated. When tested in tissue microarrays of 109 chemonaive patients, higher ATG13 positivity correlated with better outcome and a longer time to progression and provided prognostic information independent of known prognostic factors. Conclusion: Our results show that ATG13 is a static marker of the autophagic flux in 3D models of mesothelioma and may also reflect autophagy levels in formalin-fixed tumor. If confirmed, this marker would represent a novel prognostic factor for mesothelioma, supporting the notion that autophagy plays an important role in this cancer. In conclusion, we have used 3D models of mesothelioma to identify a marker of autophagy that in turn has prognostic value in a group of patients with mesothelioma. Our hope is to use these models to explore the role of autophagy in this tumor.Research support from the Simmons Mesothelioma Foundation. Keywords: Autophagy, three-dimensional models, outcome, ex vivo Keywords: PI3K/mTOR inhibition, Metabolism, Autophagy, Cell Death iMig2016.ORG 16 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS03: IMAGING AND ENDPOINT EVALUATION MONDAY, MAY 2, 2016 14:15 – 15:45 MS03.01: INDOCYANINE GREEN AND INTRAOPERATIVE IMAGING DETECTS RESIDUAL DISEASE FOLLOWING RESECTION OF MALIGNANT PLEURAL MESOTHELIOMA Jane Keating, Jarrod Predina, Ollin Venegas, Sarah Nims, John Kucharczuk, Sunil Singhal Surgery, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA Objectives: Patients with epithelioid malignant mesothelioma limited to the hemithorax benefit from an approach that includes surgery with the goal of macroscopic complete resection. At the conclusion of surgery, it can be challenging to discriminate residual disease from scar and normal tissue. We propose near-infrared (NIR) intraoperative molecular imaging with indocyanine green (ICG) for the detection of mesothelioma tumor deposits for more complete macroscopic resection. Methods: Eight patients with biopsy proven malignant pleural mesothelioma were enrolled in a pilot clinical trial. All patients underwent 5 mg/kg of intravenous ICG injection. The following day, a NIR imaging device was used to detect fluorescence intraoperatively. After what was believed to be complete tumor excision, the wound bed was reimaged for residual fluorescence indicative of retained tumor, and additional tissue was resected when feasible. Specimens were sent for pathological correlation. Results: All patients underwent ICG injection with no evidence of drug toxicity. NIR fluorescence localized to mesothelioma in all cases intraoperatively and fluorescence was confirmed on the back table. The mean in vivo NIR tumor-to-background ratio was 3.2 (IQR 2.9-3.4). Residual disease was discovered upon wound bed imaging in all 8 patients. The number of resected specimens following wound bed imaging ranged from 1 to 4 (average 1.8). Disease was typically discovered in difficult to reach places, including the costophrenic sulcus and directly beneath or adjacent to the thoracotomy incision. The mean tumor-to-background ratio of the resected residual tumor deposits was 2.8 (IQR 2.6- 3.1). Additionally, these specimens ranged in size from 0.3 mm to 2.2 cm (mean 0.9 cm). In all cases, the additionally resected fluorescent tissue was malignant mesothelioma on pathology. Conclusion: NIR intraoperative molecular imaging using ICG localizes to malignant pleural mesothelioma and aids in detection of residual disease for improved resection. A larger clinical trial is needed to investigate the impact of NIR intraoperative imaging on patient survival. Keywords: Near-Infrared, Intraoperative Imaging, Indocyanine Green MS03.02: THE VALUE OF DELAYED PHASE ENHANCEMENT FOR MAGNETIC RESONANCE IMAGING OF MALIGNANT PLEURAL MESOTHELIOMA Sharyn I. Katz1, Akash Patel2, Ian B. Berger3 , Urooj Khalid3 , Drew A. Torigian2, Charles B. Simone4 , Andrew Haas3 , Evan Alley5, Sunil Singhal6 , Keith A. Cengel4 Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, UNITED STATES OF AMERICA, 2Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, UNITED STATES OF AMERICA, 3University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, UNITED STATES OF AMERICA, 4Radiation Oncology, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 5Haematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 6Surgery, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA 1 Objectives: Radiologic staging of malignant pleural mesothelioma (MPM) on cross-sectional imaging can be challenging when evaluating for the presence of subtle local invasion. Since accurate staging is vital to inform treatment decisions, techniques that optimize pleural imaging are critical. Here we characterize the kinetics of MPM enhancement on magnetic resonance imaging (MRI). Methods: All MPM patients with intravenous (IV) contrast enhanced staging thoracic MRI between 2008-2014 at our institution were retrospectively selected for image analysis. Patients with maximum pleural tumor thickness <1 cm were excluded. Quantitative measurements of tumor signal were obtained on pre-contrast and post-contrast phases where MRI iMig2016.ORG 17 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP acquisition parameters were fixed. Using best-fit model curves, predicted maximum values were determined using a simulation of predicted values. Additionally, a qualitative assessment of tumor enhancement kinetics was performed. Two board-certified thoracic radiologists, blinded to the quantitative imaging data, assessed de-identified side-by-side sets of post-contrast images representing every time point iteration and chose the most conspicuous tumor image. Statistical analysis assessed for correlation between qualitative lesion conspicuity and quantitative tumor enhancement. Results: Of the 23 MPM patients who had undergone staging MRI, 10 patients met the exclusion criteria. Tumor enhancement kinetics of these patients are displayed (Figure 1) as maximal signal intensity as a function of time. Peak tumor enhancement was at 280 seconds(s) following IV contrast administration (Figure 2). At 280s, 70%, 70% and 60% of patients are projected to have reached >80%, >85%, and >90% of respective peak projected signal intensities. There was a correlation between degree of tumor enhancement and subjective lesion conspicuity. Conclusion: Optimal MPM contrast enhancement on MRI occurs at a time later than is typically imaged on routine clinical imaging. The impact of delayed phase enhancement on radiologic MPM staging accuracy and therapy response assessment warrants further study. Keywords: mesothelioma, enhancement, kinetics, Imaging MS03.03: OPTIMISATION OF THE METHODS FOR EARLY CONTRAST ENHANCEMENT (ECE)MAGNETIC RESONANCE IMAGING IN PATIENTS WITH MESOTHELIOMA Selina Tsim1, Catherine A. Humphreys2, David B. Stobo3 , Gordon W. Cowell3 , Rosemary Woodward4 , John E. Foster4 , Craig Dick2, Kevin Blyth1 Respiratory Medicine, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM, 2Pathology, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM, 3Radiology, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM, 4Clinical Research Imaging Facility, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM 1 Objectives: We have previously reported the preliminary diagnostic performance of a novel perfusion-based Magnetic Resonance Imaging (MRI) biomarker of pleural malignancy (PM) – Early Contrast Enhancement (ECE) (Thorax 2015;70:Suppl 3, A16, doi:10.1136/thoraxjnl-2015-207770.27). Here we describe a further analysis, which aims to resolve the potential confounding effect of signal intensity (SI) measurements from interspersed areas of benign pleural disease in patients with PM. Methods: For measurement of ECE, T1-weighted 3D-spoiled-gradient-echo MRI sequences are acquired at baseline, 40 seconds, 80 seconds and 4.5, 9 and 13.5 minutes after intravenous Gadobutrol contrast. SI is measured in up to 15 regions of interest (ROI) on areas of representative parietal pleural disease. ECE is defined objectively as an early peak in SI (≤4.5 minutes). A patient is classified as Malignant if ECE is demonstrated in at least one ROI, even if all others exhibit no ECE. 18 patients had ECE assessed and subsequent histological sampling. ROI SI gradient (ROISIG) can also be calculated, as peak SI - baseline SI divided by time, allowing Receiver Operating Characteristic (ROC) curves to be plotted, summarising discriminate performance across all ROIs. This approach would allow different cut-points to be defined for tailored diagnostic performance in subsequent studies (e.g. higher specificity for screening asbestos-exposed individuals) but does not account for heterogeneous tumour deposition, which is typical of MPM. We hypothesised that the discriminant performance of ROISIG would be improved by excluding ECE-negative ROI, if these were areas of interspersed benign disease. To test this, we plotted a ROC curve incorporating all ROISIG data and compared this to one incorporating only data from ECE-positive ROI in patients with PM. In both analyses all ROI were included in patients with benign disease. Results: Mean patient age was 73 (± 8) years. 12/18 had pleural thickening ≤10mm. ECE was present in 10/11 patients iMig2016.ORG 18 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP with PM (MPM (n=10); lung cancer (n=1)) and absent in 6/7 patients with benign disease (BAPE (n=4), fibrothorax (n=2), TB (n=1)). As previously reported, ECE demonstrated sensitivity of 91%, specificity 86%, negative predictive value 86%, positive predictive value 91% and Inter-observer agreement 0.766. ROC curves are shown in Figure 1. Conclusion: In a previously presented pilot study we have shown that ECE can be assessed in patients with minimal pleural thickening, with encouraging preliminary diagnostic results. These additional analyses suggest that exclusion of ECE-negative ROI improves the discriminant performance of ROISIG, probably because these areas represent interspersed benign disease, and may enhance the method. Keywords: Biomarkers, Imaging iMig2016.ORG 19 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS03.04: HISTOGRAM ANALYSIS OF DW-MRI DATA DURING EARLY CHEMOTHERAPY RESPONSE PREDICTS OUTCOME OF INOPERABLE MPM PATIENTS Johan Coolen1, Frederik Dekeyzer1, Philippe Nafteux1, Adriana Dubbeldam1, Walter De Wever1, Angela Botticella2, Lieven Depypere3 , Hans Van Veer3 , Herbert Decaluwé3 , Eric Verbeken4 , Stephanie Peeters2, Christophe Dooms5, Johan Vansteenkiste5, Willy Coosemans3 , Paul De Leyn3 , Dirk Van Raemdonck3 , Kristiaan Nackaerts5, Vincent Vandecaveye1, Johny Verschakelen1 Radiology, University Hospitals of Leuven, LEUVEN, BELGIUM, 2Radiotherapy, University Hospitals of Leuven, LEUVEN, BELGIUM, 3Thoracic Surgery, University Hospitals of Leuven, LEUVEN, BELGIUM, 4Pathology, University Hospitals of Leuven, LEUVEN, BELGIUM, 5Pneumology, University Hospitals of Leuven, LEUVEN, BELGIUM 1 Objectives: Patients with unresectable malignant pleural mesothelioma (MPM) are most commonly treated with palliative chemotherapy (PCT), while treatment efficacy is radiologically monitored using modified RECIST criteria. However, anatomy-based assessments have limitations, one of the reasons why determination of progression free survival (PFS) is often difficult. Even multiparametric MR imaging (mpMRI) parameters can be insufficient for differentiating long-term and shortterm surviving patients, probably due to the large heterogeneity of disease phenotypes, which deeply influences response to therapy and imaging evaluation. In this study we examined the diffusion-weighted MR imaging (DWI) values evaluating five histogram parameters (volume[V], mean[ME], standard deviation[SD], skewness[SK], and kurtosis[KU]). Methods: Fifteen patients with inoperable MPM were selected for systemic PCT (cisplatin-pemetrexed). MR examinations (including DWI with 6 b-values) were performed at baseline[BA] and after one month, just before the second chemotherapy session [DU]. ADC histograms were made for the ADCavg (calculated from all 6 b-values) and the ADClow (calculated from the first 3 b-values ranging from 0 to 100 s/mm²), and first order histogram statistics (V, ME, SD, SK, and KU) were checked for differences between long-term and short-term PFS (cut-off: 170 days) and overall survival (OS, cut-off: 440 days). Mann-Whitney U tests were used to check for differences. Results: When using baseline parameters for differentiating between long- and short-term OS, ADClow[BA]KU and ADClow[BA]SK were significantly different (p=0.004 and 0.006) with thresholds of 8.25 and 2.25, respectively (higher parameter values indicated shorter OS). Also, higher baseline volumes (V) were indicative of shorter OS (p=0.009, threshold 772 ml). Similar findings were seen at the follow-up time point, where ADClow[DU]ME, ADClow[DU]KU, and ADClow[DU]SK where significantly different between long-and short-term OS patients, with p-values of 0.004, 0.02, and 0.014, respectively. Lower ADClow[DU]ME (threshold: 3.25 x10-3mm²/s), and higher ADClow[DU]KU (threshold: 10) and ADClow[DU]SK (threshold: 2.3) were indicative of shorter OS. Again, higher lesion volumes (V) during follow-up were indicative of shorter OS (p=0.009, threshold 386 ml). As expected, the results for differentiating between long- and short-term PFS were less encouraging, with only ADCavg[BA]KU and ADClow[DU]ME nearing, but not reaching, significant values (p=0.054 and 0.07, respectively). Optimal thresholds of both parameters were 4.25 and 3.25 x10-3mm²/s, with lower ADCavg[BA]KU and ADClow[DU]ME projecting shorter PFS. Conclusion: Histogram analysis of ADC parameters during early PCT of inoperable MPM patients can differentiate between patients with long-term and short-term OS, although PFS separation is less accurate. These findings show that first order histogram analysis of DWI data could be a useful tool for personalized care in patients with inoperable MPM. However, these preliminary data need confirmation in larger patient groups. Keywords: Diffusion weighted resonance imaging, biomarker, inoperable MPM, Histogram Analysis MS03.05: CORRELATION OF CT SCAN BASED TUMOR VOLUME MEASUREMENT TO ACTUAL RESECTED TUMOR WEIGHT: A NEW T-FACTOR? Isabelle Opitz1, Martina Friess1, Thi Dan Linh Nguyen-Kim2, Thomas Frauenfelder2, Sven Hillinger1, Burkhardt Seifert3 , Ilhan Inci1, Walter Weder1 Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 2Institute of Diagnostic And Interventional Radiology, University Hospital Zurich, Zurich, SWITZERLAND, 3Department of Biostatistics, Epidemiology, Biostatistics And Prevention Unit, University of Zurich, Zurich, SWITZERLAND 1 Objectives: Tumor volume has been reported several times to be a valuable prognosticator for malignant pleural mesothelioma (MPM) survival (Pass 1998, Opitz 2015). We wanted to assess the precision of CT scan based preoperatively measured tumor volume when correlated to the actual resected tumor weight during macroscopic complete resection and their impact on overall survival. Methods: From October 2012 until November 2015 the tumor weight of surgery specimens was measured in 27 patients undergoing macroscopic complete resection. 26 patients were male (96%), 25 MPM showed epithelioid type (96%) and the median age at surgery was 66 years (range 41-77). Twenty-two patients underwent induction chemotherapy prior to surgery. In all 27 patients tumor volume was measured in the CT or PET-CT scans performed before surgery as described previously (Frauenfelder 2011). Relations between tumor weight and volume were analyzed using Pearson correlation. Tumor volume and tumor weight were also tested for correlation with pT stage using Spearman ranks correlation. Post-hoc comparisons between stages were performed using the Mann-Whitney U test. Association of dichotomized tumor volume and weight with overall survival (OS) was evaluated using the log rank test. Results: The median tumor volume assessed by CT scan was 79 ml and the median tumor weight 520 g. The analysis revealed a correlation between tumor volume and weight (r=0.53, p=0.005). There was also a significant correlation of tumor volume (p=0.001) as well as tumor weight (p<0.0005) with the pT-stage (Figure 1). No significant association of tumor volume and weight with OS was found but 82% of the cases iMig2016.ORG 20 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP were censored. Figure 1: Box plot showing association of pT stage with tumor volume (A) and weight (B) using Mann-Whitney U test. Conclusion: The preoperative assessed tumor volume in CT scan seems to be a valuable descriptor of actual tumor volume to be resected and might be a reliable future T-descriptor. Keywords: CT scan, tumor volume, tumor weight, TNM staging MS03.06: DYNAMIC CONTRAST-ENHANCED CT FOR THE ASSESSMENT OF TUMOR RESPONSE IN MALIGNANT PLEURAL MESOTHELIOMA: A PILOT STUDY Eyjolfur Gudmundsson1, Sam Armato1, Zacariah E. Labby2, Christopher M. Straus1, Feng Li1, Hedy Kindler1 Department of Radiology, University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 2Department of Human Oncology, University of Wisconsin, Madison, WI, UNITED STATES OF AMERICA 1 Objectives: Few investigations have been made into the use of imaging-derived hemodynamic parameters for the assessment of tumor response in malignant pleural mesothelioma (MPM) patients. The objective of this study was to evaluate the utility of dynamic contrast-enhanced computed tomography (DCE-CT) in the assessment of MPM tumor response. Methods: The standard CT imaging protocol for MPM was modified to include a DCE-CT component, during which a 55mm axial extent of thoracic anatomy demonstrating notable tumor burden was imaged at specific time points following the start of contrast injection. The image-acquisition protocol included two dynamic contrast-enhanced phases, one prior to and one following a standard CT scan of the full chest. 16 patients were evaluated: eight on treatment, eight on observation. Each patient underwent two DCE-CT scans at approximately 3-month intervals. To capture tumor burden in each scan, modified RECIST measurements were obtained manually by a research radiologist, and CT-based volume measurements were obtained using a semi-automated in-house method. To define a region of interest for the computation of hemodynamic parameters, visible tumor was manually contoured on the images from a single time point of the dynamic contrast-enhanced phases of each scan; these contours were automatically propagated across all time points using a deformable image registration technique. Perfusion, peak CT value enhancement, iMig2016.ORG 21 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP blood volume, and time to peak enhancement were calculated from the contrast uptake curves obtained from each pixel within the tumor contours. Mean changes in these parameters were calculated between the two DCE-CT scans, and these parameter changes were compared between the on-treatment and on-observation cohorts. Results: Although changes in hemodynamic parameters were not significantly different between the two patient cohorts for any of the measured parameters, patients on treatment demonstrated a mean relative decrease in blood volume and perfusion (-14.2% and -17.2%, respectively) compared with a mean relative increase in these parameters (+8.8% and +27.0%, respectively) for patients on observation. No statistically significant correlation was found between relative change in hemodynamic parameters and changes in tumor size, either by modified RECIST or tumor volume. MS04: CELL AND VACCINE BASED THERAPY MONDAY, MAY 2, 2016 14:15 – 15:45 MS04.02: EXPERIMENTAL MODELS OF HUMAN MALIGNANT MESOTHELIOMA IN NOD SCID MICE AND NUDE RATS FOR EVALUATION OF IN VIVO VIROTHERAPY Joëlle Nader1, Nicolas Boisgerault1, Carole Achard1, Tiphaine Delaunay1, Myriam Robard2, Jean-François Fonteneau1, Frédéric Tangy3 , Marc Grégoire1, Daniel L. Pouliquen1 UMR 892 INSERM / 6299 CNRS, Nantes, FRANCE, 2Plateforme MicroPICell, SFR F. Bonamy, Nantes, FRANCE, 3Unité de Génomique Virale et Vaccination, Institut Pasteur, Paris, FRANCE 1 Geometric mean of relative changes Δ in DCE-CT parameters from first scan to second scan for the two patient cohorts. p-values were calculated using a Student’s t-test. DCE-CT Parameter ΔTreatment ΔObservation p-value Perfusion -17.2% +27.0% 0.14 Peak Enhancement -8.4% +1.1% 0.51 Blood Volume -14.2% +8.8% 0.21 Time to Peak +0.2% -17.2% 0.80 Conclusion: Hemodynamic parameters were computed from DCE-CT scans acquired at two time points from MPM patients. Observed differences in hemodynamic parameter changes between patients on treatment and patients on observation suggest that DCE-CT could be a useful imaging modality for the assessment of tumor response. The significance of these trends should be investigated through future studies with larger numbers of patients and focused therapeutic regimens. Keywords: imaging, CT, pleural mesothelioma, perfusion Objectives: Oncolytic viruses are now considered as a new therapeutic strategy against several cancers, as they are capable of both preferential toxicity against tumor cells and simultaneous activation of the host anti-tumor immunity. Previous studies have demonstrated that attenuated strains of measles virus (MV) can infect and kill different cell lines of human malignant mesothelioma (MM) in vitro. In this study, we present a human MM cell line that produces tumors in the peritoneal cavity of immunodeficient mice and rats, which represent two interesting models for the evaluation of anti-tumor virotherapy in vivo. Methods: The Meso 34 cell line belongs to a human biocollection of MM cell lines established from the pleural effusions of patients and validated by the French MESR (n° DC-2011-1399, CNIL n° 1657097). About 5x106 cells were injected intraperitoneally to NOD SCID mice and Nude rats. The MV Schwarz strain and a modified strain with enhanced pro-apoptotic properties (MV-deltaC) were provided by Dr Frédéric Tangy (Institut Pasteur). The viruses were injected i.p. with a single dose (2.105 TCID50) 8 weeks after tumor challenge. Animals were sacrificed 15 days after virus injection and tumor mass was evaluated. Results: Eight weeks after tumor challenge, macroscopic tumors were present in both species as an omental cake together with metastatic nodules attached to the diaphragm, liver and spleen. A clear decrease of the tumor mass was observed in MV and MV-deltaC groups. Tumor regressions were even more important in the latter compared to the controls. Preliminary histological analysis revealed a modification of tumor cell morphology and tumor density after virus infection, with numerous zones of necrosis especially in the MV-deltaC group. Conclusion: Our preliminary results demonstrate for the first time that after one single intracavitary administration, both MV and its genetically-modified variant infect and kill human MM cells in vivo. Additionally, MV-deltaC, which shows enhanced pro-apoptotic properties compared with MV, induced a more significant decrease of the total tumor mass compared with untreated mice. Meso 34 tumors transplanted in the nude rat could also represent an interesting model to investigate the effects of adoptive immunotherapy with human immune cells. Keywords: Virotherapy, Animal model, Human cell line, Oncolytic measles virus iMig2016.ORG 22 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS04.03: TUMOUR SUPPRESSOR MICRORNAS REGULATE PD-L1 EXPRESSION IN MALIGNANT PLEURAL MESOTHELIOMA Marissa Williams1, Steven Kao1, Wendy A. Cooper2, Yuen Yee Cheng1, Michaela B. Kirschner3 , Jason Madore2, Trina Lum4 , Anthony Linton1, Brian C. Mccaughan5, Sonja Klebe6 , Nico Van Zandwijk1, Richard A. Scolyer7, Michael Boyer8 , Glen Reid1 Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA, 2Sydney Medical School, The University of Sydney, Sydney, NSW, AUSTRALIA, 3Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 4Department of Tissue Pathology And Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, AUSTRALIA, 5Sydney Cardiothoracic Surgeons, RPA Medical Centre, Sydney, NSW, AUSTRALIA, 6Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, SA, AUSTRALIA, 7Department of Medical Oncology, Concord Cancer Centre, Sydney, NSW, AUSTRALIA, 8Chris O’brien Lifehouse, University of Sydney, Camperdown, NSW, AUSTRALIA 1 Objectives: Programmed death 1 (PD-1) and its ligand PD-L1 have significant roles in suppressing host immune response in many cancer types. As in other cancers,PD-L1 expression is upregulated and associated with poor prognosis in malignant pleural mesothelioma (MPM) but the mechanisms causing its dysregulation are poorly understood. Characterization of the mechanisms leading to PD-L1 upregulation could improve the understanding of its dysregulation in MPM and give depth to its prognostic significance. Methods: Tissue Microarrays were constructed from formalin-fixed paraffin-embedded (FFPE) tissue blocks from patients that underwent pleurectomy ± decortication (P/D). PD-L1 protein expression in patient and cell line samples was analysed using a commercially available PD-L1 immunohistochemistry assay. RT-qPCR was used to assess microRNA expression in tumour samples with specific Taqman probe-based assays. MPM cell lines were reverse-transfected with synthetic microRNA mimics and siRNAs using Lipofectamine RNAiMAX. RNA was extracted using TRIzol and mRNA levels of PD-L1 and IRF-1 were determined using RT-qPCR and designed primers. Results: We first established the prevalence of PD-L1 expression in a series of 72 MPM patients and found 18 (25%) had positive PD-L1 staining that was more common in the non-epithelioid subtype (p=0.01), also, PD-L1 expression was associated with poor survival (median OS: 4 vs. 9.2 months, positive and negative PD-L1 respectively; p<0.001) and its prognostic significance was confirmed using the Cox Regression model after adjustment for gender, age and histological subtype (HR 2.2, 95% CI: 1.2-4.1; p<0.01). Reduced microRNA expression was related to elevated PD-L1 levels in the MPM patient panel, with previously identified tumour suppressor microRNAs in MPM showing downregulation in PD-L1 positive tumours. The median microRNA levels of miR-15b, miR-16, miR-193-3p, miR-195 and miR-200c were shown to be significantly lower in PD-L1 positive (N=13) than in the PD-L1 negative samples (N=50). miR-15a and miR-16 are both predicted to target the 3’UTR region of PD-L1, to characterize their regulatory affect, we restored their expression in MPM cell lines which led to downregulation of PD-L1 mRNA and protein expression. Transfection with miR193a-3p indirectly downregulated PD-L1 mRNA expression via its regulation of IRF-1, a known transcriptional inducer of PD-L1. This transcriptional regulation was further supported by the reduction of PDL-1 mRNA upon transfection with IRF-1 specific siRNAs. Furthermore, transfection with miR-15a and miR-16 were also shown to reduce IRF-1 expression in MPM cell lines, suggesting both direct and indirect regulation of PD-L1 expression by tumour suppressor microRNAs in MPM. Conclusion: This study has confirmed PD-L1 to be an adverse prognostic indicator in MPM. Elevated PD-L1 expression in MPM patient samples was correlated to downregulation of tumour suppressor microRNAs that were shown to directly and indirectly regulate PD-L1 expression in vitro. Keywords: tumour suppressor, microRNA, mesothelioma, PD-L1 MS04.04: PD-1+ T CELLS IN MESOTHELIOMA EFFUSIONS INDUCE TUMOR PD-L1 EXPRESSION MAKING THEM SUSCEPTIBLE TO AVELUMAB MEDIATED ADCC Swati Khanna1, Anish Thomas1, Daniel Abate-Daga2, Jingli Zhang1, Betsy Morrow1, Seth Steinberg3 , Augusto Orlandi4 , Patrizia Ferroni5, Jeffrey Schlom6 , Fiorella Guadagni5, Raffit Hassan1 Thoracic And Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA, 2Moffitt Cancer Center, Tampa, UNITED STATES OF AMERICA, 3Biostatistics And Data Management Section, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA, 4Anatomic Pathology, Dept Of Biomedicine And Prevention, University of Rome, Rome, ITALY, 5Rome And Biodat (biomarker Discovery And Advanced Technologies), Sr Research Center, University San Raffaele, Rome, ITALY, 6Laboratory of Tumor Immunology And Biology, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA 1 Objectives: To evaluate expression of programmed cell death 1 (PD-1) and PD ligand 1 (PD-L1) in patients with pleural and peritoneal mesothelioma, as well as their interactions in malignant effusions and peripheral blood. In addition, we wanted to investigate the role of avelumab, a fully humanized IgG1 anti-PD-L1 antibody, in mediating antibody dependent cellular cytotoxicity (ADCC) of PD-L1 expressing tumor cells by NK cells. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues from 44 peritoneal and 21 pleural mesothelioma patients were tested for PD-L1 expression using anti-PD-L1 rabbit monoclonal antibody (MKP-1B-196-10-Merck-Serono). Staining was recorded as positive if ≥5% of the tumor cells had membrane PD-L1 expression. All autologous tumor cells and immune cells (T, Monocytes and NK) were derived from either ascites or pleural fluid of mesothelioma patients. The PD-1 and PD-L1 positivity of T cells in paired blood and malignant effusion samples (n=3) were evaluated by flow cytometry. For co-culture studies, ascites from a mesothelioma patient (NCI-Meso29) was used as a source of lymphocytes and tumor cells. Lymphoid cells growing in suspension were tested for recognition of autologous tumor cells by IFN-γ release upon overnight co-culture. iMig2016.ORG 23 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP For ADCC experiments Carboxyfluorescein succinimidyl ester stained NK cells were cultured with autologous or allogeneic primary mesothelioma tumor cell lines (n=3; NCI-Meso21, NCI-Meso29, NCI-Meso49) at different effector target ratio with 20 ng/mL of avelumab for 4 h. The cultured cells were stained with 7-AAD and analyzed on a flow cytometer for detection of % specific lysis of tumor cells. Results: Out of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1 positive including 31 of 41 (76%) patients with peritoneal mesothelioma. A trend for inferior overall survival in patients with PD-L1 positive tumors was found, although the difference did not reach statistical significance (median 23.0 vs. 33.3 months; p=0.35). The fraction of cells expressing PD-L1 in malignant mesothelioma effusions ranged from ~12 to 43%. Two of the 3 patients with paired effusion and blood samples had high PD-1 expression on both CD4+ and CD8+ T cells (23.8%, 42.1% vs. 13.1%, 6.43%, respectively) present in effusion compared to peripheral blood. In addition, all 3 patients had higher PD-L1 expression on CD3+ T cells present in malignant effusions compared with those present in peripheral blood (7.5±2.6 % vs. 1.9±1.2%, respectively). Autologous lymphocytes present in the malignant effusion recognized tumor cells and induced IFN-γ-mediated PD-L1 expression on the tumor cell surface. Out of 3 primary mesothelioma cell lines tested, two (NCI-Meso21 and NCI-Meso29) were susceptible to ADCC by allogeneic and autologous NK cells, respectively in presence of avelumab with specific lysis of 12% and 23%, respectively at E:T ratio of 25:1. Conclusion: PD-L1 is highly expressed on tumor tissue as well as on malignant cells in ascites and pleural effusions of patients with peritoneal and pleural mesothelioma. In addition, PD-1+ T cells in malignant effusion induce tumor PD-L1 expression and, in presence of the anti-PD-L1 antibody avelumab, are susceptible to NK cell mediated cytotoxicity. Keywords: PD-1 PD-L1 checkpoint, Malignant effusions, Antibody dependent cellular cytotoxicity, mesothelioma MS04.05: HARNESSING THE IMMUNE SYSTEM-ADJUVANT IMMUNOTHERAPY FOR MESOTHELIOMA Methods: We developed a murine model of mesothelioma debulking surgery to evaluate several clinically available immunotherapy approaches (immuno-gene therapy with Ad.mIFNa and COX-2 inhibition with Celebrex) and to optimize dosing and timing strategies. Outcomes were assessed for overall survival and recurrent tumor burden. Flow Cytometry and in vivo neutralization assays were utilized to determine immune responses. Results: As compared to mice receiving a control vector, mice randomized to neoadjuvant Ad.mIFNa were associated with a 64% reduction in tumor volume at post-operative-day 14 (420mm3 vs. 1183 mm3; p<0.01) and were associated with an increase in median postoperative survival (34 days vs. 18 days, p =0.003). In vivo tumor neutralization assays demonstrated that the cytotoxic activity of CD8+ T-cells drove this response. The addition of Celebrex to adjuvant Ad.mIFNa improved potency and nearly tripled median post-operative survival as compared to controls (48 days vs 17 days;p =0.002). Additionally, 40% of mice receiving combination immunotherapy with surgery were cured vs. none in monotherapy groups (p =0.03). Mice receiving both Ad.mIFNa and Celebrex had markedly increased CD8+ T-cell trafficking in recurrent tumors. Conclusion: This evidence supports a new approach to mesothelioma which includes multi-modal immunotherapy with surgical debulking. We plan to use this preclinical data to develop a Phase I Clinical Trial incorporating immunotherapy with surgery for mesothelioma patients. Keywords: Immunotherapy, mesothelioma, Surgery MS04.06: INTRAPLEURAL MODIFIED VACCINE STRAIN MEASLES VIRUS THERAPY FOR PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA - A PHASE I TRIAL Tobias Peikert1, Sumithra Mandrekar1, Aaron S. Mansfield1, Virginia Van Keulen1, Steven Albelda2, Ileana Aderca1, Sephanie Carlson1, Allen Dietz1, Mike Gustafson1, Robert Kratzke3 , Val Lowe1, Fabien Maldonado4 , Julian Molina1, Manish Patel3 , Anja Roden1, Angelina Tan1, Evanthia Galanis1 Mayo Clinic, Rochester, UNITED STATES OF AMERICA, 2University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 3University of Minnesota, Minneapolis, MN, UNITED STATES OF AMERICA, 4Vanderbilt University, Nashville, TN, UNITED STATES OF AMERICA 1 Jarrod Predina1, Jane Keating2, Sarah Nims2, Ollin Venegas2, Daniel Sterman3 , Sunil Singhal2, Steven Albelda1 University of Pennsylvania School of Medicine, Philadelphia, UNITED STATES OF AMERICA, 2Thoracic Surgery, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 34. pulmonary, Critical Care And Sleep Medicine, NYU Langone Medical Center, NY, NY, UNITED STATES OF AMERICA 1 Objectives: Our group has been interested in immunotherapy for mesothelioma for nearly three decades. In our experiences, the most important predictor of immunotherapy response in human trials has been minimal disease at the time of drug delivery. With this in mind, we have hypothesized that “adjuvant” immunotherapy with debulking surgery can improve immunotherapy efficacy and long-term response rates. Objectives: Malignant pleural mesothelioma (MM) remains an almost universally fatal disease with limited treatment options. Preclinical models indicate the preferential oncolytic activity of the modified vaccine strain measles virus (MV) carrying the gene for the human sodium-iodine symporter (NIS) – MV-NIS. Furthermore the intraperitoneal and intravenous administration of MV-NIS was recently found to be safe and potentially effective in patients with refractory ovarian cancer and multiple myeloma respectively. However, whether MV-NIS is directly oncolytic or triggers an anti-tumor immune response in patients iMig2016.ORG 24 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP is unclear. Methods: We conducted a Phase I dose escalation study with 3+3 design. MV-NIS was administered as first or second line therapy via a tunneled intrapleural catheter to patients with MM. MV-NIS dose ranged from 108 TICID 50 (Level 1) to 9 x 109 TICID 50 (Level 4). In the absence of dose limiting toxicity and disease progression MV-NIS therapy was continued for up to six cycles. MV-NIS infection and replication were monitored by Iodine123 SPECT/CT as well as by RT-PCR and/or plaque-assay. Anti-tumor immunity was monitored in the blood and pleural fluid and patients were followed clinically by chest CT using the modified RECIST criteria for MM. Results: Twelve patients (3 patients per dose levels 1-4) received MV-NIS therapy. There were no dose limiting adverse events and therapy was well tolerated. The best therapeutic response was stable disease, which was achieved by 8/12 patients (67%). Overall survival demonstrated a median survival of 449 days (~15 months) (5/12 patients are still alive). Progression free survival was 62 days (~2 months). (Figure 1.) MV infection and replication were detectable by RT-PCR and plaque assay in the pleural fluid between 24-72 hours after treatment. I123 SPECT-CT only demonstrated marginal viral gene expression in a single patient treated with the highest dose level. MV-NIS therapy effectively boosted pre-existing anti-MV neutralizing antibody responses in the plasma and pleural fluid of most patients. We observed a transient intense inflammatory response in the pleural space after MV-NIS administration. In addition activation of cellular and humeral immunity (induction or boosting of anti-tumor antibody responses) was observed. Conclusion: The intrapleural administration of MV-NIS is safe, resulted in stable disease for 67% of patients and may be associated with favorable overall survival in MM. While there is only transient infection and viral replication, we have observed the induction of anti-tumor immune responses. The study will continue with a maximum tolerated dose expansion cohort. Keywords: measles virus, virotherapy, tumor vaccine, mesothelioma therapy iMig2016.ORG 25 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS04.07: NIVOLUMAB IN MALIGNANT PLEURAL MESOTHELIOMA (NIVOMES): AN INTERIM ANALYSIS Josine Quispel-Janssen, Marion Zimmerman, Wieneke Buikhuisen, Sjaak Burgers, Giulia Zago, Paul Baas Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, NETHERLANDS Objectives: Malignant pleural mesothelioma (MPM) is well known for its resistance to therapy. No studies in second line have yet resulted in an improvement of overall survival. Immunotherapy has attracted attention since lymphocyte infiltrates are present in many cases of mesothelioma, and PD-L1 expression has been reported in 13% of epithelioid mesothelioma and 38-100% of the sarcomatoid type. Nivolumab is a monoclonal antibody that binds PD-1 on activated immune cells and disrupts binding of PD-1 to its ligand PD-L1, thereby preventing down regulation of T-cells and augmenting the host antitumor response. Here we describe the clinical results of an interim analysis of a translational study (NivoMes trial). Methods: In this single center, Simon two-stage, phase II study, patients with progression after first line chemotherapy, are treated with nivolumab 3mg/kg i.v. every two weeks. Primary endpoint is disease control rate (DCR) at 12 weeks. Secondary endpoints include overall survival and progression free survival. Patients underwent repeat biopsies at start and after 3 courses of treatment for biomarker research. PD-L1 status is not determined upfront. A total of 33 patients will be recruited. An interim analysis is performed as planned. Results: Eighteen patients were evaluated for the interim evaluation after 12 weeks of treatment. Seven patients showed disease control (39%): five patients had a partial response (PR) and two stable disease. Two patients had pseudoprogression prior to a partial response. Nine patients had progressive disease. Two patients showed a mixed response but continued treatment because of clinical benefit. Currently, the follow up is too short to determine whether the sites of growth are due to real progression or pseudoprogression. Toxicity so far was mostly mild and manageable. One patient presented with progression after one course and discontinued treatment due to toxicity (grade 3 nausea and grade 3 pneumonitis). He was treated successfully with oral steroids and subsequently a PR was observed. A second patient with initial progression was hospitalized due to pneumonitis and pericardial tamponade. He completely recovered after oral steroids and pericardial drainage. Upon retreatment, a partial response was noted which is currently ongoing. Conclusion: Preliminary results show promising activity of nivolumab in malignant pleural mesothelioma and a manageable toxicity profile. Keywords: Immune checkpoint inhibitor, nivolumab, anti-PD1 MS04.08: IMMUNE RESPONSES FOLLOWING INTRAPLEURAL ADMINISTRATION OF ONCOLYTIC HSV1716 IN PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA Joe Conner1, Kirsty Learmonth1, Lynne Braidwood1, Penella Woll2, Chelsea Bolyard3 , Balveen Kaur3 , Kevin Blyth4 Virttu Biologics Ltd, Glasgow, UNITED KINGDOM, 2University of Sheffield, Sheffield Teaching Hospitals, Sheffield, UNITED KINGDOM, 3Ohio State University, Columbus, OH, UNITED STATES OF AMERICA, 4Respiratory Medicine, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM 1 Objectives: HSV1716 (Seprehvir) is an oncolytic immunotherapeutic herpes simplex virus type 1 mutant deleted in the gene encoding the neurovirulence factor ICP34.5. Mutants lacking ICP34.5 are selectively replication competent in cancer cells and induce anti-tumour immune responses. Data supporting immune-mediated efficacy stimulated by treatment with HSV1716 includes pre-clinical evidence of Th1 cytokine/chemokine responses that facilitate systemic anti-tumour immune responses via cytotoxic T cells that also reduce the establishment of metastases and protect from re-challenge. Recent evidence from mesothelioma patients post HSV1716 treatment supports this immunotherapy activity with robust Th1 cytokine responses detected in pleural fluids, evidence of immune cell infiltration and activity and the development of a novel anti-tumour IgG immune response. Methods: A phase I/IIa trial to determine the safety and potential for efficacy of HSV1716 given intrapleurally to patients with MPM is currently ongoing. Patients receive 1x107iu HSV1716 through their pleural catheter on one, two or four occasions a week apart, in three separate patient cohorts. To date 10 patients have been treated, 3 in the one and two dose and 4 in the four dose cohorts and HSV1716 has been well-tolerated with few adverse events in any patients. Pleural fluid and plasma samples have been collected pre- and post treatment and analysed to assess patient responses to HSV1716 administration. Results: HSV1716 replicated/persisted in most patients with HSV DNA detected in the pleural fluids for, in some cases, up to 28 days post-administration. Increased levels of HMGB1 and HSP70 were detected in pleural fluids during this time indicating the potential for immunological cell death associated with HSV1716 oncolysis. Robust Th1 responses with increased IFNγ, IP-10, MIG, I-TAC and TNFα were observed in most patients after HSV1716 administration with additional IL-2, IL-10 and IL-12 responses most prominent in patients receiving 4 doses. There was evidence of immune cell infiltration into pleural fluids after HSV1716 treatment and increased levels of Granzyme B in pleural fluids indicate immune cell-mediated cytotoxicty. Analysis of plasma samples indicated anti-HSV IgG responses post-HSV1716 administration, particularly after 2 and 4 doses. Analysis of pleural fluid samples also indicated anti-HSV IgG responses post-HSV1716 administration. Crucially, in most patients, there was a novel anti-tumour IgG response as detected by immunoblotting against extracts from MPM cell lines indicating additional, tumour-directed immune responses. Further studies on the identities of the infiltrating immune cells and their targets are ongoing. Conclusion: Our trial demonstrates that oncolytic HSV1716 iMig2016.ORG 26 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP has immunotherapeutic potential capable of inducing novel anti-tumour immune responses in mesothelioma patients and further studies are ongoing. This also confirms pre-clinical studies that clearly demonstrated HSV1716’s immunotherapeutic mode of action. Keywords: pleural fluids, Immunotherapy, Th1 responses, anti-tumour immune responses MS05:OPTIMUM DIAGNOSTIC PATHWAY FOR SUSPECTED MESOTHELIOMA MONDAY, MAY 2, 2016 16:30 – 18:00 MS05.01: MESOBANK - TODAY’S BIOSPECIMENS FOR TOMORROW’S MEDICINE sample undergoes centralised frozen section/H&E to QC for percentage tumour nuclei and necrosis. To date, 461 samples (355 epithelioid, 68 biphasic; 38 sarcomatoid) from 83 patients have undergone QC. In keeping with the heterogeneity of mesothelioma tumour/stroma, the percentage of tumour present in each sample ranges from 6% to >75%. TMA construction (4-6 cores per case) has begun at Cancer Research UK Cambridge Centre using surgical resection tissue blocks of 800 cases from 10 centres. 26 novel mesothelioma cell lines are available. The original tumour cell type and patient gender/age are available alongside cell immunoreactivity data, HLA typing and SEM for most lines. All samples are barcoded at source for tracking and storage. A secure web-based multi-user database has been developed for sample and data collection. Conclusion: High quality QC mesothelioma tissue, DNA, blood derivatives, pleural fluid, TMA sections and cell lines, all of which have linked-anonymised clinical data, are now being supplied to research groups on a cost-recovery basis. For enquiries about tissue and data availability please contact www.mesobank.com. 1) Rintoul RC et al., Thorax 2015; Oct14 Keywords: Tissue banking, mesothelioma, Tissue microarray, Cell lines Robert C. Rintoul1, Doris M. Rassl2, Jacki Gittins1, Nick Maskell3 , John Edwards4 , Dean Fennell5, Peter Szlosarek6 , Richard Booton7, Anoop Chauhan8 , Stefan J. Marciniak9 Thoracic Oncology, Papworth Hospital NHS Foundation Trust, Cambridge, UNITED KINGDOM, 2Department of Pathology, Papworth Hospital NHS Foundation Trust, Cambridge, UNITED KINGDOM, 3Academic Respiratory Unit, University of Bristol, Bristol, UNITED KINGDOM, 4Northern General Hospital, Sheffield, UNITED KINGDOM, 5Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 6Centre For Molecular Oncology, Barts Cancer Institute & St. Bartholomew’s Hospital, London, UNITED KINGDOM, 7University Hospitals South Manchester, Manchester, UNITED KINGDOM, 8Portsmouth Hospital NHS Trust, Portsmouth, UNITED KINGDOM, 9Cambridge Institute For Medical Research (cimr), University of Cambridge, Cambridge, UNITED KINGDOM 1 Objectives: MesobanK UK, funded by the British Lung Foundation and Mick Knighton Mesothelioma Research Fund was set up in 2012 to provide quality assured mesothelioma tissue to facilitate basic and translational research in mesothelioma. Such work may lead to the development of personalised treatments for mesothelioma in the future1. Methods: 1 Using standardized collection protocols and kits we aim to collect 300 cases of fresh mesothelioma tissue, whole blood, serum, plasma and pleural fluid linked to a clinical data set with follow-up data from the UK National Cancer Registration Service. Germline DNA from whole blood is extracted by the East Anglian Regional Genetics Laboratory. 2 To construct a tissue microarray (TMA) using formalin fixed paraffin embedded tissue with linked clinical data. 3 To develop at least 20 new fully annotated mesothelioma cell lines MesobanK abides by all relevant UK and EU legislation regarding the collection of tissue and data. MesobanK is overseen by a Steering Committee and a Research Advisory Board advises on applications for samples. Results: 103 patients with confirmed mesothelioma (all subtypes) have donated up to 5 tissue samples each (in RNA Later™) with matched blood from 13 centres. Each tumour MS05.02: HAPTOGLOBIN PHENOTYPE IS A RISK FACTOR FOR MALIGNANT PLEURAL MESOTHELIOMA Kevin Lamote1, Sigurd Delanghe2, Ruben De Smet3 , Joris R. Delanghe3 , Jan Van Meerbeeck4 Respiratory Medicine, Ghent University Hospital, Ghent, BELGIUM, 2Internal Medicine, Ghent University Hopital, Ghent, BELGIUM, 3Clinical Biology, Micriobiology And Immunology, Ghent University Hospital, Ghent, BELGIUM, 4Department of Thoracic Oncology, University Hospital Antwerp, Edegem, BELGIUM 1 Objectives: Malignant pleural mesothelioma (MPM) is an asbestos-related rare tumor of the serous membranes of the lungs. The pathogenesis of MPM is linked to asbestos-induced chronic inflammation, oxidant formation, haemolysis and subsequent haemoglobin release, potentiating oxidative injury. Haptoglobin (Hp) serves as a major antioxidant by binding free haemoglobin in order to prevent oxidative damage and lipid peroxidation. The Hp-Hb-complex binds the CD163 receptor on accumulated macrophages which induces the uptake of the Hp-Hb-complex and the transfer of iron into the macrophages. Dependent on the Hp-phenotype (Hp 1-1, Hp 2-1 and Hp 2-2), this complexing and coupling to the CD163 receptor can be divergent, leading to the additional formation of reactive oxygen species (ROS) next to ROS directly induced by asbestos fibers or released by inflammatory cells. We hypothesize that, dependent on the Hp phenotype, asbestos-exposed individuals can have additional radical formation next to asbestos-induced radicals and could relate to the risk of MPM. In order to determine the Hp-phenotype as a risk factor in MPM, this cross-sectional, retrospective study compares the Hp-phenotype distribution in MPM patients with controls from a European population. iMig2016.ORG 27 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Methods: Hp-phenotyping was done on 118 archived serum samples of MPM patients by starch gel electrophoresis. In short, starch gel is prepared using 11.5% hydrolyzed starch in a 0.1 M Tris citrate buffer. Electrophoresis is performed in a 0.3 M borate buffer for 1 hour at 200V. Visualization of the Hp-Hb-complexes is done by peroxidase staining. The frequencies of Hp types (Hp 1-1, Hp 2-1 and Hp 2-2) were compared with those from 918 healthy control subjects by a Chi²-test (Table I). Results: Table I: Study results. Conclusion: Our results indicate an important role of the Hp-phenotype in MPM pathogenesis suggesting that Hp 1-1 phenotypic persons are more prone for MPM development and have a 74% increased risk of developing MPM. Apart from the asbestos-induced radical formation, this finding underlines the importance of oxidative stress in cancer development and opens new perspectives for screening. Asbestos-exposed individuals with the Hp 1-1 phenotype could then be subjected to a more intensive monitoring and screening for early detection and hence, lead to a better prognosis and management of the disease. Keywords: reactive oxygen species, oxidative stress, mesothelioma, haptoglobin MS05.03: HMGB1 AND ITS ISOFORM ARE SENSITIVE AND SPECIFIC BIOMARKERS TO DETECT ASBESTOS EXPOSURE AND TO IDENTIFY MESOTHELIOMA PATIENTS Andrea Napolitano1, Daniel J. Antoine2, Laura Pellegrini1, Francine Baumann1, Ian Pagano1, Sandra Pastorino1, Chandra M. Goparaju3 , Kirill Prokrym3 , Claudia Canino3 , Harvey I. Pass3 , Michele Carbone1, Haining Yang1 University of Hawaii Cancer Center, Honolulu, HI, UNITED STATES OF AMERICA, 2University of Liverpool, Liverpool, UNITED KINGDOM, 3New York University, New York, NY, UNITED STATES OF AMERICA 1 Objectives: To determine whether serum levels of High Mobility Group Box Protein-1 (HMGB1) could differentiate malignant mesothelioma (MM) patients, asbestos-exposed individuals, and unexposed controls. Methods: Hyper-acetylated and non-acetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from MM patients (n=22), individuals with verified chronic asbestos exposure (n=20), patients with benign pleural effusions (n=13) or malignant pleural effusions not due to MM (n=25), and healthy controls (n=20). Blood levels of previously proposed MM biomarkers fibulin-3, mesothelin, and osteopontin were also measured in non-healthy individuals. Results: HMGB1 serum levels reliably distinguished MM patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in MM patients and asbestos-exposed individuals compared to healthy controls. Hyper-acetylated HMGB1 was significantly higher in MM patients compared to asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/ml, the sensitivity and specificity of serum hyper-acetylated HMGB1 in differentiating MM patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating MM patients from patients with cytologically benign or malignant non-MM pleural effusion. Conclusion: Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyper-acetylated HMGB1 is an accurate biomarker to differentiate MM patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon. Keywords: HMGB1, mesothelioma, asbestos, biomarker MS05.04: EXPRESSION OF MICRORNAS IN MPM AS TOOL TO IDENTIFY NOVEL THERAPEUTIC TARGETS AND DIAGNOSTIC/PROGNOSTIC BIOMARKERS Chiara De Santi1, Ombretta Melaiu2, Alessandra Bonotti3 , Luciano Cascione4 , Rudy Foddis5, Alfonso Cristaudo5, Marco Lucchi6 , Marco Mora7, Anna Truini7, Andrea Tironi8 , Bruno Murer9, Renzo Boldorini10, Federica Gemignani1, Pierluigi Gasparini11, Luciano Mutti12, Stefano Landi1 Department of Biology, University of Pisa, Pisa, ITALY, 2Immuno-Oncology Laboratory, Department of Paediatric Haematology/Oncology, Ospedale Pediatrico Bambino Gesù, Rome, ITALY, 3cPreventive and Occupational Medicine, University Hospital of Pisa, Pisa, ITALY, 4dLymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, SWITZERLAND, 5Department of Translational Research and of new Technologies in Medicine and Surgery, University of Pisa, Pisa, ITALY, 6Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Pisa, ITALY, 7IRCCS H. San Martino-IST Genova, Genova, ITALY, 8hSection of Anatomic Pathology, Oncology and Experimental Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, ITALY, 9Azienda ULSS 12 Veneziana, Venezia, ITALY,10Department 1 iMig2016.ORG 28 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP of Health Sciences, School of Medicine, University Hospital Maggiore della Carità, Novara, ITALY, 11Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, UNITED STATES OF AMERICA, 12School of Environment and Life Sciences, University of Salford, Manchester, UNITED KINGDOM Objectives: Malignant pleural mesothelioma (MPM) is one of the most aggressive human cancers and miRNAs can play a key-role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. Methods: We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS). In silico analyses were also performed to understand the pathways involving the evaluated miRNAs. Results: We identified 63 miRNAs deregulated in a statistically significant way. The top five significant were: miR-185-5p, miR197-3p, miR-299-5p, miR-337-3p, and miR-485-3p. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. We also identified a 2-miRNA signature (Let-7c-5p and miR-151a-5p) related to overall survival. Conclusion: With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM. We also suggested that alterations in miRNA expression could modify cell pathways regulation, allowing the discovery of new druggable targets. Moreover, a two-miRNA signature can be a new useful tool for prognosis in MPM. Keywords: mirnas, Survival, microarray, target prediction iMig2016.ORG 29 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS05.05: THE ROLE OF MULTIDISCIPLINARY DIAGNOSTIC/THERAPEUTIC PATHWAY IN THE CASE-MANAGEMENT OF SUSPECTED PLEURAL MESOTHELIOMA Filippo Lococo1, Cristian Rapicetta1, Roberto Piro2, Carla Galeone1, Patrizia Ciammella3 , Sofia Taddei2, Debora Formisano4 , Lorenzo Agostini2, Francesca Zanelli5, Francesco Falco2, Sara Tenconi6 , Angelina Filice7, Giorgio Sgarbi1, Massimiliano Paci1, Luigi Zucchi2 Chirurgia Toracica, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, ITALY, 2Pneumologia, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, ITALY, 3Radiation Oncology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, ITALY, 4Scientific Directorate, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, ITALY, 5Oncology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, ITALY, 6University Hospitals of Leicester, Leicester, UNITED KINGDOM, 7Nuclear Medicine, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, ITALY 1 Objectives: There is significant variation between physicians in care patterns of patients affected by malignant pleural mesothelioma (MPM). In the emerging era of “systems/network medicine”, the degree of complexity of such disease requires an integrative and multidimensional approach. The aim of this study is to compare the management of MPM-patients, before and after the introduction of a structured multidisciplinary diagnostic/therapeutic pathway (MDTP). Methods: We introduced MDTP in May 2012.; a dedicate “case manager” (usually pulmonologist) accounted for the entire pathway of the patient with suspected MPM (Figure-1). If diagnosis of MPM was confirmed, a specific multidisciplinary team of experts discussed on clinical case, assessed the staging, established and directly planned the best therapeutic proposal according with the current ESMO-Clinical-Practice-Guidelines. All clinical, surgical, pathological and follow-up data were recorded into a dedicated prospective database (from 01/2010 to 06/2014), enrolling 75 consecutive MPM-patients: 48 before the introduction of MDTP (Group pre-MDTP) and 27 thereafter (Group post-MDTP). A comparative analysis was performed evaluating two main indicators : 1) “Diagnosis Time” (D-Time): the interval between the “first access” of the patient and diagnosis; 2) “Treatment Time” (T-Time): the interval between diagnosis and treatment. Results: The main characteristics of the patients did not differ between the two groups (see Table 1). In pre-MDTP, the median “D-Time” and “T-Time” were 22 and 26.5 days, respectively. After the introduction of the MDTP we observed a reduction of both indicators (median “D-Time” and “T-Time” of 17 and 21 days, respectively), despite such differences did not reach the statistical threshold. Conclusion: Despite only preliminary, our data suggest that a structured multidisciplinary diagnostic/therapeutic pathway may help the management and clinical assistance of MPM-patients, shortening the diagnostic and therapeutic delay. Figure 1 Flowchart of the MDTP in suspected MPM-patients iMig2016.ORG 30 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Table 1: The main characteristics of the population and compar- ative analysis between pre-MDTP and post-MDTP mesothelioma nursing support and access to treatment and clinical trials. Methods: The regional thoracic oncology centre in Manchester, The University Hospital of South Manchester has launched a Regional Mesothelioma MDT to serve the needs of the North West Populatuion. The core MDT members are representatives from Respiratory Medicine, Thoracic Surgery, Medical Oncology, Thoracic Radiology, Thoracic Histopathology, Cancer Nurse Specilaists, Research Support and Administration; all with a specialist interest in mesothelioma. Results: The patinet pathway for our Regional Mesothelioma MDT is outlined below. Keywords: Malignant pleural mesothelioma, structured multidisciplinary diagnostic/therapeutic pathway, multidisciplinary team, case manager MS05.06: LAUNCHING THE NORTH WEST REGIONAL MESOTHELIOMA MDT; DEFINING THE PATIENT PATHWAY Conclusion: The North West Mesothelioma MDT has been launched in Manchester following the pathway above. Outcome data audited against the standards set out in the National Mesothelioma Audit will be presented in poster form at IMIG 2016. Keywords: mesothelioma, MDT Lorraine Creech, Anshuman Chaturvedi, Marie Kirwan, Sue Jackson, Rajesh Shah, Paul Taylor, Matthew Evison, Jayne Holme Manchester Thoracic Oncology Centre, University Hospital of South Manchester, LT, UNITED KINGDOM Objectives: The North West of the United Kingdom has a high prevalence of mesothelioma. There is a clear need to provide multi-discplinary expertise for the region to facilitate accurate staging, histological confirmation, tumour sub-typing, specialist iMig2016.ORG 31 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS06:ASBESTOS CONTROL MONDAY, MAY 2, 2016 16:30 – 18:00 MS06.01: TURKEY NATIONAL MESOTHELIOMA SURVEILLANCE PROGRAM AND ASBESTOS CONTROL Muzaffer Metintas Department of Chest Diseases, ESKISEHIR OSMANGAZI UNIVERSITY MEDICAL FACULTY, ESKISEHIR, TURKEY Objectives: Malignant mesothelioma is an important health problem because of environmental and occupational asbestos and erionite exposure in Turkey. However, there is no sufficient data about surveillance of mesothelioma in Turkey. Between 2012 and 2015, Turkey National Mesothelioma Surveillance Program and Turkey Asbestos Control Strategic Plan (TAKSAP) were prepared with participation of hospitals from 30 provinces, where mesothelioma is endemic, and support of Turkey Public Health Agency. The aim of the program was to determine incidence of mesothelioma for Turkey, determine risk of cities regarding environmental asbestos exposure and develop strategies to solution the problem. Methods: In hospitals from 30 provinces, the patients diagnosed with “mesothelioma” under the code of C45.0-C45.9 between 2008 and 2012 were identified with approbation. The cases were checked in the Central Register System too. In this study, “from case to the field method” has been used. After obtaining the final records of the cases with mesothelioma, the cases born in villages/rural areas were determined; the villages where these cases were born were identified as “villages required to be examined in terms of asbestos exposure risk”. The soil samples from these villages were examined in the TUBITAK Marmara Research Centre Material Institute for mineral analysis with x-rD (x-ray diffactometer). Direct Standardized Average Annual Mesothelioma Incidence Rates (AMIRs) were calculated from WHO standard population, 2002. Estimates the population exposed to standardized incidence ratios were calculated by multiplying the standard population rates with the ratio of expected values to the observed values, and standard error was calculated as the inverse fraction of the square root of observed value (1 / √ observed value). Results: The numbers of mesothelioma cases confirmed were 5,617 according to TAKSAP within 5 years. The crude incidence rates of mesothelioma were 1.53/100,000 for all cases, 1.75/100,000 for men and 1.30/100,000 for women. AMIRs were 3.79/100,000 for all cases, 2.28/100,000 for men, and 2.94/100,000 for women. The crude incidence rates of mesothelioma were 73.42/100,000 for all cases, 79.94/100,000 for men and 66.92/100,000 for women in villages where asbestos exposure was continuing. The crude incidence rates of mesothelioma were 26.94/100,000 for all cases, 32.98/100,000 for men and, 20.87/100,000 for women in villages where asbestos exposure was stopped. The 98.3% of mesothelioma cases were from 30 provinces where TAPSAP was organized. The first four provinces were Elazığ (RR 34.74), Eskişehir (25.58), Diyarbakır (14.08), Tokat (8.01), when provinces were sorted in terms of mesothelioma risk. The first four provinces were Elazığ (RR 18.21), Eskişehir (9.07), Diyarbakır (8.37) and, Tunceli (7.60), when RR were sorted according to birth villages of cases. 158,068 people live in the 397 villages where asbestos exposure is continuing. 286,510 people live in the 174 villages where there was asbestos exposure in the past. It is expected that 17,961 new cases of mesothelioma will emerge among exposed population between 2013 and 2033. Conclusion: We determined that mesothelioma due to environmental and occupational asbestos exposure in Turkey is a more serious problem than previously anticipated. Turkish Mesothelioma Working Group Coordinators: Muzaffer Metintas1 and Hasan F Batırel2. 1Eskisehir Osmangazi University Lung and Pleural Cancers Application and Research Center, Eskisehir-Turkey, [email protected]. 2Marmara University Medical Faculty Department of Thoracic Surgery, İstanbul-Turkey, [email protected]) Researchers: Drs. Abdurrahman Abakay, Sedat Altın, Güntülü Ak, Şule Akçay, Hasan Bayram, Mehmet Bayram, Serdar Berk, Mehmet Bilgin, Nilgün Yılmaz Demirci, Figen Deveci, İsa Döngel, Ahmet Erbaycu, Dilek Ernam, Sebahat Genç, Murat Gültekin, Ezgi Hacikamiloğlu, Hüseyin İlter, Selahattin Kadir, Hasan Kahraman, Mehmet Karadağ, Özkan Kaan Karadağ, Talat Kılıç, Gamze Kirkıl, Berna Kömürcüoğlu, Selma Metintaş, Arzu Mirici, Ömer Özbudak, Sibel Özkurt,Önder Öztürk, Dursun Tatar, Engin Tutkun, Umran Toru, Toros Selçuk, Zehra Seyfikli, Nazan Şen, Abdurrahman Şenyiğit, Gaye Ulubay, Huseyin Yalcin, Ülkü Yılmaz, Adil Zamani Keywords: incidence, mesothelioma, asbestos, environmental exposure MS06.02: MESOTHELIOMA MORTALITY AT 10YEAR FOLLOW-UP IN THE ATOM 002 SCREENING STUDY Ornella Belvedere Dept. Of Oncology, York Hospital, York, UNITED KINGDOM Objectives: We previously reported the results of a prospective, non-randomized trial of low-dose computed tomography (LDCT) screening in 1,045 asbestos exposed subjects already under surveillance at the local Occupational Health Unit with annual clinic review and chest X-ray (ATOM002 study); overall, nine early stage lung cancers but no malignant mesotheliomas were detected in the prevalence screening performed between February 2002 and October 2003 (Fasola et al., The Oncologist 2007; 12:1215). Here, in the context of the ATOM002 study, we explore the impact of the participation in a screening study on overall, all cancer, lung cancer and mesothelioma specific mortality. Methods: After an incidence screening LDCT at one year, the ATOM002 subjects were returned to the Occupational Health surveillance program. At 10-year follow up, cause of death data were obtained from the regional population registry, classified according to the ninth revision of the International Classification of Disease (ICD-9). Standardized mortality ratios (SMR) were iMig2016.ORG 32 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP calculated for the ATOM002 participants and nonparticipants using the regional and Italian mortality rates. Univariate and multivariate analyses were performed to assess the relationship between mortality and smoking status, age at start of follow-up, level of exposure to asbestos, Charlson-Quan comorbidity index and participation in the ATOM 002 study; all these variables were included in the Cox model. Results: Within the cohort of 2,433 asbestos-exposed subjects enrolled in the public health surveillance program at the Occupational Health Unit in Monfalcone, Italy in 2002, we compared the 10 year overall, cancer-related, lung cancer and pleural mesothelioma specific mortality of the participants and nonparticipants in the ATOM002 study (n = 926 and 1,507, respectively). There was no difference in overall cancer mortality (HR=0.97, 95% CI 0.62-1.50) or pleural mesothelioma mortality (HR=0.86, 95% CI 0.31-2.41) between the ATOM002 participants and nonparticipants. However, mortality from all causes (HR=0.61, 95% CI 0.44-0.84) and lung cancer mortality (HR=0.41, 95% CI 0.17-0.96) were significantly reduced among subjects who participated in the ATOM002 study. Conclusion: The role of mesothelioma screening in asbestos exposed subjects remains unclear, with most authorities currently advising against screening, mainly based on the lack of effective intervention even for early disease. Our findings do not support LDCT based screening for mesothelioma in asbestos exposed subjects but warrant further investigation of LDCT screening for lung cancer in this high-risk population. MS06.03: FACTORS INFLUENCING THE ASBESTOS BODIES AMONG PLEURAL MESOTHELIOMAS AND LUNG CANCERS EXAMINED FOR RETAINED ASBESTOS FIBRES Paolo Girardi1, Anna B. Somigliana2, Pietro G. Barbieri3 , Enzo Merler1 analysed for AF by means of a Scanning Electron Microscopy equipped with X-rays fluorescence microanalyzer at 12,000 magnification for fibres longer than 1 μm, after ashing at low temperature, and for AB by means of an Optical Microscope at 500 magnification, after chemical digestion with hypoclorite. Whereas the MPM samples were derived from pleuro-pneumonectomies or autopsies, LC samples were because of autopsies ordered by a coroner in subjects known to have been shipyard workers. All subjects have been investigated and classified for probability and periods of exposure to asbestos. For 121 subjects each fibre counted at SEM was defined for its length and diameter and a fibre volume (mass) was calculated. Uni- and multi-variate linear regression analyses were used to evaluate the relationship between AB and AF and influencing factors. Results: Out of 154 subjects (145 males) under study, 144 have been classified with a certain occupational asbestos exposure (97/104 for MPM; 47/50 for LC) with a long time since ceased exposure (mean 28.3 years). Overall, the Geometric Mean (GM) was 2,7 (95% CI 2.0-3.6) million AF/g dry tissue (dt) and 29,500 AB/g dt (95% CI 20,900-41,800). A strong association was found between the log10 AB and log10 AF among occupational exposed (Pearson Correlation Index, PCI=0.78), less among non occupational (PCI=0.53). The multivariate regression analysis showed that dimension and fibre type influenced the AB lung burden: a clear positive association was observed with AB count and both fibre mass and prevalent presence (>80%) of amphiboles among AF. Time since last exposure positively influenced the AB count: every 1-year increment since the end of the exposure implies an increase of 2.4% (95% CI 0.8-4.0) of the AB count. Conclusion: The AB burden increases with the amount of retained AF composed, among the subjects under study, of high percentages of amphiboles. The AF mass correlates with AB count, suggesting a role of the fibre dimension in the endless sequences of the inflammatory process induced by fibres. Not only amphiboles but also chrysotile fibres, even if with definitively a minor weight, are involved in the development of AB. The time factors are crucial for the formation of AB. Keywords: asbestos fibres, Lung cancer, mesothelioma, asbestos bodies Local Health Authority Of Padua, Venetian Mesothelioma Registry, Occupational Health Unit, Padova, ITALY, 2Centre of Electronic Microscopy, Lombardy Environmental Protection Agency, Milan, ITALY, 3Retired; formerly, Mesothelioma Registry, Occupational Health Unit, Local Health Authority of Brescia, Brescia, ITALY 1 Objectives: A marker of exposure to asbestos is the detection of asbestos fibres (AF) and asbestos bodies (AB) in the lungs of subjects. Factors such as the amount, type, dimension of the AF reaching the distant part of the lungs contribute to the development of AB. AB develop, after undefined lengths of time, in the framework of an inflammatory process as the result of a biotransformation of longer asbestos fibres, usually amphiboles. Because AB can be observed at the resolution of an Optical Microscope, they have been more often investigated, usually after a chemical digestion of a tissue sample, but with a poor standardization of methods. We evaluate the correlation between retained AF and amount of AB, by asbestos exposure and time-related variables. Methods: Freeze dried lung samples from 104 Malignant Pleural Mesothelioma (MPM) and 50 Lung Cancer (LG) have been MS06.04: AN ECOLOGICAL ANALYSIS OF COHORTS WITH ENVIRONMENTAL AND OCCUPATIONAL MINERAL FIBER EXPOSURE Selma Metintas1, Guntulu Ak2, Muzaffer Metintas2 Lung And Pleural Cancers Research And Clinical Center And Medical Faculty Department of Public Health, Eskisehir Osmangazi University, Eskisehir, TURKEY, 2Lung And Pleural Cancers Research And Clinical Center And Medical Faculty Department of Chest Diseases, Eskisehir Osmangazi University, Eskisehir, TURKEY 1 Objectives: Exposure to asbestos and erionite are well established etiological factors for the development of malignant mesothelioma (MM). Exposure to asbestos is classified in three iMig2016.ORG 33 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP groups, i.e. occupational, environmental, and para-occupational, with differential etiologic roles. The aim of the present study was to assess the factors associated with MM incidence using a logistic regression model based on the reported incidence of MM in these exposure groups Methods: A total of 21 cohort datasets were retrieved from a total of 39 publications regarding the MM incidence with asbestos or erionite exposure. Of these cohorts 10, 17, and 3 represented environmental, occupational, and para-occupational populations, respectively. Data were analyzed using a multiple linear regression analysis model with SPSS 15.0 statistical software pack. The natural logarithm of MM incidence as the dependent variable for MM incidence was determined. Independent variables included the gender, median exposure dose (f/ mL) for the fiber in question, cumulative exposure dose (f/mLyears), latent period, median age, age at the time of initial exposure, the type of the fiber, type of exposure, or the nature of the exposure (continuous vs. interrupted). Dummy variables were defined for the fiber type and exposure type. Regression model was extended using the subject-year data for the cohorts. Results: In studies examined, the reported incidence for MM ranged between 7,27 and 1267,00 per 100,000 population, with a median incidence of 82.7. In the environmental cohorts, the corresponding figures for males and females were 298,10 (minmax: 11,20 – 639,00) and 400,90 (min-max: 9.40-1267,00), in the occupational cohorts, the corresponding figures for males and females were 43,69 (7,80-206,25) and 82,70 (15,40245,89). There were two para-occupational cohorts, for these cohorts the corresponding figures were males and females 7,27 to 91,00 and 46,26 to 57,0, respectively. The median exposure doses to asbestos in the environmental and occupational groups were 47,0 f/mL (20,8-60,30) and 19,0 (0,65-36,0), respectively. Modelling could not be performed due to small sample size in the para-occupational groups. The median cumulative exposure doses in the environmental and occupational exposure cohorts were 5.40 f/mL-years (2,60-8,70) and 20,78 f/mL-years (3,60-36,25), respectively. The median duration of the latent period in environmental and occupational asbestos exposure groups were 55,30 (48,0-60,70) and 36,10 (24,60-47,60) years, while the median of the median ages were 53,0 years (48,0 – 60,70) and 62,90 years (50,20 – 69,80), respectively. The median age at the time of first exposure was 0 in the environmental cohorts and 25,60 years (18,0 – 30,60) in the occupational cohorts. In the multiple regression analysis, the following were associated with MM incidence in the overall cohort: the median duration of exposure β (95%CI) -0.80 (-0.105; -0.055) (p<0.001), cumulative exposure dose 0.028 (0.013-0.043) (p<0.001), exposure to erionite type fiber 1.916 (0.040-3.791) (p=0.045), continuous exposure 2.93 (0.287-5.58) (p=0.030). In the model R2 was 0.771 and F was 29,371 (p<0.001). Factors associated with MM incidence in the environmental exposure group included the following: gender β (95%CI) -2.082 (-2.29 to -1.87) (p<0.001), median duration of exposure -0.30 (-0.31 to -0.28 ) (p<0.001), cumulative exposure dose 0.36 (0.29-0.43) (p<0.001), exposure to erionite type fiber 3.05 (3.41-2.68) (p<0.001), continuous exposure 8.88 (8.56-9.20) (p<0.001), and the median age of the patient -0.38 (-0.430 to -0.33 ) (p<0.001). R2 was 0.998 and F was 7668,178 for the model (p<0.001). The following emerged as the factors associated with MM incidence in occupational exposure groups: median duration of exposure β (95%CI) -0.07 (-0.095 to -0.036) (p<0.001), cumulative exposure dose 0.031 (0.012-0.049) (p=0.001), and single exposure fiber type of asbestos -1.12 (-1.69 to -0.533) (p<0.001). R2 was 0.686 and F was 20,545 for the model (p<0.001). Conclusion: Despite well-established etiological factors for MM, the need remains for better defining the epidemiological associations to the characteristics of asbestos exposure, since a number of factors such as the type and type of asbestos exposure, age at the onset of exposure, and duration of exposure appear to be related with the incidence. Keywords: incidence, epidemiology, Erionite, asbestos MS06.05: THE IMPACT OF GEOGRAPHIC AND SOCIOECONOMIC FACTORS ON PROGNOSIS AND TREATMENT PROVISION IN MALIGNANT PLEURAL MESOTHELIOMA Anthony Linton1, Matthew J. Soeberg1, Richard Broome2, Nico Van Zandwijk1 Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA, 2Public Health Observatory, Sydney, NSW, AUSTRALIA 1 Objectives: The impact of clinico-pathological factors including age, gender and histological subtype on the prognosis on malignant pleural mesothelioma (MPM) are well understood. However the effect of socio-economic and geographic factors are less certain. Whilst the majority of Australian’s reside in major cities, a significant proportion of patients are located in regional and remote areas, where access to clinical services may be limited. We analysed the relation between geographic and socio-economic factors upon survival and treatment provision in a large series of patients from New South Wales. Methods: All patients registered with the NSW Dust Diseases Board (2002-2009) diagnosed with MPM were assessed. Geographic remoteness, distance from oncological multidisciplinary teams (MDT) and index of relative socio-economic advantage and disadvantage(IRSAD) , were assessed with known prognostic factors using Kaplan Meir and Cox-regression analysis. Chi-square testing compared categorical variables to analyse impact of these factors upon clinical features and treatment received. Results: We identified 910 patients: 90% male, histology (epithelioid 60%;non-epithelioid 30%),geographic remoteness (major city 67%; regional or remote 33%), distance to MDT (<10km 65%, <50km 92%), IRSAD (above average 50%, below average 50%). Median overall survival was 10.0 months. On multivariate analysis age >70 (HR=1.39), male gender (HR=1.37), non-epithelioid histological subtype (HR.2.19) and IRSAD status by decreasing quintile (HR=1.07) were independent prognostic factors. Trend to improved survival when residing in major cities (10.6 vs 8.8 months;p=0.162) and within 50km of MDT (10.3 vs 7.8 months;p=0.539). Patients geographic location and distance to MDT did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were significantly less likely to receive chemotherapy (40.3% vs 47.7%; p=0.032) iMig2016.ORG 34 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Conclusion: Socioeconomic disadvantage was an independent and significant prognostic factor for MPM in NSW Australia despite access to ‘universal’ health care. A significant reduction in chemotherapy utilisation was also noted. A trend to improved survival was noted in patients residing in major cities within closer proximity to oncology units however this was not statistically significant. Reassuringly, treatment provision did not differ in patients regardless of geographic location. Socioeconomic factors appear to be a greater cause of disparity in mesothelioma outcomes in comparison to geographic factors. Further prospective research analyzing specific factors including comorbidity, income, and individual preference will be required to better understand these findings. Keywords: prognosis tional association of pleural MM with unknown primary cancer restricted to follow-up ≥1 year, suggesting shared genetic or non-genetic risk factors. Keywords: pleural mesothelioma, Peritoneal mesothelioma, second primary cancers, Malignant mesothelioma MS06.07: MESOTHELIOMA INCIDENCE IN SWEDEN - WHY DOES IT NOT GO DOWN? Gunnar Hillerdal Pulmonary, Gavle Hospital, GAVLE, SWEDEN MS06.06: RISK OF SECOND PRIMARY CANCERS AFTER MALIGNANT MESOTHELIOMA AND VICE VERSA Tianhui Chen1, Elham Kharazmi2, Jianlin Lou1, Xing Zhang1, Kristina Sundquist3 , Kari Hemminki2 Institute of Occupational Diseases Prevention, Zhejiang Academy of Medical Sciences, Hangzhou, CHINA, 2Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, GERMANY, 3Lund University, Malmö, SWEDEN 1 Objectives: Investigations on risk of second primary cancers (SPCs) after malignant mesothelioma (MM) and vice versa have not been reported. We aimed at investigating risk of specific SPCs after MM and vice versa. Methods: Patients diagnosed with pleural MM and peritoneal MM in Sweden during 1997-2012 were selected, respectively. Standardized incidence ratios (SIRs) were used to assess risk of specific SPC after MM, compared to risk of the same first cancer in the Swedish general population. Calculations were also performed in a reverse order by assessing risk of second MM after any first cancers and same methodology was adopted. Results: Among survivors of 3,672 pleural MM and 895 peritoneal MM, overall 113 and 28 SPCs were recorded, respectively, while reverse analyses included overall 431 second pleural and 88 peritoneal MMs after any first cancers. Elevated SIR after pleural MM was observed for total combined SPCs (SIR=1.4; 95%CI:1.1-1.6), ovarian [4.7 (1.3-12)] and kidney cancers [4.4 (2.0-8.3)], while reverse analyses found elevated SIR for second pleural MM after total combined [1.2 (1.1-1.3)], connective tissue [4.5 (1.7-9.9)], kidney [2.3 (1.3-3.9)] and lung cancers [1.9 (1.2-2.9)]. The bidirectional association of pleural MM with kidney cancer was restricted to follow-up <1 year [5.4 (2.0-12) and 4.9 (2.0-10), respectively] and with total combined cancers was restricted to follow-up ≥1 year [1.4 (1.1-1.8) and 1.2 (1.1-1.3), respectively; considering unknown primary cancer: 3.9 (1.1-10) and 2.8 (1.3-5.1), respectively]. Objectives: The use of asbestos in Sweden was mainly in the 1960ies and import and use of the mineral was banned in the early mid-seventies, as one of the first countries in the world. The incidence of mesothelioma in the country started to rise from very low levels around 1975 and reached around 100 cases a year in 1985, as expected with a latency of 30 years. The number of cases ought to start sinking in the early 21st century, especially since strict regulations of asbestos use were in use already in the mid-1960ies. Methods: The incidence of pleural mesothelioma for both sexes cab be seen in the official Swedish publication “Cancer Incidence in Sweden”, the latest available figures of which is 2012. Results: Since 1984, a plateau has been reached, with around 100 cases of new pleural mesotheliomas occurring in Sweden every year, sometimes a little less, more often a little more. No tendency to declining figures can be seen so far. The median age at diagnosis has remained the same since the 1960ies, 5470 years. Furthermore, the percentage of women is the same, 15-20 % of the total. Conclusion: The heaviest exposure took place in Sweden around 1965; after this the exposure was diminished, but continued until early 1970ies. It has been postulated that 40 years after exposure, the risk of mesothelioma should decline, but as stated there are no signs of this in the statistics. The relative risk for men and women remains about the same, thus it is unlikely that general environmental exposure to asbestos can explain it. Furthermore, the median age at diagnosis has remained the same. Most of those exposed in the 1960ies should by now have a fairly advanced age, and thus new age groups must have had some kind of exposure after 1970. These findings are disturbing giving the present exposure in many countries. Keywords: incidence, Sweden, mesothelioma Conclusion: We found a bidirectional association of pleural MM with kidney cancer restricted to follow-up within first year, suggesting increased medical surveillance, while a bidireciMig2016.ORG 35 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS07:BAP1 AND GENETICS MONDAY, MAY 2, 2016 16:30 – 18:00 MS07.01: ASSOCIATION OF BAP1 GENE EXPRESSION WITH PROTEIN LOCALIZATION AND SURVIVAL IN EPITHELIOID MPM Assunta De Rienzo1, Lucian R. Chirieac2, Beow Y. Yeap3 , William G. Richards1, Raphael Bueno1 Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA, 2Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA, 3Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA 1 Objectives: We have recently demonstrated that diverse molecular mechanisms may be involved in the tumorigenesis of malignant pleural mesothelioma (MPM) (Cancer Research, in press). Unexpectedly, we found that BAP1 gene expression was associated with significant reduction in survival and was not correlated with the mutational status of the gene as determined by sequencing. These observations would seem inconsistent with its presumed tumor suppressor role. A recent study documents that frequency of BAP1 mutation is underestimated by Sanger sequencing which fails to detect large chromosomal deletions commonly inferred from absence of nuclear BAP1 protein localization by immunohistochemistry (IHC). Here, we explore BAP1 protein localization by IHC in relation to gene expression, sex and overall survival (OS). Methods: One hundred and twenty-eight samples were selected from the International Mesothelioma Program Tumor Bank to explore the molecular basis for differential prognosis observed between the two sexes. To minimize competing prognostic influences, the sample set consisted of only epithelioid MPM samples obtained from equal numbers of male and female patients who underwent extrapleural pneumonectomy, matched by nodal status and age. Microarray analysis was performed using 0.25 mg of total RNA and the Ambion WT Expression Kit. The cRNA was hybridized to Affymetrix® Human Gene 1.1 ST Array, labeled with GeneChip WT Terminal Labeling Kit, and then scanned with a GeneAtlas™ Workstation as recommended by the manufacturer. Quantile normalization was performed using Bioconductor, and differentially expressed probes were identified using the LIMMA package. IHC was performed using BAP1 antibody (Santa Cruz, sc-28383) on a tissue microarray containing 103 of the 128 samples included in the microarray analysis. Overall survival was estimated by the Kaplan-Meier method, with group differences assessed by the log-rank test. The normalized expression level of BAP1 was initially grouped into quartiles for exploratory survival analysis. Patient subgroups with comparable survival were combined for further analysis in order to detect a meaningful difference using proportional hazards regression to estimate the hazard ratio (HR), adjusting for the effect of sex. Results: After adjusting for the independent effect of sex on OS (female > male), the highest 3 quartiles of BAP1 expression were associated with twice the risk of death [HR=2.31; p<0.001] compared to the lowest quartile, indicating an adverse effect of elevated BAP1 expression on survival. The survival difference was similar across sex subgroups (male: HR =2.20; p=0.005; and female: HR=2.38; p=0.004). BAP1 IHC revealed that only 1 of 27 (4%) cases in the lowest quartile of BAP1 expression exhibited nuclear protein staining, with 21 cases (78%) exhibiting cytoplasmic staining, and 5 (19%) no staining. By contrast, 17 of 26 (65%) cases in the highest quartile of BAP1 expression exhibited nuclear staining, 8 (31%) cytoplasmic and 1 (4%) no staining (p<0.001). Conclusion: The results suggest that mutations of BAP1, as indicated by absence of nuclear protein localization, are associated with lower BAP1 gene expression levels and longer survival in epithelioid MPM. Further analyses are in progress to elucidate the clinical correlates of BAP1 status in MPM. Keywords: BAP1, epithelioid MPM, immunohistochemistry, suvival MS07.02: SOMATIC BAP1 AND NF2 MUTATIONS IN PLEURAL MALIGNANT MESOTHELIOMA AND THEIR CORRELATION WITH CLINICAL PHENOTYPES Spyridon Gennatas1, Shir Kiong Lu1, Hima Anbunathan1, Sanjay Popat2, Mary E. O’Brien2, Eric Lim3 , Angeles Montero4 , Taqdir Benepal5, Brendan Tinwell6 , Andrew Nicholson4 , Mark Lathrop7, Miriam Moffatt1, William O. Cookson1, Anne M. Bowcock1 National Heart And Lung Institute, Imperial College London, London, UNITED KINGDOM, 2Royal Marsden Hospital NHS Foundation Trust, London and Surrey, UNITED KINGDOM, 3Royal Brompton Hospital, London, UNITED KINGDOM, 4Deparatment Of Histopathology, Royal Brompton and Harefield Hospitals, London, UNITED KINGDOM, 5Department of Oncology, St George’s Hospital, London, UNITED KINGDOM, 6Department of Histopathology, St George’s Hospital, London, UNITED KINGDOM, 7McGill University and Genome Quebec’s Innovation Centre, Quebec, AB, CANADA 1 Objectives: We set out to further explore the molecular alterations underlying pleural MM with the expectation that this would permit stratification of patients, provide correlations with clinical information and reveal potential driver mutations that could provide insights into the development of novel therapeutic targets. Methods: We performed whole exome sequencing (WES) on 50 fresh frozen MM tumours (36 epithelioid, 12 biphasic and 2 sarcomatoid). DNA from matched blood was available for 21 of the cases and was also sequenced (Discovery cohort). The remaining 29 cases were unmatched (Validation Cohort). The variants were identified with GATK tools and annotated with ANNOVAR. Germline variants, single nucleotide variants (SNV) and indels with a quality score of less than 50 or those present in either dbSNP138, 1000 Genomes Project or NHLBI GO Exome Sequencing Project were filtered out. Potential driver mutations iMig2016.ORG 36 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP were then identified conditional upon meeting at least one of the following criteria: 1. SNVs predicted to alter protein function by Polyphen-2, SIFT and Mutation Taster, 2. Recurrent gene mutations, 3. Detection of mutation hotspots, 4. Detection of genes known to be implicated in the tumourogenesis of other solid tumours. Mutations identified were validated with Sanger sequencing. Results: BAP1 and NF2 have been previously described as genetic drivers of MM. In the discovery cohort we determined that 19% of tumours (4 of 21) harboured deleterious somatic mutations in BAP1 and 14% (3 of 21) harboured deleterious somatic mutations in NF2. In the validation set the frequency was 28% (8 of 29) and 14% (4 of 29) respectively. The higher frequency of BAP1 mutations in the validation set is potentially due to BAP1 mutations of germline origin. We did not see a difference in presence or absence of BAP1 or NF2 mutations and age at diagnosis of MM. Two tumours had both BAP1 and NF2 mutations and both of these were biphasic. Additionally, we identified a BAP1 mutation in the splice acceptor site of exon 3 in an MM patient with early onset breast cancer, suggesting that a germline alteration had contributed to both cancers. A patient with a deleterious BAP1 mutation (Q684X) from the validation set had no reported asbestos exposure and had a brother with lung cancer, a brother with mesothelioma and a brother with oesophageal cancer. This could expand the spectrum of tissues implicated in the familial cancer syndrome due toBAP1 mutations. A number of loss-of-function mutations in other important genes were identified in tumours without BAP1 or NF2 mutations that are being validated and investigated in additional MMs. Conclusion: BAP1 and NF2 are the most commonly mutated genes in MM, but the contribution of germline versus somatic alterations varies between the two genetic drivers, and a large percentage of additional drivers remain to be discovered. Keywords: mesothelioma, BAP1, whole exome sequencing, genetic drivers MS07.03: FAMILIES WITH MULTIPLE CASES OF PLEURAL MALIGNANT MESOTHELIOMA WITHOUT INHERITANCE OF A BAP1 PREDISPOSING MUTATION Valeria Ascoli1, Simona Vatrano2, Luisella Righi2, Ilaria Cozzi1, Paolo Visca3 , Francesco Facciolo4 , Lucia Rosalba Grillo5, Mauro Papotti2 genomic status as predisposing risk factor for MM. We report update data on BAP1 analysis in four families with multiple cases of MM and asbestos exposure. Preliminary results were presented at the IMIG Conference 2014, Cape Town. Methods: Genomic DNA from formalin-fixed paraffin-embedded (FFPE) tissues of one selected case for each family was obtained (3 epithelioid and 1 biphasic MM), since germline DNA was not available from peripheral blood. Manual microdissection was performed to separate in all cases the correspondent normal/neoplastic counterparts, which were analyzed separately. Using Sanger sequencing, the entire sequence of the BAP1 gene was analyzed to screen genetic alterations in coding and in exonic/intronic junctions. Putative pathogenic variants were validated via bidirectional re-sequencing of an independent PCR amplification. Variants were annotated according to the longest isoform RefSeqs from the Genome Reference Consortium Human Build 37.3 (NM_004656.3) and described according to the Human Genome Variation Society guidelines. The biphasic MM was further microdissected in the two neoplastic populations: epithelioid and sarcomatoid cells. BAP1 immunohistochemistry (IHC) was performed on FFPE tissues (clone-C4, Santa-Cruz Biotechnology, CA/USA). Results: Sequencing analysis of BAP1 gene of tumor samples of three epithelioid index cases showed no mutations neither in heterozygosis nor in homozygosis. In the biphasic index case a non-frameshift InDel was detected in heterozygosis in exon 5 (c.329_335delinsTC) in the epithelioid cells. The same genetic alteration was identified in sarcomatoid cells with a lower allelic frequency than that seen in epithelioid cells. This BAP1 alteration that led to a shorter BAP1 protein (p.Pro110_Ser111del) has never been reported. Normal tissue from the same case showed no abnormalities in the BAP1 gene. Therefore, the identified alteration was proved as a somatic event. For the other three index cases, IHC showed loss of nuclear BAP1 staining, suggesting other somatic inactivating events, as large deletions or epigenetic silencing, which could not be identified by Sanger sequencing (Nasu et al. J Thorac Oncol 2015; Emi et al. J Hum Genet 2015). Conclusion: In these four families, there is no evidence of an inherited mutation of BAP1 by Sanger sequencing. The wild-type status was proven in tumour tissue (three cases/families) and in normal tissue (one case/family). Our families with multiple cases of MM and without inheritance of a predisposing BAP1 mutation are similar to those reported by other investigators (Popova et al. Am J Hum Genet 2013; Betti et al. Gene Chromosomes Cancer 2014; Sneddon et al. Gene 2015; Cheung et al. Cancer Genet 2015), suggesting that other genetic or epigenetic factors may play a role in the high incidence of MM in these families. Keywords: BAP1, familial mesothelioma Radiological, Oncological And Anatomo-pathological Sciences, Sapienza University, Rome, ITALY, 2Department of Oncology, University of Turin, Turin, ITALY, 3Department of Pathology, Regina Elena Cancer Institute, Rome, ITALY, 4Department of Oncologic Thoracic Surgery, Regina Elena Cancer Institute, Rome, ITALY, 5Department of Pathology, San Camillo Hospital, Rome, ITALY 1 Objectives: BAP1 gene germline alterations have been reported in some families with multiple cases of malignant mesothelioma (MM) and very rarely in sporadic MM. Familial clusters among blood-relatives are ideal candidate to explore BAP1 iMig2016.ORG 37 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS07.04: BAP1 AND MESOTHELIOMA Michele Carbone1, Erin Flores1, Mitsuru Emi1, Todd Johnson2, Tatsuhiko Tsunoda2, Dusty Behner1, Harriet Hoffman3 , Mary Hesdorffer4 , Masaki Nasu1, Andrea Napolitano1, Amy Powers1, Michael Minaai1, Francine Baumann1, Peter Bryant-Greenwood1, Olivia Lauk5, Michaela Kirschner5, Walter Weder5, Isabelle Opitz5, Harvey I. Pass6 , Giovanni Gaudino1, Sandra Pastorino1, Haining Yang1 University of Hawaii Cancer Center, Honolulu, HI, UNITED STATES OF AMERICA, 2RIKEN Center for Integrative Medical Science, Kanagawa, JAPAN, 3Genealogy from the Hart, Honolulu, AL, UNITED STATES OF AMERICA, 4Mesothelioma Applied Research Foundation, Alexandra, AL, UNITED STATES OF AMERICA, 5Klinik fur Thoraxchirurgie Universitatsspital, Zurich, SWITZERLAND, 6NYU Langone Medical Center, New York, AL, UNITED STATES OF AMERICA 1 Objectives: Germline BAP1 mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives. Through screening MM patients with histories of multiple cancers, we studied the prognosis of MM in carriers of germline BAP1 mutations compared to sporadic mesotheliomas, we investigated the pattern of trasnmission fo these mutations (i.e., de novo versus transmission accross multiple generations) and studied mechanisms of BAP1 carcinogenesis. Methods: We used a combination of epiedmiological, genealogical studies together with molecular genetics and pathological analyses. Results: We found that MM in families carrying germline BAP1 mutations have better prognosis compared to sporadic mesotheliomas, and we identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 100 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Conclusion: Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies). MS07.05: BAP-1 CANCER SYNDROME ASSOCIATED MALIGNANCIES WERE NOT DETECTED AMONG 558 DANISH PATIENTS WITH MALIGNANT MESOTHELIOMA Vasiliki Panou1, Mogens Vyberg2, Christos Meristoudis3 , Oluf D. Røe4 Department of Respiratory Diseases & Clinical Cancer Research & Faculty Of Medicine, Aalborg University Hospital & Aalborg University, Aalborg, DENMARK, 2Institute of Pathology & Clinical Institute, Aalborg University Hospital & Aalborg University, Aalborg, DENMARK, 3Institute of Pathology, Aalborg University Hospital, Aalborg, DENMARK, 4Department of Clinical Medicine, Aalborg University Hospital, Aalborg, DENMARK 1 Objectives: Recently germline BAP1 mutations were found to predispose to a cancer syndrome, including malignant mesothelioma (MM), uveal malignant melanoma (UVM), renal cell carcinoma (RCC) and benign atypical melanocytic tumours (atypical Spitz tumors [AST]). In the literature there are described families of American and European origin, including a Danish family, that are reported to be carriers of BAP1 germline mutations and present with high incidence of MM, UVM, RCC and AST. Importantly, previous research indicates that MM patients with BAP1 mutations tend to develop UVM and AST some years before the MM diagnosis. Hence, it is suggested that patients with UVM and AST should be tested for BAP1 mutations and if confirmed closely monitored as to early MM diagnosis. Our aim was to examine whether there was excess of BAP-1 related tumors in a Danish MM cohort. Methods: A retrospective analysis of pathology reports of 558 patients diagnosed with MM in pleura, peritoneum, pericardium and tunica vaginalis in the period 1972-2014 in the Region of North Jutland, Denmark was performed. Epithelioid, sarcomatoid and biphasic MM subtypes were included in the study population. We investigated whether these patients were previously or subsequently diagnosed with UVM, RCC or AST. Results: None of the 558 MM patients had a previous diagnosis of UVM, RCC or AST. Conclusion: The lack of UVM, RCC and AST tumours in the large MM study population in North Jutland raises questions as to how common germline BAP1 mutations that result in both UVM, RCC, AST and MM appear to be. The current study indicates that the occurrence of UVM, RCC and AST prior or subsequent to a diagnosis of MM is infrequent in Danish patients and thus, AST´s value as an early MM clinical marker for the general population is limited. However, research is needed to elucidate the true incidence of Danish BAP-1 MM patients and their tumor spectrum. Keywords: Malignant mesothelioma, BAP1, atypical Spitz nevus Keywords: Malignant mesothelioma, BAP1, Cancer Syndrome iMig2016.ORG 38 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS08:PATHOLOGY MONDAY, MAY 2, 2016 16:30 – 18:00 MS08.01: IMMUNOHISTOCHEMICAL DETECTION OF MTAP OR BAP1 PROTEIN LOSS FOR MESOTHELIOMA DIAGNOSIS: COMPARISON WITH P16 FISH Kazuki Nabeshima1, Tomoyuki Hida1, Makoto Hamasaki1, Shinji Matsumoto1, Ayuko Sato2, Tohru Tsujimura2, Kunimitsu Kawahara3 , Ainori Iwasaki4 , Yoshinao Oda5 Pathology, Fukuoka University School of Medicine, Fukuoka, JAPAN, 2Pathology, Hyogo College of Medicine, Hyogo, JAPAN, 3Pathology, Osaka Prefectural Medical Center for Respiratory and Allergic Disease, Habikino, JAPAN, 4Thoracic Surgery, Fukuoka University School of Medicine, Fukuoka, JAPAN, 5Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, JAPAN 1 Objectives: Objectives. Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is sometimes difficult. In this setting, homozygous deletion (HD) of p16INK4A ( p16; detected using fluorescence in situ hybridization (FISH)) and loss of BAP1 protein expression (detected using immunohistochemistry (IHC)) are reliable markers for MPM. Not all laboratories are equipped to perform p16 FISH; IHC is a more common and feasible technique. The combined loss of methylthioadenosine phosphorylase (MTAP) and p16 expression has been proposed as a surrogate marker for p16 HD in pancreatic and lung cancers. We investigated whether detection using IHC of the loss of expression of the products of genes located in the 9p21 region ( p14ARF, p15INK4B, p16, and MTAP) could predict the deletion status detected by p16 FISH in MPM. We also examined the sensitivity of a combination of IHC of these gene products and BAP1 for the differentiation of MPM versus RMH, compared with a combination of BAP1 IHC and p16 FISH. Methods: Methods. IHC was used to investigate expression levels of p14ARF, p15INK4B, p16, and MTAP for 43 epithelioid MPM and 20 RMH. Concordance between their results, including those for combined expressions, and the deletion status of the 9p21 locus (detected using FISH) was analyzed statistically. We also examined sensitivities and specificities of combinations of the IHC expression status of these gene products and BAP1 for differentiating MPM from RMH, and compared them with those of BAP1 IHC and p16 FISH. Results: Results. IHC revealed that loss of expression of p14ARF, p15INK4B, p16, MTAP and BAP1 occurred in 23.3%, 39.5%, 34.9%, 46.5% and 65.1% of MPM, respectively. p16 HD was detected in 68.6% of MPM when FISH was used. Among the four genes, the results of MTAP IHC had the best concordance with the p16 FISH results (kappa coefficient = 0.65). Moreover, the loss of p15INK4B -p16 -MTAP revealed using IHC had better concordance. For predicting p16 HD detected using FISH, loss of p15INK4B, p16, and MTAP (but not p14ARF) had specificity values of 100%. The loss of MTAP-BAP1 expression (detected using IHC) was observed in 85.7% of MPM. The loss of BAP1 using IHC-p16 HD using FISH was revealed in 94.3% of MPM. Both combinations had specificity values of 100%. Conclusion: Conclusion. Combinations of MTAP-BAP1 loss revealed using IHC can likely detect MPM with good sensitivity that is higher than those of BAP1 IHC alone or p16 FISH alone. These combinations could thus serve as useful ancillary IHC for discrimination of MPM from RMH. A combination of BAP1 IHC and p16 FISH remains the most accurate ancillary tool. Keywords: FISH, p16, BAP1, MTAP MS08.02: UTILITY OF BAP1 IMMUNOHISTOCHEMISTRY AND FISH IN THE DIFFERENTIAL DIAGNOSIS OF MALIGNANT MESOTHELIOMA Kenzo Hiroshima1, Di Wu1, Mizue Hasegawa2, Yasuo Sekine3 , Daisuke Ozaki4 , Toshikazu Yusa4 , Zhi Bin Gao5, Yuji Tada6 , Hideaki Shimada7, Masatoshi Tagawa8 1 Pathology, Tokyo Women’s Medical University, Yachiyo, JAPAN, 2Respirology, Tokyo Women’s Medical University, Yachiyo, JAPAN, 3Thoracic Surgery, Tokyo Women’s Medical University, Yachiyo, JAPAN, 4Chiba Rosai Hospital, Ichihara, JAPAN, 5Yuyao People’s Hospital, Yuyao, CHINA,6Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, JAPAN, 7Department of Surgery, School of Medicine, Toho University, Tokyo, JAPAN, 8 Chiba Cancer Center Research Institite, Chiba, JAPAN Objectives: Distinction between malignant mesothelioma and reactive mesothelial proliferation is sometimes difficult, especially when the biopsy specimen is small. However, correct diagnosis is crucial to patient care and compensation. The aim of this study was to analyze immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) of BAP1 in malignant mesotheliomas and to determine whether they are useful for the differential diagnosis of malignant mesothelioma. Methods: IHC and FISH analysis of BAP1 was performed in 28 surgical biopsies from histologically confirmed malignant mesotheliomas. Sixteen were epithelioid mesotheliomas, seven were biphasic mesotheliomas, and five were sarcomatoid mesotheliomas. We also analyzed surgical biopsies from nine cases with fibrous pleuritis for control. For FISH analysis, at least 100 cells were scored for each case. A cut-off value of >15% for homozygous deletion pattern was defined for homozygous deletion. Results: BAP1 loss by IHC was observed in 56% (9/16) of epithelioid mesotheliomas, and 57% (4/7) of biphasic mesotheliomas, and none (0/5) of sarcomatoid mesotheliomas. Homozygous deletion of BAP1 by FISH was observed in 50% (8/16) of epithelioid mesotheliomas, 14% (1/7) of biphasic mesotheliomas, and none (0/5) of sarcomatoid mesotheliomas. Heterozygous deletion of BAP1 was observed in 13% (2/16) of epithelioid mesotheliomas, 71% (5/7) of biphasic mesotheliomas, and 60% (3/5) of sarcomatoid mesotheliomas. Abnormality of BAP1 was detected in 81% (13/16) of epithelioid mesothelioma by BAP1 IHC and/or BAP1 FISH. Abnormality was iMig2016.ORG 39 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP not detected in surgical biopsies from fibrous pleuritis by BAP1 IHC and BAP1 FISH. Conclusion: Both BAP1 IHC and BAP1 FISH are useful for the differential diagnosis of epithelioid mesothelioma, although only BAP1 IHC is useful for the differential diagnosis of biphasic mesothelioma. Heterozygous deletion of BAP1 is frequently observed in non-epithelioid mesothelioma and further studies are needed for clarification of its meaning in malignant mesothelioma. Keywords: BAP1, mesothelioma, immunohistochemistry, FISH Conclusion: While reviewing the cases we encountered several diagnostic issues especially regarding patterns that share many features (solid and deciduoid, acinar and adenomatoid etc.) as well as subclassifying sarcomatoid variants. Another issue is the relative small number of tumor cells in needle biopsies which makes it harder to evalute and firmly categorize the pattern into one of the proposed options. A meeting to furtherly define criteria and recognize specific patterns was needed to improve the inter-observer agreement and to minimize subjectivity. Intra-observer agreement was moderate to substantial which indicates that the proposed classification is quite reproducible but additional efforts should be probably made to make it an even more powerful tool. Keywords: histology, pleural mesothelioma, classification MS08.03: HISTOLOGICAL EVALUATION OF MESOTHELIOMAS Izidor Kern1, Luka Brcic2, Gregor Vlacic1 Pathology, University Clinic Golnik, Golnik, SLOVENIA, 2Pathology, Institute of Pathology, Medical University of Graz, Graz, AUSTRIA 1 Objectives: Mesothelioma is the most frequent primary neoplasm affecting the pleura and still has a very grim prognosis. The classification is based on the histomorphological appearance and distinguishes epitheliod, sarcomatoid and biphasic variants with the epithelioid type having a longer overall survival compared to the other two. A new classification has been proposed by the International mesothelioma working group. It divides the epithelioid variant into subcategories based on the histological pattern, namely solid, acinar, adenomatoid, micropapillary, tubulopapillary, trabecular, small cell, clear cell, signet ring cell, adenoid cystic, deciduoid, rhabdoid and pleomorphic. The sarcomatoid variant was subclassified as conventional (spindle cell), desmoplastic, lymphohistiocytoid and with heterologous differentiation. Our goal was to assess inter-observer and intra-observer agreement between two senior pathologists and one pathology resident applying the new classification. Methods: We reviewed the HE slides of 200 consecutive mesotheliomas. There were resection specimens, needle biopsies (blind and CT guided) and thoracoscopic biopsies from two different institutions. Following a meeting during which a set of mesothelioma slides displaying typical patterns for each histological category was agreed upon and shared among the pathologists, all the cases were re-evaluated. Fleiss’ kappa was used to assess inter-observer agreement and Cohen’s kappa to assess intra-observer agreement. Results: After the first evaluation the inter-observer agreement was fair with a kappa value of k=0,372. Following the meeting the second evaluation round yielded a higher kappa value of k=0,635 which represents a substantial agreement between the pathologists. One of the senior pathologists had a substantial intra-observer agreement with a kappa value of k=0,641 while the other senior pathologist and the pathology resident had a moderate agreement with kappa values of k=0,598 and k=0,539 respectively. MS08.04: A GENE PANEL TO DIFFERENTIATE MALIGNANT PLEURAL MESOTHELIOMAS FROM BENIGN PLEURAL LESIONS Rossella Bruno1, Greta Alì2, Riccardo Giannini1, Marco Lucchi3 , Franca Melfi4 , Alfredo Mussi3 , Gabriella Fontanini5 Department of Surgical, Medical, Molecular Pathology And Critical Area, University of pisa, Pisa, ITALY, 2Unit Of Pathological Anatomy, Azienda Ospedaliero Universitaria, Pisa, ITALY, 3Department of Surgical, Medical, Molecular Pathology And Critical Area, Division of Thoracic Surgery, University of pisa, Pisa, ITALY, 4Unit Of Thoracic Surgery, Azienda Ospedaliero Universitaria, Pisa, ITALY, 5Program Of Pleuropulmonary Pathology, Azienda Ospedaliero Universitaria, Pisa, ITALY 1 Objectives: Malignant pleural mesothelioma (MPM) is an aggressive and rare tumour associated with asbestos exposure. The diagnosis of malignant pleural mesothelioma (MPM) is based on the histological analysis of pleural lesions, however the morphological separation of benign mesothelial hyperplasia (MH) from MPM can be exceedingly difficult. As a matter of fact reactive MH may be extremely florid mimicking mesothelioma. Nowadays the only robust criterion for malignancy is the presence of mesothelial cells invasion of the chest wall soft tissue or of the underlying lung parenchyma. Several deregulated gene pathways have been described in MPM, we investigated how the over and down expressed genes work together in the differential diagnosis of MPM and MH. We aimed to assess a genes panel to be used in the clinical practice by the nCounter System - NanoString technologies®. Methods: We designed a custom NanoString Codeset including 113 genes with a crucial role in cancer and 6 reference genes. The gene expression analysis by the nCounter System was performed directly, without any amplification steps, on RNA from 48 formalin-fixed and paraffin-embedded tissues of epithelioid MPM (32) and MH (16) samples. Raw NanoString counts for each gene were normalized and statistically processed using the nSolver Analysis Software and the STATISTICA Software, respectively. To model the gene expression profiles of MPM and MH samples, both before and after we filtered the differentially expressed genes, a cluster analysis of expressed genes was performed using the Euclidean distance between iMig2016.ORG 40 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP samples. Results: A total of 43 genes resulted deregulated in MPM in comparison with MH (Mann–Whitney U test; P<.005): 24 genes exhibited an over expression (EGFR, ITGA3, PAK4, MSLN, GLI2 and others) and 19 showed a down expression (BAP1, ITGA5, CD44, MMP9, PDGFRB and others). The cluster analysis exposed an evident difference between MPM and MH, particularly after we filtered the differentially expressed genes. Conclusion: We analysed a panel of genes, some of which known as deregulated in MPM, however none of these genes have yet to be used as a biomarker. To evaluate how transcriptomic data could be applied in the diagnosis of MPM we used an enzyme-free digital count of mRNA molecules to analyse simultaneously all the selected genes and to reduce the potential errors associated with multiple qPCR assays. We identified a specific panel composed of 43 genes, whose expression profile resulted clearly distinct between MPM and MH. This genes panel may constitute, after further validation on a larger series of samples, a powerful tool for the separation of MPM from MH, improving the current diagnostics methods. Keywords: Malignant mesothelioma, mesothelial hyperplasia, differential diagnosis, gene expression profiling MS08.05: NECROSIS AND SOLID GROWTH PATTERN AUGMENT NUCLEAR GRADING IN PREDICTING SURVIVAL IN EPITHELIOID MALIGNANT MESOTHELIOMA Alexander J. Gallan1, Viju Ananthanarayanan2, Kenzo Hiroshima3 , Alberto Marchevsky4 , Stephanie Mcgregor1, Angeles Montero5, Kazuki Nabeshima6 , Wickii Vigneswaran7, Ann Walts4 , Thomas Krausz1, Aliya Husain1 Department of Pathology, The University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 2Loyola University, Maywood, IL, UNITED STATES OF AMERICA, 3Pathology, Tokyo Women’s Medical University, Yachiyo, JAPAN, 4Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, UNITED STATES OF AMERICA, 5Deparatment Of Histopathology, Royal Brompton and Harefield Hospitals, London, UNITED KINGDOM, 6Department of Pathology, Fukuoka University, Fukuoka, JAPAN, 7Department of Surgery, The University of Chicago, Chicago, IL, UNITED STATES OF AMERICA 1 Objectives: A recently described nuclear grading system has been shown to predict survival in patients with epithelioid diffuse malignant pleural mesothelioma (EMM). The current study was undertaken to identify additional prognostic characteristics to augment the nuclear grading system and more accurately predict survival. Methods: We analyzed cases of EMM from five institutions across the United States, England, and Japan from 1998-2013. Nuclear grade was computed combining nuclear pleomorphism and mitoses into a grade of I-III using the published system. The presence or absence of necrosis and patterns of growth were also evaluated. Overall survival (OS) was used as the primary endpoint. Data were examined using Student’s t-test. Results: A total of 117 cases of EMM were analyzed. Of these, 53 (45%) were Grade I, 47 (40%) were Grade II, and 17 (15%) were Grade III. The mean OS was 28 months. Our multi-institutional data confirmed that higher nuclear grades are associated with worse OS (Grade I - 40 months, Grade II – 20 months, Grade III – 13 months, I vs II p<0.001, II vs. III p=0.05, I vs. III p<0.001). Importantly, Grade II tumors with associated necrosis behave similarly to Grade III tumors (10 vs 13 months, p=0.37), and significantly worse than Grade IIs without necrosis (10 vs. 24 months, p=0.003). Additionally, a solid growth pattern was associated with worse OS (22 vs. 33 months, p=0.02). Conclusion: This study confirms that nuclear grade predicts survival in EMM, and identifies the presence of necrosis as a predictor of especially aggressive behavior in Grade II tumors. Therefore, we recommend that Grade II tumors with necrosis be regarded as equivalent to Grade III tumors in behavior. Additionally, a solid growth pattern, regardless of the nuclear grade, is associated with a worse overall survival. In conclusion the assessment of non-nuclear features such as necrosis and the architectural pattern serve to augment nuclear grading in predicting survival in patients with EMM. Keywords: mesothelioma, Nuclear grade, Necrosis MS08.06: PERITONEAL MESOTHELIOMA: EVALUATION ON PATHOLOGY REPORTING Valeria Ascoli1, Ilaria Cozzi2, Giada Minelli3 , Caterina Carnovale Scalzo2, Emma Rullo1, Elisa Romeo2, Laura Ancona2, Francesco Forastiere2 Radiological, Oncological And Anatomo-pathological Sciences, Sapienza University, Rome, ITALY, 2Department of Epidemiology, Lazio Regional Health Service, Rome, ITALY, 3Unit Of Statistics, Italy’s Institute of Public Health, Rome, ITALY 1 Objectives: Peritoneal mesothelioma (PeM) has not been investigated as extensively as pleural mesothelioma. Incidence rates are low: 0.12/100,000 person-years in men and 0.08 in women in United States (Am J Epidemiol 2004), and 0.26 in men and 0.12 in women in Italy, the largest European asbestos producer (Am J Industr Med 2015). The diagnostic process can be challenging. Guidelines for the pathological diagnosis have focused on some site-specific issues. The aim of this study was to give a contribution to the knowledge of diagnostic practice of PeM on the basis of pathology reporting. Methods: The source of pathology reports were a regional section of the Italian network of Mesothelioma Registries (Lazio; 2001-2014; 5.5 million people, one tenth of the Italian population), and a pathology-based archive operating before the implementation of the registry (1990-2000). We reviewed our database of 928 mesothelioma cases. Of these, 102 were PeM (10.3% of all mesotheliomas). We evaluated the report content and whether and how pathologists follow the immunohistochemistry (IHC) recommendations of the literature (Husain et al, Arch Pathol Lab Med 2013): a panel of at least 2 mesothelioma markers and 2 carcinoma markers as standard. All pathology information was manually entered into a specific iMig2016.ORG 41 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP dataset devised for the study. Asbestos exposure was evaluated through clinical chart review. Results: Reports consisted of 79 histological diagnoses, 23 cytological diagnoses and 1 autopsy. The mean age at diagnosis was 68.5 years in women and 63.4 in men; there was a male predominance (M:F=2.16:1). Available data on asbestos exposure revealed that all persons with ascertained exposure (22% of 102 PeM) were males. More of 60% of women have unknown exposure versus 38% of men. The histology ‘subtype unspecified’ was more frequent (n=47; 46%) than epithelioid (n=41; 40%), well-differentiated papillary (n=8), biphasic (n=5) and sarcomatoid (n=1) mesothelioma. IHC results from 89 reports (87.3%) showed a wide choice of IHC markers (up to 40 different antibodies, with a mean number for each diagnosis of 5.2). The most used markers were calretinin (84.3%, pos=98.6%), HBME-1 (39.3%, pos=97.1), EMA (48.3%, pos=97.7%), pan-cytokeratin (42.6%, pos=97.3%), CEA (41.5%, pos=0%), Ber-EP4 (36%, pos=18.7%) and cytokeratin 7 (37%, pos=90.9%). The compliance to the IHC standard panel was quite low (16 cases; 18%) with no difference by gender (Pearson’s Chi-squared P=0.930). Instead, most frequently used panels were those consisting of at least 2 mesothelioma markers plus 1 carcinoma marker (26 cases; 29%) and of calretinin-only plus either CEA or BerEP4 (27 cases; 30%). 55 pathologists were involved, with a mean number of 5 diagnoses each; 48 pathologists (87%) reported between 1-2 diagnoses; only 2 pathologists reported more than 10 diagnoses. Conclusion: From our small dataset, it emerges an inhomogeneous approach to the diagnosis of PeM, much more than that observed in pleural mesothelioma. Although the guidelines are designed to improve the reporting practice, there is a large scope for improvement in their application, since only a few pathologists are following them for a standardized diagnosis. Keywords: pathology reporting, guidelines, immunohistochemistry MS08.07: THE CRUCIAL CLINICOPATHOLOGICAL APPROACH IN SUPERFICIAL MESOTHELIAL PROLIFERATIONS; MESOPATH EXPERIENCE Francoise Galateau Salle1, Nolwenn Le Stang1, Sylvie Lantuejoul1, Daniel Pissaloux2, Experts Pathologists Mesopath1, Anabelle Gilg Soit Ilg3 , Patrick Brochard4 , Jean Claude Pairon5, Arnaud Scherpereel6 with early mesothelioma is crucial for the optimal management of the patient and also to understand the multistage of carcinogenesis at the dawn of high resolution sequencing. Loss of BAP1 tumor suppressor gene by immunohistochemistry and loss of CDKN2A ( p16 ) by FISH analysis are useful biomarkers of malignancy working on paraffin embedded tissue biopsy samples. In this study we aimed to analyze the profiles of such cases and to propose an algorithm for their clinical management. Methods: We have selected 78 patients including 40 Atypical Mesothelial Hyperplasia of undetermined malignancy (AMH), 16 reactive mesothelial hyperplasia (RMH) and 22 mesothelioma with minimal invasion [MMI], from the MESOPATH files since 1998. Cases included clinicoradiological annotations, survival and were certified according to the standardized procedure of certification of the MESOPATH panel. Cases were evaluated when available for BAP1 loss of expression and P16 by immunohistochemical analysis. FISH studies were performed on paraffin embedded blocks, with more than 50 nuclei counted. A cut off value of >20% for homozygous deletion was considered positive. P16 Heterozygous deletions were excluded. Survival was evaluated with Kaplan Meier analysis and log rank tests. Results: We observed a younger mean age in patients with RMH (55 yrs old range [19; 77]) compared to AMH (68 range [36;90]) and to MMI (69 range [54;84]) p=0.007 with no significant difference for gender and context of asbestos exposure. BAP 1 loss was seen in 35/73 (37%) of the tissue biopsy specimens available, and none observed in RMH, while 22 (63%) was observed in AMH, and 13 (59%) in MMI (p<0.001). Homozygous Deletion of p16 was seen by FISH (22% of cases), and none in RMH, compared to (18%) in AMH and (43%) in MMI p<0.004). BAP1 loss and P16 deletion were not mutually exclusive and both were observed in 6 cases of MMI and 2 cases of AMH. The sensitivity of BAP1 loss by immunohistochemistry and P16 Homozygous deletion by FISH to separate benign versus malignant proliferation (AMH and MMI) was 8/12 (67%) with a specificity 27/41 (66%). RMH have a median survival > to 150 months compared to AMH 31 months and to MMI 15 months. A poorer prognosis was observed in patients with p16 homozygous deletion. Conclusion: Our results confirmed the 100% specificity of BAP1 loss and p16 deletion in separating benign versus malignant proliferation. Interestingly in difficult cases of atypical mesothelial proliferation our study allow to select patients with superficial malignant proliferation to determine a specific clinical scheme for the management of the patients. Keywords: AMH, p16 homoygous deletion, BAP1 loss, clinical management Mesopath, Cancer Center Leon Berard, Lyon Cedex , FRANCE, 2Biopathology, Cancer Center Leon Berard, Lyon Cedex, FRANCE, 3Dst, National French Health Institute, Saint Maurice, FRANCE, 4LSTE-ISPED, Bordeaux Cedex, FRANCE, 5Inserm U 955, CH CRETEIL, Creteil, FRANCE,6Inserm U774, CHRU Calmette, Lille, FRANCE 1 Objectives: Separating benign versus malignant proliferation of the pleura is one of the most challenging situations facing either the pneumologist or the pathologist. Mesothelioma is a multistep process of carcinogenesis with a long delay of latency after asbestos exposure (>40 years). Identification of patient iMig2016.ORG 42 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS08.08: MULTI-OMICS INTEGRATION FOR MALIGNANT PLEURAL MESOTHELIOMA SUBTYPES CHARACTERIZATION Yuna Blum1, Annie Renier2, Nabila Elarouci1, Françoise Galateau-Sallé3 , Marie-Christine Copin4 , Paul Hofman5, Fabien Petel1, Françoise Le Pimpec-Barthes6 , Jessica Zucman-Rossi6 , Aurélien De Reyniès1, Marie Claude Jaurand6 , Didier Jean6 Programme Cartes D’identité Des Tumeurs (cit), Ligue Nationale Contre Le Cancer, Paris, FRANCE, 2Inserm U.1162, INSERM U.1162, PARIS, FRANCE, 3MESOBANK, Lyon, FRANCE, 4CHRU Lille, Lille, FRANCE, 5CHU Nice, Nice, FRANCE, 6Inserm U.1162, INSERM U.1162, Paris, FRANCE 1 Objectives: Identification of patient tumor homogeneous molecular subtypes is essential to understand the underlying oncogenic scenarii and to develop specific therapies. Malignant Pleural Mesothelioma (MPM) molecular heterogeneity was highlighted by previous studies, mainly based on a single omic technology. We recently defined a robust molecular classification defining two groups (C1 and C2), related to prognosis and differing by their mutation frequency of the BAP1 tumor suppressor gene and by their engagement in the epithelial-mesenchymal transition (EMT). In this study, we analyzed multi-omics profiles of MPM with the aim of better characterizing molecular homogeneous subtypes of MPM. Methods: The molecular profiles of 50 MPM cultures and 70 frozen MPM tumor samples were obtained for four types of omics: 1) Transcriptome (Affymetrix/HG-U133-plus-2.0 array), 2) MiRNome (miRNA sequencing), 3) Methylome (Illumina/ Meth450 array), 4) Genome (SNP/Omni-Express-v12.Hg19 array). sification only based on culture samples. Centroid prediction showed a high match between the 2 groups C1 and C2 obtained from the two types of samples. Consistent with our previous findings, the overall survival rate of patients was lower in C2 than in C1 in both types of samples. Pathway analyses again identified EMT as deregulated between C1 and C2, and found new pathways such as angiogenesis, VEGF and BMP signal pathways. SNP array data showed that the chromosome region 3p21, containing the BAP1 locus, is more frequently deleted in the C1 group in agreement with the most frequent BAP1 mutations (Fig.1A). Unsupervised clustering based on methylation profiles classified MPM in groups similar to C1 and C2 both in culture and tumor samples (Fig.1A). As shown in Fig.1B, significant correlation between gene expression and methylation status was observed for several EMT biomarkers. MiRNome data identified several miRNAs deregulated between C1 and C2 groups in the two types of samples. For example, MIR96 was significantly downregulated in MPM of the C2 group associated with upregulation of potential target genes, including CAV1, a gene recently identified as a biomarker of an epithelioid MPM subgroup of poor prognosis (Fig.1C). Conclusion: Multi-omics integration confirms that MPM cultures are representative of the heterogeneity of primary tumors and the occurrence of two main molecular groups in MPM, linked to genetic and epigenetic changes. This integrative genomic analysis highlights new biomarkers, pathways and epigenetic regulatory mechanisms specific to each MPM groups. Keywords: Tumor molecular classification, Signal pathway, Genomics Results: Unsupervised consensus clustering based on gene expression profiles defined two MPM groups both in culture and tumor samples (Fig.1A) in agreement with our previous clas- iMig2016.ORG 43 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS09:SURGERY (TECHINICAL ASPECTS) TUESDAY, MAY 3, 2016 14:15 – 15:45 MS09.01: EXTENDED PLEURECTOMY DECORTICATION FOR PLEURAL MESOTHELIOMA IN THE ELDERLY - THE NEED FOR AN INCLUSIVE YET SELECTIVE APPROACH Annabel J. Sharkey, Ricky Vaja, Sara Tenconi, Apostolos Nakas, David Waller University Hospitals of Leicester, Leicester, UNITED KINGDOM Objectives: The median age at diagnosis of patients with malignant pleural mesothelioma in the United Kingdom is 72 years. In order to continue performing radical surgery we have employed extended pleurectomy decortication (EPD) in favour of extrapleural pneumonectomy given the strict selection criteria required. Recent series have shown the feasibility of EPD in the elderly but with continuing debate about the efficacy of this treatment we reviewed our experience in order to identify more detailed selection criteria. Methods: We reviewed prospectively collected data on all patients from 1999 to 2015 undergoing EPD with the intent of achieving macroscopic complete resection. We compared postoperative outcome and survival in patients 70 years and over with those younger than 70 years. We correlated clinical and pathological data with outcome in the two groups. Results: Seventy nine of 282 patients (28.0%) were 70 years or over at the time of surgery (median age 65, range 42-81 years) There were no differences in demographic or pathological characteristics between the two groups (male; under 70 years, 171 patients (84.2%), 70 years or over, 66 patients (83.5%), epithelioid; under 70 years, 155 patients (76.4%), 70 years or over 62 patients (78.5%)). A higher number of patients in the elderly group required intensive care post-operatively (11 patients (5.4%) vs. 13 patients (16.8%) p=0.004) and developed atrial fibrillation (29 patients (14.4%) vs. 19 patients (24.7%) p=0.051). There were no differences in the prevalence of other post-operative complications between the groups, or in median length of hospital stay (under 70 years 12 days (range 0-70 days), 70 years or over; 14 days (range 2-93 days) p=0.118). There was no intergroup difference in in-hospital (3.5 % vs. 6.5 p=0.323), or 90-day mortality (7.9 vs. 10.1% p=0.635). Elderly patients were less likely to receive adjuvant chemotherapy than younger patients (75 patients (45.7%) vs. 16 patients (29.6%) p=0.040) but overall survival was similar; 10.5 months vs. 13.0 months(p=0.683). However, in those node positive patients survival was significantly decreased in the elderly with non-epithelioid tumours, (3.8 vs. 6.6 months p=0.024) and was also decreased in the elderly with epithelioid disease (9.6 vs. 13.5 months, p=0.485). Survival was similar in all node negative patients. On multivariate analysis, age was not a significant prognostic factor, although lack of adjuvant therapy (HR 2.088 95%CI 1.372-3.176 p=0.001) and pre-operative anaemia (HR 1.976 95%CI 1.294-3.017 p=0.002) remained poor prognostic factors. Conclusion: Whilst age in isolation should not be an exclusion criterion for EPD for pleural mesothelioma, in the elderly a more rigorous preoperative evaluation of nodal disease and an additional assessment of fitness for adjuvant chemotherapy or the consideration of neoadjuvant therapy are recommended. MS09.02: A NEW PROGNOSTIC SCORE FOR TREATMENT ALLOCATION FOR MULTIMODALITY THERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA - AN UPDATE Isabelle Opitz1, Martina Friess1, Olivia Lauk1, Thomas Frauenfelder2, Thi Dan Linh Nguyen-Kim2, Ilhan Inci1, Sven Hillinger1, Didier Schneiter1, Burkhardt Seifert3 , Rolf Stahel4 , Walter Weder1 Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 2Institute of Diagnostic And Interventional Radiology, University Hospital Zurich, Zurich, SWITZERLAND, 3Department of Biostatistics, Epidemiology, Biostatistics And Prevention Unit, University of Zurich, Zurich, SWITZERLAND, 4Clinic For Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 Objectives: We developed a Multimodality Prognostic Score (MMPS) in our patient cohort receiving induction chemotherapy followed by extrapleural pneumonectomy (EPP) or pleurectomy/ decortication (P/D) to facilitate the decision for surgery after induction chemotherapy. Methods: A 4 variable MMPS was developed including pre-chemotherapy tumor volume (>500 ml), progressive disease (PD) after induction chemotherapy (according to modified RECIST criteria), pre-chemotherapy CRP (> 30mg/ml) and non-epithelioid histological subtype. Overall survival (OS) was calculated from the first cycle of induction chemotherapy until death, and association with the score was analyzed using Kaplan-Meier curve and log rank test. Results: Between 1999 and 2015, 253 patients were intended to be treated with induction chemotherapy plus EPP. In 63 undergoing EPP and 20 undergoing pleurectomy/decortication (P/D) all variables of MMPS were available. Median age at diagnosis was 61 years in the EPP group and 65 in the P/D group. Epithelioid type was diagnosed in 81% of the EPP and 95% of the P/D group. IMIG stage III in EPP group was 63% and 65% in the P/D group. In the EPP cohort patients with score 0 survived significantly longer than patients with score 3 or higher (Figure 1). The median OS for patients of the EPP cohort was 34 months (95% CI, 18-50) for score 0, 15 months (9-21) for score 1, 12 months (8-16) for score 2 and 4 months (3-6) for score 3 and 4. In the P/D group the maximum score reached was 2 in only one patient. All the others had a score of 0 or 1. The median OS for score 1 was 30 months (95%CI: 25-36) and 17 months for score 2, but 70% percent of the cases were censored. iMig2016.ORG 44 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Results: Patients undergoing salvage EPD had similar survival to those undergoing more recognized regimes of planned surgery before or after chemotherapy and had better survival than those patients in whom chemotherapy was reserved for disease progression after surgery. This was even though the salvage group were more likely to have nodal metastases. Sal- Neoadvage juvant n=29 n=18 Adjuvant n=67 Reserved for rep currence n=50 Median survival from diagnosis (months) 22.6 25.5 22.2 14.6 tion chemotherapy followed by EPP with different MMPS. Cycles of chemotherapy 4 (212) 4.5 (2-7) 4 (1-10) 5 (1-7) Conclusion: Our Multimodality Prognostic Score considering clinical variables already available before surgery allows identification of mesothelioma patients who would not get any relevant benefit from an intensified therapy. The concept is currently under prospective evaluation Age (years) 61 (4577) 61 (5077) 63 (4276 (52-80) 0.06 80) Male gender (%) 86.2 66.7 92.5 82.0 0.035 Epithelioid cell type (%) 72.4 66.7 86.6 80 0.272 Node positive (%) 74.2 47.1 67.8 46.7 0.035 0 4.5 0 II 6.9 33.3 15.2 22 III 62.1 44.4 62.1 62.0 IV 27.6 22.2 18.2 16.0 Figure 1: Median OS and 95% CI of patients undergoing induc- Keywords: multimodality treatment, prognosis, Macroscopic Complete Resection MS09.04: IT’S NEVER TOO LATE TO OPERATE - AN ANALYSIS OF SALVAGE SURGERY FOR PROGRESSING MALIGNANT PLEURAL MESOTHELIOMA Annabel J. Sharkey, Rocco Bilancia, Ricky Vaja, Sara Tenconi, Apostolos Nakas, David Waller University Hospitals of Leicester, Leicester, UNITED KINGDOM Objectives: The use of extended pleurectomy decortication (EPD) as part of multimodality therapy for malignant pleural mesothelioma remains debatable and many patients receive chemotherapy primarily. We have been asked to consider EPD as an afterthought following the failure of primary oncological treatment, therefore we aimed to determine whether there is a benefit in performing a potentially morbid operation in those thought to have a poor prognosis. Methods: From a prospective database we analyzed 184 patients undergoing EPD as part of multimodality therapy. The clinicopathological data and outcome of patients undergoing salvage surgery for disease progression after initial chemotherapy were compared with the 3 other main therapeutic strategies: neoadjuvant chemotherapy, adjuvant chemotherapy and chemotherapy reserved for disease progression after EPD. All patients underwent similar preoperative staging with CT but without routine mediastinoscopy or CTPET. IMIG stage I 3.4 0.007 0.873 0.325 Conclusion: Lung sparing radical surgery for malignant pleural mesothelioma should not necessarily be denied to patients who have undergone first line chemotherapy and in whom their disease has progressed but remains resectable. MS09.06: EVOLUTION OF SURGICAL APPROACH IN MALIGNANT PLEURAL MESOTHELIOMA Seiki Hasegawa1, Toru Nakamichi1, Ayumi Kuroda2, Masaki Hashimoto1, Teruhisa Takuwa1, Seiji Matsumoto1, Yoshitomo Okumura3 , Nobuyuki Kondo1, Fumihiro Tanaka4 , Noriaki Tsubota5, Norihiko Kamikonya6 , Tohru Tsujimura7, Takashi Nakano8 Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, JAPAN, 2Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, JAPAN, 3Thoracic Surgery, Itami City Hospital, 1 iMig2016.ORG 45 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Itami, JAPAN, 4Surgery Ii, University of Occupational and Environmental Health, Kitakyusyu, JAPAN,5Thoracic Oncology, Hyogo College of Medicine, Nishinomiya, JAPAN, 6Radiation Oncology, Hyogo College of Medicine, Nishinomiya, JAPAN, 7Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, JAPAN, 8Respiratory Medicine, Hyogo College of Medicine, Nishinomiya Hyogo, JAPAN Conclusion: Less invasive surgery for MPM yielded lower surgical risk and also comparable or better survival. Keywords: extrapleural pneumonectomy, Surgery, pleurectomy/decortication, mesothelioma Objectives: The aim of this study was to verify whether or not our approach for less invasive surgery for malignant pleural mesothelioma (MPM) yielded lower surgical risks as well as comparable survival in comparison with highly invasive surgery. Methods: We retrospectively reviewed all patients in a prospective database of MPM Surgery Program at Hyogo College of Medicine between July 2004 and December 2015. Patients with histologically confirmed resectable MPM, IMIG cT13N0-1M0 disease, PS 0-1, no major comorbidity, and written informed consent were registered. All the patients underwent multimodality treatment with neoadjuvant/adjuvant chemotherapy, surgery with or without 54Gy hemithoracic radiation therapy. Group 1; Patients underwent trimodality treatment with conventional extrapleural pneumonectomy (EPP) until August 2009. Group 2: Patients underwent trimodality treatment with less invasive EPP, using hybrid VATS/open technique, since September 2009 to date. Group 3: Patients underwent bimodality treatment with pleurectomy/decortication (P/D) and neoadjuvant plus adjuvant chemotherapy as far as macroscopic complete resection could be achieved since September 2012. All the patients were followed every three months after discharge until death. There was no censored case. Results: Of a total of 129 patients registered, 104 (81%) completed surgery: Group 1 (n=26), Group 2 (n=34), and Group 3 (n=44). Patient characteristics and the results are shown in Table 1. Macroscopic complete resection was achieved in 95% (99/104) of patients, and 30-/90-day mortality rates were 1.9% (2/104) and 3.9% (4/104), respectively. 2-year survival rate and median survival time of Group 1/2/3 were 38%/75%/77%, and 17.7m/43.3m/not reached, respectively (Figure 1). MS10:NOVEL TARGETS ENTERING IN THE CLINIC TUESDAY, MAY 3, 2016 14:15 – 15:45 MS10.01: PHASE I STUDY OF ANTI-MESOTHELIN ANTIBODY DRUG CONJUGATE ANETUMAB RAVTANSINE IN PATIENTS WITH METASTATIC MESOTHELIOMA Raffit Hassan1, Johanna C. Bendell2, George R. Blumenschein, Jr3 , Hedy Kindler4 , Kathleen N. Moore5, Alessandro D. Santin6 , Shelly M. Seward7, John Nemunaitis8 , Prabhu Rajagopalan9, Annette Walter10, Nenad Sarapa9 Thoracic And Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA, 2Drug Development Unit, Sarah Cannon Research Institute, Nashville, TN, UNITED STATES OF AMERICA, 3The University of Texas MD Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 4Radiology, University of Chicago Hospital, Chicago, IL, UNITED STATES OF AMERICA, 5University of Oklahoma Health Sciences Center, Oklahoma City, OK, UNITED STATES OF AMERICA, 6Yale Cancer Center, New Haven, CT, UNITED STATES OF AMERICA, 7Karmanos Cancer Center, Detroit, MI, UNITED STATES OF AMERICA, 88. Mary Crowley Medical Research Center, Dallas, TX, UNITED STATES OF AMERICA, 9Bayer HealthCare Pharmaceuticals, Whippany, NJ, UNITED STATES OF AMERICA, 10Bayer Pharma AG, Berlin, GERMANY 1 Objectives: Anetumab ravtansine (BAY 94-9343; AR) is a novel fully humanized anti-mesothelin IgG1 antibody conjugated to a ravtansine, a maytansine derivative DM4 antitubulin cytotoxic agent. A phase I study evaluating the safety, PK and tumor response with AR was conducted in patients (pts) with advanced solid tumors (NCT01439152). We report here results with q3w dosing in patients with mesothelioma. Methods: AR was administered IV every 21 days (q3w) in 77 pts: 45 pts in 10 dose escalation cohorts from 0.15 to 7.5 mg/ kg (21 mesothelioma, 9 pancreatic, 5 breast, 4 ovarian, 6 other), and 32 pts in 2 expansion cohorts (12 mesothelioma and 20 ovarian); 38 pts were treated at MTD in escalation and expansion cohorts (16 mesothelioma, 21 ovarian, 1 breast). Clinical and laboratory safety assessments were made on D1, D8 and D15 in C1-C3 and on D1 in subsequent cycles. Tumor assessments were made q6wks up to C8 and q12wks thereafter. Mesothelin expression in archival tumor samples was assessed retrospecively by IHC (SP74, Ventana). Results: A total of 77 pts (45 females) were treated with AR q3w and evaluable for safety; mean age 62 yrs (range, 18-84 iMig2016.ORG 46 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP yrs), body weight 77 kg (44-113 kg), ECOG ≤1, median prior cytotoxic regimens: overall 4 (1-9), mesothelioma 1 (1-4). The MTD for AR was 6.5 mg/kg q3w (one DLT: G3 AST increase); DLTs at 7.5 mg/kg indcluded 1 pt with G2 keratitis and G3 neuropathy, and 1 pt with G4 keratitis and G2 neuropathy. Only one DLT (G3 hyponatremia, 5.5 mg/kg) and markedly fewer AEs occurred at doses below the MTD. No drug-related deaths and few drug-related SAEs (7 total and 5 at MTD) were reported. Seventeen of 38 (45%) pts in total or 7 of 16 (44%) mesothelioma pts at MTD had drug-related AE requiring dose reduction (G1-4 keratitis, G2-3 neuropathy, G3 fatigue, anorexia, asthenia, diarrhea, N&V, AST increase). LFT increases were the most common drug-related laboratory abnormality at MTD: AST in 7 pts (2 G3), ALT in 6 pts (no G3), alkaline phosphatase in 4 pts (one G3) and bilirubin increase in 1 pt (no G3). There were no drug-related G3 hematological abnormalities at any dose. Fourteen of 38 (37%) pts total or 4 of 16 (25%) mesothelioma pts at MTD had G1-4 keratitis (worst G3-4 in 3 pts, blurred vision in 10, dose reduction in 8, dose delay in 11, all fully reversible). Five of 16 (31%) mesothelioma pts treated with AR at the MTD had a durable partial response (PR; >600 days in 4 pts) and 7 (44%) had stable disease. The five PRs occurred in 10 mesothelioma pts who received AR as second line treatment (50% response rate). Conclusion: AR at the MTD (6.5 mg/kg) showed encouraging efficacy with durable PRs in pts with metastatic mesothelioma. At the MTD, all drug-related AEs were reversible, non-life-threatening and manageable by dose modification. Given this benefit-risk ratio, the recommended phase II dose of AR in second line treatment of advanced mesothelioma is 6.5 mg/kg IV q3w. Keywords: antibody drug conjugate, mesothelioma, mesothelin MS10.02: PHASE 1 DOSE EXPANSION EXPERIENCE OF ADI-PEG20, PEMETREXED AND CISPLATIN IN PATIENTS WITH MALIGNANT MESOTHELIOMA (TRAP STUDY) Peter Szlosarek1, James Spicer2, Melissa Phillips3 , Jeremy Steele3 , Hannah Rush4 , Monica Diaz5, Adalberto Barba5, Amanda Johnston5, Ramsay Khadeir1, Michael Sheaff3 , John Bomalaski5, Simon Pacey6 Centre For Molecular Oncology, Barts Cancer Institute, London, UNITED KINGDOM, 2King’s College London, London, UNITED KINGDOM, 3Medical Oncology, St. Bartholomew’s Hospital, London, UNITED KINGDOM, 4Guy’s & St Thomas’ NHS Foundation Trust, London, UNITED KINGDOM, 5Polaris Pharma Inc., San Diego, AL, UNITED STATES OF AMERICA, 6Oncology, University of Cambridge, Cambridge, UNITED KINGDOM 1 chemotherapy that included patients with ASS1-deficient malignant pleural mesothelioma (MPM) and observed a 78% partial response (PR) rate in the dose-escalation portion of the study (AACR-NCI-EORTC, Boston 2015). Here, we describe our dose-expansion experience at the maximum tolerated dose (MTD) in patients with MPM. Methods: Main inclusion criteria were: ≥ 18 years, PS ≤ 1, tumour ASS1 loss (≤ 50% ASS expression by IHC) with adequate organ function and written, informed consent. Patients were excluded with: symptomatic CNS metastases, significant concurrent morbidity, therapeutic anticoagulation, history of seizures, or allergy to trial medication(s). Patients were treated at the MTD as follows: weekly ADI-PEG 20 (36 mg/m2 IM) plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 both given every 3 weeks. ADI-PEG 20 alone was allowed after 18 weeks if there was stable disease (SD) or better. Adverse events were graded using CTCAE v4.03. Radiological disease response was assessed every 6 weeks by modified RECIST and peripheral blood samples were collected to measure plasma arginine and citrulline levels and antibodies to ADI-PEG 20. Results: 82 patients were screened for MPM ASS1 expression, 32 (39%) were ASS1-deficient and 20 (62.5%) were enrolled. Subsequently, 17 patients were eligible for toxicity and response assessment, that included 5 patients from the dose-escalation cohort. Demographics - 16 M:1 F, Age range 60-82, Subtype (epithelioid 4, biphasic 6, sarcomatoid 7). Grade 3 or higher AEs related to pemetrexed and cisplatin were (6 pt): nausea/vomiting (2), neutropenia (2), others 3 (number of events 6); 16 AEs were reported possibly related to ADI-PEG 20. Mean cycles (weeks) of treatment: 22.0 (range 5.7-44.3 weeks). Mean (weeks) arginine depletion is 9.6 (range 3-18) weeks in all treated patients. Response by modified RECIST was as follows: 53% (9/17) had a PR and 47% (8/17) had SD for a disease control rate (DCR) of 100% (17/17). Conclusion: The triplet combination of ADI-PEG 20+Pemetrexed+Cisplatin was well tolerated as described in the earlier dose-escalation portion. Robust clinical activity has been observed with a 100% DCR in a population enriched for biphasic and sarcomatoid pathology. The tolerability and high response rate in the poorer prognosis patients suggest that this combination may have clinical utility as first line treatment for ASS1-deficient MPM. The expansion-phase study is ongoing to recruit 30 patients in total and a global randomized placebo-controlled P2/3 study is planned in patients with ASS1-deficient mesothelioma. Keywords: personalized therapy, mesothelioma, ADI-PEG20, ASS1 Objectives: Loss of the metabolic tumor suppressor, argininosuccinate synthetase (ASS1), results in an aggressive phenotype but sensitizes malignant mesothelioma cells to apoptosis with the arginine depleting agent, pegylated arginine deiminase (ADI-PEG 20) which potentiates the cytotoxic effect of pemetrexed. Thus, we initiated a phase I study (NCT02029690) of ADI-PEG 20 combined with first-line pemetrexed and cisplatin iMig2016.ORG 47 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS10.03: TREMELIMUMAB AND DURVALUMAB COMBINATION FOR FIRST AND SECOND-LINE TREATMENT OF MESOTHELIOMA PATIENTS: THE NIBIT-MESO-1 STUDY MS10.04: PHASE 2 NEOADJUVANT STUDY OF VS-6063, A FAK INHIBITOR, IN SUBJECTS WITH SURGICALLY RESECTABLE MALIGNANT PLEURAL MESOTHELIOMA Luana Calabro’1, Aldo Morra2, Diana Giannarelli3 , Diego Annesi1, Erica Bertocci1, Riccardo Danielli1, Maresa Altomonte1, Anna Maria Di Giacomo1, Michele Maio1 Raphael Bueno1, William Richards1, Ritu Gill1, Julianne Barlow1, Patrick Lizotte2, Kwok Wong2, Mark Bittinger2, Yan Wang3 , Lou Vaickus3 , David T. Weaver3 1 Medical Oncology And Immunotherapy Division, University Hospital of Siena, Siena, ITALY, 2Euganea Medica Radiology Center, Padua, ITALY, 3Regina Eelena National Cancer Institute, Rome, ITALY 1 Objectives: Malignant mesothelioma (MM) has a very dismal prognosis and treatment of MM patients remains largely unsatisfactory highlighting the need for new therapeutic approaches. The anti-CTLA-4 monoclonal antibody (mAb) tremelimumab has shown promising activity in pre-treated MM patients: disease control rate (DCR) was 31%, and survival rate at 1- and 2-years was 48.3% and 36.7%, respectively (Calabrò et al., Lancet Oncol, 2013). These initial findings were corroborated by a second study in which, based on pharmacokinetic analyses, an intensified schedule of tremelimumab was utilized. Fifty-two % of patients achieved a DCR (median duration 10.9 months) (Calabrò et al., Lancet Respir Med, 2015). These intriguing clinical results and the emerging efficacy of immunomodulatory mAb targeting the PD-1/PD-L1 axis in different tumor types, prompted us to design the NIBIT-MESO-1 study aimed to investigate the efficacy of tremelimumab combined with the anti-PD-L1 durvalumab (MEDI4736) in MM patients. Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung with early recurrence and a mortality rate of 95-99%. VS-6063 is an oral Focal Adhesion Kinase (FAK) inhibitor that prevents integrin-mediated activation of multiple downstream signal transduction pathways inhibiting tumor cell migration, proliferation and survival in MPM. The primary objectives of this study are to identify biomarkers associated with response to VS-6063, and to establish target inhibition in tumor. Secondary endpoints include safety, pharmacokinetics, and objective response to VS-6063. Methods: Trial Design: The NIBIT-MESO-1 trial is a phase II, open-label, study that will enroll 40 unresectable, first-or second-line pleural or peritoneal MM patients with ECOG performance status 0 or 1. Patients will receive tremelimumab at 1 mg/Kg i.v. every 4 weeks (Q4W) for 4 doses, and durvalumab at 20 mg/Kg i.v. Q4W for 12 months. Patients with progressive disease during the first 12 months of treatment or in the follow-up phase may be retreated with the combination of the two drugs. Modified RECIST (Byrne et al., Ann Oncol, 2004) and RECIST 1.1 will be utilized to assess tumor responses in pleural and peritoneal MM, respectively. Primary objective is immune-related (ir)-objective response rate; secondary objectives are ir-DCR; ir-progression free-survival (PFS), overall survival, DCR, PFS, and safety. Efficacy secondary endpoints will be explored per PD-L1 expression on tumor tissues. Clinical results will be correlated with extensive phenotypic, functional and humoral studies (ClinicalTrials.gov Id: NCT02588131). The study is actively recruiting and 10 patients have been so far enrolled. Results: From October 2015 to December 2015, 10 MM patients (9 pleural, and 1 peritoneal), median age 64 years (range 45-77), M/F= 8/2, have been enrolled. Mesothelioma histology was epithelioid (n=9) or undefined (n=1). Patients received a median of 2.5 doses of therapy (range= 1 to 3) in first (2 patients) or second line (8 patients), and are all on treatment. No grade 3-4 treatment-adverse events have been observed so far. A preliminary safety analysis is ongoing. Conclusion: The study is in progress and actively recruiting Keywords: tremelimumab, mesothelioma, durvalumab, immunomodulatory monoclonal antibody Brigham and Womens Hospital, Boston, MA, UNITED STATES OF AMERICA, 2Belfer Center Dana Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA, 3Verastem, Inc., Needham, UNITED STATES OF AMERICA Methods: An open label, single center, neoadjuvant window of opportunity study design was incorporated to monitor biomarker changes from tumor biopsies and plasma in subjects with MPM who are eligible for extirpative surgery. Approximately 19 subjects received VS-6063 400mg BID for 12 days (Cohort 1) or 35 days (Cohort 2). Tumor volume measurements were calculated from PET-CT. Definitive surgery occurred after a 30 day follow-up period for Cohort 1 and after 7 days for Cohort 2. Analysis of tumor immunomodulation was investigated by comparing tumor specimens collected at diagnosis/screening, on drug treatment at Day 12 or Day 35, and at surgery. Likewise, blood samples were collected at Day 0 and Day 12 to investigate circulating biomarkers. Results: Four of the nineteen patients from Cohort 1 and Cohort 2 had tumor volume reduction of 30% or greater during neoadjuvant VS-6063 treatment. Surgical specimens from Cohort 2 patients and mesothelioma patients not receiving VS-6063 treatment were compared by multi-parameter flow cytometry with immune biomarkers. Whereas tumor CD3+ T cell infiltrates were observed over a wide range, the T, B, myeloid populations were not statistically different between these groups. However, the CD123+ plasmacytoid dendritic cells were decreased (p = 0.03) in VS-6063-treated patients. Comparing the specimens isolated before and after VS-6063 treatment, two patients showed increased CD8+ T cells, and one of the patients showed 40% fewer FOXP3+ T cells (Tregs) by IHC. Higher baseline FOXP3+ T cells were an indicator of tumor reduction in the Cohort 2 patients. Plasma cytokine changes were monitored by comparing blood samples isolated at screening with Day 12 of VS-6063 treatment. Notably, IL-10, an immunosuppressive cytokine was significantly diminished after VS-6063 (p = 0.0186). Conclusion: Neoadjuvant treatment of mesothelioma patients with VS-6063 for either 12 or 35 days was associated with a tumor volume reduction and tumor immunomodulation. As IL-10 is an immunosuppressive cytokine produced by FOXP3+ T cells the decreased circulating IL-10 levels are potentially indicative iMig2016.ORG 48 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP of tumor immunomodulation by VS-6063. Further evaluation of biomarker responses to VS-6063 in the neoadjuvant setting is warranted. Keywords: FAK, immunomodulation, neoadjuvant, mesothelioma MS10.05: PHASE I EXPERIENCE WITH TARGOMIRS IN MALIGNANT PLEURAL MESOTHELIOMA Nico Van Zandwijk1, Nick Pavlakis2, Steven Kao3 , Stephen Clarke4 , Anthony Linton5, Michael Boyer3 , Himanshu Brahmbhatt6 , Jennifer Mcdiarmid6 , Yennie Huynh7, Felicity Leslie7, Helen Foster6 , Scott Pattison6 , Glen Reid7 Northern Cancer Institute, Asbestos Diseases Research Institute, Concord, NSW, AUSTRALIA, 2Northern Cancer Institute, Sydney, NSW, AUSTRALIA, 3Chris O’Brien Lifehouse, Camperdown, NSW, AUSTRALIA, 4Northern Cancer Institute, University of Sydney, Sydney, NSW, AUSTRALIA,5Dept Oncology Concord Hospital, Concord, NSW, AUSTRALIA, 6EnGeneIC, Lane Cove, NSW, AUSTRALIA, 7Asbestos Diseases Research Institute, Concord, NSW, AUSTRALIA than 40 weeks. Repeat imaging revealed 9 patients with SD at 8 weeks (modified RECIST). Updated results will be presented. Conclusion: Weekly infusions of 5 billion TargomiRs are rather well tolerated. Rapidly transient inflammatory (cytokine-mediated) symptoms were noticed shortly after the infusions. Blood examinations reveal a dynamic pattern of changes in heamatologic and non-heamatologic parameters after TargomiR infusion. It is assumed that transient hypophosphatemia is induced by the cytokine reactions elicited by TargomiRs. The transient subtle ST-T changes noted at repeat electrocardiography are also thought to be associated with the inflammatory syndrome. Documentation of 2 objective responses and 9 patients with stable tumour measurements after 8 weeks of TargomiR treatment point to single agent activity of TargomiRs. Keywords: phase I study, microRNA-based therapy, Inflammatory reactions, Malignant pleural mesothelioma 1 Objectives: MesomiR 1 is the first-in-man phase I study testing the intravenous administration of TargomiRs. TargomiRs are nanoncells (EDVTM) packaged with miR-15/16- derived microRNA mimics targeted with EGFR antibodies. Patients with malignant pleural mesothelioma (MPM) recurring after standard therapy were asked to participate. Methods: A 3-6 patient dose escalation cohort design examining weekly/twice weekly TargomiR infusions is being used (Clinical Trials.gov: NCT02369198/ ANZCTR-ACTRN12614001248651). Patients tolerating TargomiR infusions well were allowed to continue protocol therapy for at least 8 weeks. Fifty percent of the Maximal Tolerated Dose (MTD) previously established for EDVs was chosen as a first dose level (= 5 billion TargomiRs packaged with a total of 1.5 microgram miR-15/16 mimics). CT, FDG-PET and pulmonary function assessment were scheduled at 8 week intervals and Quality-of-Life (QoL) questionnaires (EORTC) were requested on a weekly basis. Results: Fifteen male and three female MPM patients, failing on standard therapy received different doses and schedules of TargomiRs ranging from 1 billion (once a week) to 5 billion (twice a week). Currently a total of 221 weeks of TargomiR treatment is being analysed. TargomiRs at a dose of 5 billion were rather well tolerated when administered once a week. Rapidly transient inflammatory symptoms including shivering/ rigor, temperature elevation and pain at tumour sites in the chest were noted shortly after TargomiR infusion but seldomly exceeded CTC grade 3. The transient inflammatory symptoms were accompanied by neutrophilia, lymphopenia, hypophosphatemia, and sometimes elevation of liver enzymes. Transient (asymptomatic) ECG (ST-T) changes were noted in 4 patients and were also suspected to be part of the inflammatory reactions noted. Repeat imaging revealed 2 objective responses (PR) and both patients remained on experimental therapy for more MS10.06: ONCOLYTIC HERPESVIRUS THERAPY FOR MESOTHELIOMA - A PHASE I/IIA TRIAL OF INTRAPLEURAL HSV1716 (NCT01721018) Penella Woll1, Sarah Danson1, John Edwards2, Patricia Fisher1, Kevin Blyth3 , Joe Conner4 University of Sheffield, Sheffield Teaching Hospitals, Sheffield, UNITED KINGDOM, 2Northern General Hospital, Sheffield, UNITED KINGDOM, 3Respiratory Medicine, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM, 4Virttu Biologics Ltd, Glasgow, UNITED KINGDOM 1 Objectives: Malignant pleural mesothelioma (MPM) remains a major challenge, with limited therapeutic options. Multifocal intrapleural disease can cause disabling symptoms of pain and breathlessness, in the absence of distant metastases, so an intrapleural treatment approach is attractive. HSV1716 (Seprehvir) is a mutant herpes simplex virus type 1 deleted in the RL1 gene which encodes the protein ICP34.5, a specific determinant of virulence. Mutants lacking the RL1 gene are capable of replication in actively dividing cells but not in terminally differentiated cells – a phenotype exploited to selectively target and kill tumour cells. Additionally, oncolysis of the target cancer cell also stimulates an anti-tumour T-cell mediated immune response Activity against mesothelioma has been demonstrated in animal models. Clinical studies with HSV1716 have been completed in adult glioma, melanoma, H&NSCC and it is well-tolerated with no shedding in patients. We have therefore designed and implemented a phase I/IIa trial to determine the safety and potential for efficacy of HSV1716 given intrapleurally to patients with MPM. Methods: The study is an open label, dose escalation, phase I/IIa trial currently open at two clinical centres. Patients with a histological diagnosis of MPM and a Rocket® or PleurX® indwelling pleural catheter (IPC) are eligible if they have performance status ≤ 2 and adequate hematologic, renal and liver function. Patients will receive 1x107 pfu HSV1716 through their pleural catheter on one, two or four occasions a week apart, in three separate patient cohorts. An extension cohort of three iMig2016.ORG 49 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP patients will be treated at the highest tolerated dose. The primary objectives are to determine the safety and tolerability of HSV1716 given intrapleurally in patients with inoperable MPM. Detailed safety analyses will be undertaken. The secondary objective is to obtain evidence of HSV1716 replication/persistence and patient immune responses through analysis of pleural fluid collected on alternate days for one week, after the last HSV1716 administration, then weekly. An exploratory objective will be to assess tumour response by CT using modified RECIST criteria. Results: Three patients have received a single dose of HSV1716 through their IPC, three have received two doses and four have received four doses with recruitment of an additional two patients required at the four dose level to complete the trial. HSV1716 is well-tolerated with a limited number of possibly related adverse events identified. There is evidence of HSV1716 replication/persistence in most patients and the potential for anti-tumour immune responses has also been observed in patients. Conclusion: Two patients receiving 4 doses of HSV1716 are required to complete the study and a randomised phase II study of intrapleural HSV1716 is under consideration. Keywords: intrapleural, Immunotherapy, oncolytic HSV, clinical study 20-85 years with chemotherapy-resistant malignant pleural mesothelioma who had not received chemotherapy in the last 6 weeks, had an Eastern Cooperative Oncology Group performance status of 0-1, had certain functions of bone marrow, liver, kidney, and lung at the screening visit, had evaluable or measurable lesion with CT or MRI, had lesion which can be administrated with HVJ-E, and a life expectancy of >8 weeks. Exclusion criteria were presence of central nervous system metastases, autoimmune disease, interstitial pneumonia or pulmonary fibrosis needed to treatment, hemostatic disorder, and other malignant lesions, use of systemic glucocorticosteroids, a history of treatment with other investigational products last 4 weeks before the informed consent. The protocol is consistent of initial intra-tumoral administration of HVJ-E and the subsequent three subcutaneous administration within two weeks and then washed out for two weeks. This one cycle will be repeated twice. HVJ-E will be given at a lower dose for each injection. If dose-escalation is permitted by independent data monitoring committee, another cohort will be given at a higher dose of each injection. Results: This phase I clinical trial is now in progress. Conclusion: We will make a presentation of the detail about this trial, and the preclinical study of HVJ-E. Keywords: immunotherapy, HVJ, HVJ-derived nanoparticle MS11: CRITICAL SIGNALING PATHWAY TUESDAY, MAY 3, 2016 14:15 – 15:45 MS10.07: A PHASE I CLINICAL TRIAL OF HVJDERIVED NANOPARTICLE FOR CHEMOTHERAPYRESISTANT MALIGNANT PLEURAL MESOTHELIOMA Chunman Lee1, Atsuhiro Saito1, Yoshihisa Kadota2, Shinji Atagi3 , Takashi Nakano4 , Yasufumi Kaneda5, Meinoshin Okumura6 Medical Ctr. For Translational Research, Osaka University, SUITA, JAPAN, 2Surgery, Osaka Prefectual Medical Center for respiratoy and allergic diseases, Habikino, JAPAN, 3Kinki-Chuo Chest Medical Center, Sakai, JAPAN, 4Hyogo College of Medicine, Nishinomiya, JAPAN, 5Division of Gene Therapy Science, Osaka University, Suita, JAPAN, 6Department of Thoracic Surgery, Osaka University, Suita, JAPAN 1 Objectives: Hemagglutinating Virus of Japan Envelope (HVJ-E): HVJ-derived nanoparticle, possess the various antitumor activities whose mechanism is different from chemotherapy. One is enhancing multiple antitumor immunities such as activation of dendritic cells, induction of natural killer cells and CTL, and suppression of regulatory T cells. Other activities are direct tumor-killing by the induction of cell death through the RIG-I/MAVS pathway. We examined the actual antitumor activities of HVJ-E on the orthotopic implantation model, and HVJ-E had significant antitumor activity compared with control group. We therefore do the phase I dose escalation safety/ tolerability and preliminary efficacy study of intra-tumoral and subcutaneous administration of HVJ-E in patients suffering from chemotherapy-resistant malignant pleural mesothelioma for clinical applications. Methods: In this phase I trial, we are recruiting patients aged MS11.01: ANTAGONIZING THE HEDGEHOG PATHWAY WITH VISMODEGIB IMPAIRS MALIGNANT PLEURAL MESOTHELIOMA GROWTH IN VIVO BY AFFECTING STROMA Mayura Meerang1, Karima Bérard1, Emanuela Felley-Bosco2, Olivia Lauk1, Bart Vrugt3 , Andreas Boss4 , David Kenkel4 , Angela Broggini-Tenzer5, Rolf Stahel6 , Stephan Arni1, Walter Weder1, Isabelle Opitz1 Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 2Department of Molecular Oncology, University Hospital Zurich, Zurich, SWITZERLAND, 3Institute of Surgical Pathology, University Hospital Zurich, Zurich, SWITZERLAND, 4Institute of Diagnostic And Interventional Radiology, University Hospital Zurich, Zurich, SWITZERLAND, 5Laboratory For Molecular Radiobiology, Radiation Oncology, University Hospital Zurich, Zurich, SWITZERLAND, 6Clinic For Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 Objectives: Upregulation of the Hedgehog (Hh) signaling pathway is associated with poor prognosis of malignant pleural mesothelioma (MPM) patients. An autocrine driven upregulation of the Hh pathway was described in MPM, in which the ligand, desert hedgehog (DHH), was produced from tumor cells. Paracrine activation of Hh signaling has been described in other iMig2016.ORG 50 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP solid tumors and our recent investigation revealed that the Hh pathway was activated in both tumor and stroma of human MPM specimens. In this study, we investigated the importance of paracrine Hh signaling in MPM progression in vivo. Methods: We employed an orthotopic immunocompetent rat MPM model. Sarcomatoid rat MPM cells transfected with luciferase (IL45-luc) were implanted subpleurally in Fischer rats. After tumors were formed, rats were treated orally with a FDA approved Hh antagonist, vismodegib, (once daily, 100 mg/ kg; n=6) for 6 days while control group (n=6) received vehicle alone. Tumor load was monitored by bioluminescence, magnetic resonance imaging (MRI) and macroscopically. Tumors were harvested and evaluated for Hh target genes expression by quantitative real time PCR and immunohistochemistry. Tumor cells were isolated and cultured in medium without serum at 37°C, 5%CO2 and 3%O2. Tumor cell culture supernatant was collected freshly and applied to confluent mouse embryonic fibroblasts (NIH3T3). The expression of Hh pathway target genes in NIH3T3 cells were analysed at 72h afterwards by quantitative real time PCR. Results: Similar to that observed in human MPM specimens, positive immunohistochemical staining of Hh pathway components, Glioma associated oncogene 1 (GLI1) and Patched1 (PTCH1), were detected in both tumor and stromal fractions of the rat MPM model. Hh ligand, DHH, was predominantly expressed in the tumor fractions. Daily treatment with vismodegib in vivo efficiently downregulated Hh target genes, Gli1, Hedgehog Interacting Protein (Hhip) and Ptch1, and caused a significant reduction of tumor volume, and tumor growth delay. Tumor cell proliferation, Ki-67 and phospho-histoneH3 positive indices, were significantly reduced in the treated group. Immunohistochemical analyses revealed that vismodegib treatment primarily down regulated Hh target genes, GLI1 and HHIP, in the stromal compartment along with a reduced expression of previously described fibroblast Hh responsive genes such as Fibronectin (Fn1) and vascular endothelial growth factor (Vegf ). Primary cells isolated from the rat tumors cultured in physiological O2 level (3%) continued to express Dhh but did not respond to vismodegib treatment in vitro. However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse fibroblasts NIH3T3 which was suppressed by vismodegib treatment. Conclusion: MPM cells expressed ligand and induced Hh response in fibroblasts, implying the role of paracrine Hh signaling in MPM. Hh pathway activated fibroblasts in turn produced growth factors important for tumor progression. Hh pathway antagonization in MPM stroma efficiently delayed tumor cell growth, emphasizing the importance of Hh pathway as a treatment target for MPM. In addition, our study highlights the significant aspect of tumor-stroma crosstalk in promoting MPM progression. Keywords: Paracrine, Orthotopic rat mesothelioma model, Hedgehog signaling pathway, Stroma MS11.02: SIRT1 AT THE CROSSROADS OF AKT1 AND ERβ IN MALIGNANT PLEURAL MESOTHELIOMA CELLS Giulia Pinton1, Sara Zonca1, Arcangela G. Manente1, Maria Cavaletto2, Ester Borroni3 , Antonio Daga4 , Puthen V. Jithesh5, Dean Fennell6 , Stefan Nilsson7, Laura Moro1 Pharmaceutical Sciences, University of Piemonte Orientale, Novara, ITALY, 2Sciences And Technological Innovation, University of Piemonte Orientale, Alessandria, ITALY, 3Health Sciences, University of Piemonte Orientale, Novara, ITALY, 4IRCCS San Martino-IST, Genova, ITALY, 5Sidra Medical and Research Center, Doha, QATAR, 6Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 7Biosciences And Nutrition, Karolinska Institutet, Huddinge, SWEDEN 1 Objectives: Characterize the role of AKT isoforms in human malignant pleural mesothelioma (MPM). Methods: We have evaluated the expression and function of AKT isoforms in MPM tumor samples and MPM derived cell lines. Results: Here we show that MPM patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independent cell growth in vitro and highlight the AKT1 isoform-specific nature of these effects. We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1. Our data demonstrate a role of the AKT1/SIRT1/FOXM1 axis in the expression of the tumor suppressor ERβ. We further demonstrate an inhibitory feedback loop by ERβ, activated by the selective agonist KB9520, on this axis both in vitro and in vivo. Conclusion: Our data broaden the current knowledge of ERβ and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM. Keywords: Malignant pleural mesothelioma, AKT isoforms, ERbeta MS11.03: EVALUATION OF SENSITIVITY TO PI3K/ MTOR AND FAK INHIBITION IN PRE-CLINICAL MODELS OF MALIGNANT MESOTHELIOMA Ian R. Powley1, Xiao-Ming Sun1, Tatyana Chernova1, Sara Galavotti1, Stefano Grosso1, Joaquin Zacarias-Cabeza1, John Le Quesne2, Jonathan Bennett2, Apostolos Nakas2, J. H. Pringle3 , Anne E. Willis1, Dean Fennell2, Marion Macfarlane1 MRC Toxicology Unit, Leicester, UNITED KINGDOM, 2Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UNITED KINGDOM, 3University of Leicester, Leicester, UNITED KINGDOM 1 iMig2016.ORG 51 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Objectives: Despite the increasing prevalence of Malignant Mesothelioma (MM), there remains a paucity of approved, effective therapy for this cancer. There is therefore an urgent need for novel treatments targeting this disease. Recent studies of MM cell lines and primary tumours revealed a high level constitutive activation of both the phosphotidylinoside 3 kinase (PI3K) and Focal Adhesion Kinase (FAK) signalling pathways; events which have previously been associated with poor patient prognosis. Therefore, dual inhibition of these key pathways may prove beneficial in targeting MM cells for growth arrest and/or apoptosis. The objective of this study is to evaluate the sensitivity of pre-clinical MM patient models to PI3K/mTOR and FAK inhibition, and correlate this to genetic and other biomarkers. Methods: Patient-derived MM cell lines were established (Chernova, Sun et al, Cell Death Differ., in press) and used to evaluate the efficacy of the pan-PI3K/mTOR inhibitor VS-5584 and the FAK inhibitor VS-6063, which are both in clinical trials for MM, in 2D and 3D culture models. Cell cycle status and apoptotic cell death were assayed by flow cytometry using propidium iodide incorporation and phosphatidylserine externalisation and/or Caspase-Glo® assay, respectively. Inhibition of cell signalling pathways was assessed by western blotting. In addition, using an ex-vivo 3D tumour explant model that retains the tumour microenvironment, we have treated freshly resected MM patient explants with VS-5584 and/or VS-6063 and assessed on-target drug effects and induction of apoptosis by histology and immunohistochemistry. Results: In 2D culture, treatment of patient-derived MM cell lines with VS-5584 and VS-6063 results in a rapid inhibition of their respective signalling pathways and concomitant inhibition of cell proliferation and induction of cell cycle arrest, without induction of apoptosis. In contrast, combination treatment of both 3D tumour explants ex vivo and cells cultured in a 3D matrigel model with VS-6063, results in inhibition of FAK signalling and corresponding induction of apoptosis. Conclusion: In a MM patient-derived ex-vivo 3D explant model, VS-6063 both as a single agent and in combination with VS5584 induces apoptotic cell death; this platform enables us to correlate drug sensitivity to genetic and other biomarkers and has the potential to permit molecular stratification of MM patients for future clinical trials. Keywords: FAK, PI3K/mTOR, Cell Death, Pre-Clinical Models are restored using mimics. Results from our lab have led to the world’s first clinical trial of a microRNA replacement strategy in thoracic cancer patients, currently nearing the end of Phase I. The study presented here consisted of a head-to-head comparison of microRNA mimics and aimed at identifying the most potent microRNAs for future development as therapeutic agents. Methods: Synthetic mimics were designed based on mirbase sequences of previously reported tumour suppressor microRNAs: miR-1, miR-15a, miR-15b, miR-16, miR-29c*, miR-31, miR-34a, miR-34b, miR-34c, miR-126, miR-137, miR-145 and miR-193a-3p. These were used at three concentrations (1.1, 3.3 and 10 nM) to transfect a panel of MPM cell lines (MSTO-H211, H2052, H28, MM05, VMC23), and effects on growth were measured using standard proliferation and colony formation assays. The most growth inhibitory microRNA mimics were further investigated to understand mechanism of growth inhibition using apoptosis, cell cycle, senescence and migration assays. Active mimics were used together to identify synergistic combinations, with bioinformatics used to predict pathways affected by mimic combinations. Results: Of the microRNAs previously reported to have growth inhibitory activity, mimics corresponding to miR-15a, miR-15b, miR-16, miR-34a, miR-34b, miR-34c, miR-137 and miR-193a-3p were strongly growth inhibitory in all cell lines, showing greater than 50 % growth inhibition at a concentration of 3.3 nM, with miR-137 the most active overall in all cell lines tested. In contrast, miR-126 was highly active in only 2 of the investigated cell lines, whereas the other microRNA mimics were modestly active at 10 nM or inactive at all concentrations used. Induction of apoptosis and cell cycle arrest were the most common mechanisms of action. The highly active microRNAs had multiple common target genes involved in cell cycle and apoptosis, and these targets were downregulated following transfection of the mimics. Synergistic activity of mimic combinations was exemplified by the combination of miR-16 with miR-193a-3p, which exceeded the activity of either mimic alone. In general, microRNAs with less overlap in target genes yielded the greatest combinatorial effect. Conclusion: Multiple microRNAs exhibit tumour suppressor characteristics with growth inhibitory activity, and this head-tohead comparison reveals miR-137 to be the most effective at inhibiting MPM cell growth in vitro. This, and combinations such as miR-16 with miR-193a-3p, represent candidates for future clinical development as therapeutic agents. Keywords: tumour suppressor, microRNA MS11.04: IDENTIFYING MICRORNAS WITH THERAPEUTIC POTENTIAL IN MALIGNANT PLEURAL MESOTHELIOMA Glen Reid, Andrew Della Gatta, Hyerim Suh, Marissa Williams, Yuen Yee Cheng, Ruby Lin, Nico Van Zandwijk Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA Objectives: MicroRNA expression is globally downregulated in cancers including malignant pleural mesothelioma (MPM). We and others have shown that multiple microRNAs have tumour suppressor activity in MPM cell lines when the levels MS11.05: MICRORNA-31 REGULATES CHEMOSENSITIVITY IN MALIGNANT PLEURAL MESOTHELIOMA VIA ALTERED INTRACELLULAR DRUG LOCALISATION Hannah L. Moody1, Michael J. Lind2, Stephen G. Maher3 School of Biological, Biomedical And Environmental Sciences, University of Hull, Hull York Medical School, Hull, UNITED KINGDOM, 2Centre For Oncology And Haematology, Hull and 1 iMig2016.ORG 52 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP East Yorkshire NHS Trust, Hull, UNITED KINGDOM, 3School of Biological, Biomedical And Environmental Sciences, University of Hull, University of Hull, Hull, UNITED KINGDOM Objectives: Malignant pleural mesothelioma (MPM) is associated with extremely poor prognosis and many patients are unresponsive to treatment; developing resistance to chemotherapeutics. MicroRNA (miRNA/miR) are small, non-coding RNA that function to regulate gene expression and have been demonstrated to alter cellular sensitivity to cytotoxic agents in various cancers. MiR-31 is encoded on chromosome 9p21.3, which is reportedly the most frequently deleted genomic location in MPM tumours. Here, we examined if dysregulation of miR-31 alters MPM chemosensitivity. Methods: The miR-31 deficient NCI-H2452 and miR-31 positive P31 epithelioid cell lines were used as in vitro models of MPM. Stable miR-31 overexpression or suppression was achieved via liposomal-based transfection of plasmid-based vectors and antibiotic selection. Clonogenic assay was employed as a measure of cellular sensitivity to cisplatin and carboplatin; colonies were enumerated in an unbiased manner using a GelCount device. Inductively coupled plasma mass spectrometry (ICP-MS) was utilised to quantify cellular cisplatin flux. Subcellular fractionation via sucrose gradient centrifugation was used to isolate intracellular organelles. Immunofluorescent microscopy was used to visualise intracellular localisation and protein density. Gene expression was assessed by qPCR and protein expression by Western Blot. Results: Surprisingly, reintroduction of miR-31 into cisplatinand carboplatin-treated NCI-H2452 cells significantly increased chemoresistance compared to vector controls; conversely, suppression of miR-31 in P31 cells increased cellular sensitivity to cisplatin. Additionally, miR-31 reintroduction mediated a delay in the cytotoxic activity of chemotherapy. Interestingly, a higher relative intracellular concentration of platinum was observed in miR-31 transfected cells, potentially as a result of increased expression of the plasma membrane-bound cisplatin influx transporter CTR1. However, a concurrently significantly decreased intranuclear concentration of platinum was determined in miR-31 expressing cells, suggesting altered nuclear transport or sequestration within the cytosolic compartment. Consequently, DNA damage was found to be greatly reduced in miR-31 expressing NCI-H2452 cells, and antagonistically higher in miR-31 suppressed P31 cells, supporting the alteration in transit to the nucleus. Subsequently, we identify that a miR-31-mediated increase in the lysosomal-associated drug transporter ABCB9, in conjunction with reduced expression of the associated bipotential transcription factor OCT1, may promote the extranuclear sequestration of chemotherapeutic agents in lysosomes in MPM cells expressing miR-31. Conclusion: Here, miR-31 expression was found to significantly enhance chemoresistance in MPM cells in vitro. While deletions in the genomic location encoding miR-31, 9p21.3, may be associated with an overall poor prognosis, the loss of miR-31 may not actually contribute to the chemoresistance observed in MPM patients. Our current work further examines the impact of how miR-31 functionally modulates intracellular spatial distribution of cisplatin. Additionally, the manipulation of both OCT1 and ABCB9 expression is ongoing in order to determine the relative contributions of these molecules to the chemoresistant phenotype observed. Keywords: microRNA, ABCB9, DNA damage, chemotherapy MS11.06: TARGETING THE RATE-LIMITING STEP OF PROTEIN SYNTHESIS OVERCOMES CHEMORESISTANCE IN MALIGNANT MESOTHELIOMA Stefano Grosso1, Kate Dudek1, Carolyn Jones1, Jack Godfrey1, Ruth Spriggs1, Ania Wilczynska1, Tatyana Chernova1, Xiao-Ming Sun1, Gareth J. Miles1, David Dinsdale1, Jonathan Bennett2, Apostolos Nakas2, John Le Quesne1, Kelvin Cain1, Marion Macfarlane1, Martin Bushell1, Anne E. Willis1 MRC Toxicology Unit, Leicester, UNITED KINGDOM, 2Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UNITED KINGDOM 1 Objectives: Translation of mRNA into protein is a metabolic energy demanding process. As a consequence, protein synthesis is highly regulated, mainly at the stage of initiation; a process that requires eukaryotic initiation factors (eIFs) to recruit the mRNA to the ribosomes. eIFs are downstream targets of signal transduction pathways activated by growth factor stimulation, first leading to an increase of translation and cell size, then to cell division, finally to tumour formation. The objective of this study is to modulate and re-shape tumour cell protein synthesis to prevent cancer progression. Methods: Malignant Mesothelioma (MM) primary cell lines were established from freshly resected patient tumours (Chernova, Sun et al., Cell Death Differ., in press). Transcription, translation and miRNA expression were analysed by specific arrays, followed by bioinformatics analysis. To analyse translation status ribosomes from MM primary cell lines (in addition to untransformed controls) were separated on sucrose gradients and translating mRNAs were analysed with an unbiased array approach. Northern and western blot were used to confirm the proteins overexpressed in MM patients compared to healthy control mesothelial cells. Candidate novel biomarkers were identified and their biological role in MM was evaluated. Results: Analysis of the transcriptome and the translatome of MM primary cells relative to untransformed control identified distinct changes in tumors samples in subset of mRNAs (Fig 1A). Our data showed that the upregulation of translation (Fig 1B) was, in part, driven by increased expression of factors required for both the initiation and elongation stages of proteins synthesis (Grosso et al., PLoS One, 2011; Miluzio et al., Oncotarget, 2015). Interestingly, there was a direct correlation between eIFs expression and the degree of MM sensitivity to cisplatin treatment. Furthermore, the data suggest an increase in polyribosomal association of mRNAs involved in the mitochondrial stress response and a corresponding increase in synthesis of these proteins in MM. Finally, bioinformatics analysis allowed the identification of 5’UTR consensus motifs in the mRNAs that were preferentially translated in MM cells. iMig2016.ORG 53 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Conclusion: Alteration of signalling pathways upstream of the translational machinery and/or the expression of key translation initiation factors modulates the response of MM tumour cells to cisplatin-based chemotherapy. The link between translation and the energetic metabolism of this tumour is currently under consideration. Taken together, these studies may elucidate new strategies to treat this disease. Keywords: miRNA, Translation, Transcription, Ribosome MS11.07: THE ROLE OF MONOCYTE CHEMOTACTIC PROTEIN-1 (MCP-1) IN MESOTHELIOMA-INDUCED MALIGNANT PLEURAL EFFUSION FORMATION Sally M. Lansley1, Hui Min Cheah2, Catherine A. Rinaldi3 , Jenette Creaney3 , Yc Gary Lee4 Pleural Medicine Unit, Institute for Respiratory Health, Perth, WA, AUSTRALIA, 2Institute for Respiratory Health and School of Medicine & Pharmacology, University of Western Australia, Perth, WA, AUSTRALIA, 3School of Medicine and Pharmacology, National Centre Of Asbestos Related Diseases, University of Western Australia, Nedlands, WA, AUSTRALIA, 4Institute for Respiratory Health, School of Medicine & Pharmacology, University of Western Australia and Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, WA, AUSTRALIA 1 Objectives: More than 90% of malignant pleural mesothelioma (MPM) patients present with a pleural effusion. Current methods of managing effusions are limited. Therefore, identifying mechanisms of malignant effusion formation may provide novel therapeutic options. We recently demonstrated that MCP1 plays a major role in the formation of fibrinolytic-induced pleural effusion. Others have established MCP-1 as a driver of malignant pleural effusion in a mouse model of lung cancer. We therefore aimed to determine whether MCP-1 contributes to MPM effusion development. Methods: Expression of MCP-1 mRNA and protein in human (n=11) and mouse (n=9) mesothelioma cell lines was measured by RT-PCR and MCP-1 protein expression and distribution in human and mouse cells examined by immunocytochemistry. MCP-1 levels were quantified by ELISA in pleural fluid supernatants from 197 patients. Pleural fluid samples (n=298) collected longitudinally from MPM patients were also assessed for iMig2016.ORG 54 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP changes in MCP-1 levels. In vivo effects of MCP-1 inhibition on MPM-induced pleural effusion were examined using an MCP-1 receptor (CCR2) antagonist (up to 6 daily injections) or MCP-1 neutralising antibody (4 daily injections) delivered intraperitoneally. Results: All mouse and human mesothelioma cell lines tested expressed MCP-1 mRNA and protein. MCP-1 protein was distributed within the nucleus and cytoplasm of mesothelioma cells. MCP-1 levels were significantly higher in MPM pleural effusions (n=78) than in non-MPM pleural fluids (n=119; from metastatic pleural carcinomas/benign causes): median 1140 vs 450 pg/ml respectively, p =0.02. Longitudinal measurements of pleural fluid MCP-1 levels in 35 patients showed a significant increase in expression (0.37±0.13 pg/ml/100 days, p =0.005) as tumour progressed. Extensive pleural mesothelioma tumour and large pleural effusions were induced in CBA mice (n=63) by intrapleural injection of murine mesothelioma (AC29) cells. CCR2 antagonist treatment significantly reduced pleural effusion volumes (median (IQR); controls: 843 (583-1234) μL vs treatment group 270 (146-835) μL, p =0.03. Treatment with MCP-1 neutralising antibody also significantly reduced pleural effusion volumes (mean±SEM; 72.9±12.4 μL) compared to IgG isotype (174.0±39.8 μL) and saline (127.4±10.3 μL) controls, p =0.03. Tumour weights did not differ significantly between any treatment groups. Conclusion: MCP-1 is significantly over-expressed in MPM effusions and inhibition of MCP-1 activity potently reduced the formation of MPM effusion. MCP-1 represents a potential therapeutic target to control MPM malignant effusions. Keywords: MCP-1, Pleural effusion MS12: TREATMENT ADVANCES IN PERITONEAL MESOTHELIOMA / PALLIATIVE CARE FOR ALL MESOTHELIOMA TUESDAY, MAY 3, 2016 14:15 – 15:45 MS12.01: PERITONEAL MESOTHELIOMA: PHASE-II TRIAL OF TAILORED SYSTEMIC CHEMOTHERAPY BASED ON SENSITIVITY TESTS ON PRIMARY CELL CULTURES Dario Baratti1, Shigeki Kusamura1, Rossella Bertulli2, Federica Perrone3 , Antonello D. Cabras3 , Marzia Pennati4 , Marcello Guaglio1, Nadia Zaffaroni4 , Marcello Deraco1 Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milano, ITALY, 2Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, ITALY, 3Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, ITALY, 4Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, ITALY 1 tive surgery and hyperthermic intra-peritoneal chemotherapy (CRS/HIPEC). However, the comprehensive management of this disease has yet to be optimized, and the role of perioperative systemic chemotherapy (s-CT) is still poorly defined. The aim of this phase-II trial was to assess the impact of individualized postoperative s-CT in DMPM patients treated with CRS/HIPEC, based on the chemosensitivity profile on primary cell cultures. Methods: CRS involved peritonectomy procedure and mutivisceral resections, according to a standardized technique. HIPEC was performed with cisplatin plus doxorubicin. In each patient, primary cell cultures were obtained from DMPM surgical specimens. Chemosensitivity was determined in vitro by a proliferative assay, based on 3H-thymidine incorporation. Cytotoxic (cisplatin, carboplatin, pemetrexed, gemcitabine, vinorelbine, doxorubicin, vincristine), and molecularly targeted agents (everolimus, sorafenib) were tested. Cell proliferation was assessed by immunohistochemical staining of Ki-67 nuclear antigen with monoclonal antibody MIB-1. s-CT was planned within 8 weeks after CRS/HIPEC. Overall survival was the primary study endpoint. Results: From January 2012 to October 2015, 38 consecutive s-CT naïve patients were enrolled in the study. CRS/HIPEC was performed in 33 patients. The quality of surgical cytoreduction was rated as adequate (residual disease nodules ≤ 2.5 mm) in 28 of them, and grossly incomplete in 5. Only palliative/debulking surgery (and no HIPEC) was possible in five. Operative death occurred in one patient and severe complications in 15 (39.5%). At pathological examination, epithelial DMPM was diagnosed in 33 patients, and biphasic DMPM in 5; positive lymph-nodes were found in 5 patients. Primary cell cultures could not be obtained in 13 patients, due to poor cell vitality. Cultures were not assessable for chemosensitivity in 15, due to insufficient 3H-thymidine incorporation. Of the remaining 10 patients, six were resistant to all tested drugs, and four were sensitive to ≥1 drug (everolimus, doxorubicin, gemcitabine, cisplatin, vincristine). Proliferative activity was relatively low, with a median percentage of Ki-67-expressing cells of 18.2% (range 5-45%). Thirteen of 28 patients undergoing adequate CRS/HIPEC did not receive postoperative s-CT, due to operative death (n=1), or poor condition/refusal (n=12). Fiveteen were treated with cisplatin/carboplatin and pemetrexed. Chemosensitivity tests were available and multiresistant in 4 of them Median follow-up was 10.7 months (range 1-34.4). Two-year survival was 46.4% in the overall series, and 62.6% in those undergoing adequate CRS/HIPEC. The completeness of cytoreduction was the only significant prognostic predictor (P=0.003, log-rank). Conclusion: Our findings confirm the poor sensitivity of DMPM to systemic agents and do not support the role of currently available s-CT. The malignant potential of the disease appears to be related to its chemoresistance, rather than elevated cellular proliferation. Prognostic improvements may depend on aggressive comprehensive local-regional management. Better understanding of DMPM molecular features, and development of new systemic and/or targeted therapies are needed. Keywords: systemic chemotherapy, Peritoneal mesothelioma, targeted therapy, HIPEC Objectives: The prognosis of diffuse malignant peritoneal mesothelioma (DMPM) has recently improved with cytoreduciMig2016.ORG 55 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS12.02: GENDER AND MENOPAUSAL STATUS: SURVIVAL IN PERITONEAL MESOTHELIOMA women. With increased survival for premenopausal women, it would be important to better understand the role of ERβ and Ki-67 in mesothelioma. Keywords: Survival, Estrogen, ERβ, Gender Yaakov Bressler, Gleneara E. Bates, Robert N. Taub Medicine, Columbia University Medical Center, New York, NY, UNITED STATES OF AMERICA Objectives: It is well recognized though not fully understood that women live longer than men with mesothelioma. We have investigated survival difference related to gender and pre- and post-menopausal status in peritoneal mesothelioma. We wished to determine whether there are survival differences related to gender, age, and menopause. Methods: An IRB approved retrospective analysis of mesothelioma patients treated from 1990 – 2015 was done at CUMC. Patients with peritoneal diagnoses and recipients of CRS and HIPEC were included. Patient characteristics (gender, histology, and pre/post menopausal status) were collected. Survival and prognosis analyses were performed using Kaplan-Meier curves and univariate cox proportional hazards model. Other established prognostic factors were evaluated with multivariate analysis. Results: Median survival time of all MPM patients (n=195) was 3.21 years with (95% CI: 2.38- 5.53), with median follow-up of 3.44 years (SD=3.4, minimum=0.014 and maximum=16.752) years from first operation. Patient set included 111 men (57%) and 84 women (43.1%) with female sex having favorable survival [HR: 0.442 95% (CI: 0.296-0.659), p<0.001] of 110.1 months with (95% CI: lower bond: 48.3). Mean age at diagnosis was 54.8 years [HR: 1.027 (95% CI: 1.012-1.042)] with 111 men (57%) and 84 women (43.1), with female gender having favorable survival [HR: 0.442 95% CI: 0.296-0.659)]. Majority of patients had epithelioid histology (n=161(82.6%), with the remainder biphasic/sarcomatoid (n=34, 17.4%), with increased risk of death with non-epithelioid histology [HR: 2.46(95%CI 1.59-3.82)], (P=0.001). Median age for all female MPM patients (n=84) was 53 years (SD=14.5), minimum=14.7, maximum=79.9. Median survival was 110.1 months (95% confidence interval lower bound: 48.3) months, mean survival=93.4 (SE=8.69). Median Age of premenopausal patients was 36 years (SD=9.26), minimum=14.7, maximum=48.1. Median survival cannot be determined as at follow up of 110 months, survival was 72% (n=23). Conclusion: These data show that women with MPM have a better survival than men and that premenopausal women have better survival than either men or postmenopausal women. No significant genetic difference between gender in MPM has been identified, aside from an increased TP53 mutation – a result not yet fully understood. Estrogen receptor β (n) has shown to be expressed (with IHC >6) in 15% of mesotheliomas and is associated with an increased survival in MPM. Receptor frequency between genders has demonstrated the level of ERβ in women to be triple that of men, with higher expression in post-menopausal women than pre-menopausal women. Activation of ERβ from estradiol may contribute to survival differences. Data has shown that administration of KB9520, an ERβ agonist, leads to less aggressive tumors and sensitization of tumors to chemotherapy. Further, Ki-67, a biomarker for cellular proliferative activity where low Ki-67 is associated with increased survival, has been found to be expressed in men twice as much as in MS12.03: SIMULTANEOUS CARE (SIMC) IN MESOTHELIOMA (MM): A DEDICATED TEAM TO PREVENT URGENT AND UNPLANNED HOSPITAL ADMISSIONS Giulia Gallizzi1, Federica Grosso1, Alma Kasa2, Barbara Oneglia2, Giacomo Taverna3 , Fausto Pernazza4 , Paola Ballarino2, Annalisa Roveta5, Liana Todisco6 , Silvia Zai1, Ezio Piccolini7, Alberto Muzio8 , Gianmauro Numico1, Massimo D’Angelo9, Daniela Degiovanni10 Oncology Unit, SS. Antonio e Biagio e C. Arrigo, Hospital, Alessandria, ITALY, 2Hospice Monsignor Zaccheo / Uocp, Santo Spirito, Hospital, Casale Monferrato, ITALY, 3Radiology Unit, Santo Spirito, Hospital, Casale Monferrato, ITALY, 4Chirurgia Toracica, SS. Antonio e Biagio e C. Arrigo, Hospital, Alessandria, ITALY, 5Ssa Sviluppo E Promozione Scientifica, SS. Antonio e Biagio e C. Arrigo, Hospital, Alessandria, ITALY, 6Radiotherapy Unit, SS. Antonio e Biagio e C. Arrigo, Hospital, Alessandria, ITALY, 7Pneumologia, Santo Spirito, Hospital, Casale Monferrato, ITALY, 8Oncology Unit, Santo Spirito, Hospital, Casale Monferrato, ITALY, 9Centro Sanitario Amianto, Azienda Sanitaria Locale AL, Casale Monferrato, ITALY, 10 Ss Hospice Monsignor Zaccheo/ Uocp, Santo Spirito, Hospital, Casale Monferrato, ITALY 1 Objectives: MM is a fatal cancer with great symptom burden and treatment has only a modest impact on survival. Palliative care is crucial in clinical management and helps patients and families dealing with disease related symptoms and psychological implications. In 2012 the Italian Centro Controllo per le Malattie (CCM) supported a project that aimed at assuring Early Palliative Care (SimC) and psychological support to newly diagnosed patients and families in order to improve quality of care and reduce unplanned Accident and Emergency Department (A&E) admissions. Here we report on the preliminary results of the SimC Program at a referral centre in the high asbestos polluted area of Casale Monferrato. Methods: An Integrated Palliative Care Team, available 8 am to 10 pm, 7 days a week, followed each patient since diagnosis throughout the whole course of the disease, both at home and in every other place. The most relevant clinical variables and symptoms were registered into a dedicated web database. Specific questionnaires were delivered to collect data about awareness of the disease and satisfaction regarding the care after the cessation of SimC. Results: Since 4/2013 to 10/2015, 79 MPM patients, 39 M (49%) and 40 F (51%), median age 71 (IQR 65-78; range 53-99) were included. PS according to Karnofsky was 30-40 in 38 (48%), 50-60 in 38 (48%) and >70 in 2 (4%) pts. The median duration of the SimC support was 33 days (mean 56; range 10-465). At the time of inclusion 39 patients (49%) complained with pain, median NRS 4.5 (range 2-9). Other reported sympiMig2016.ORG 56 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP toms were dyspnea in 58 (73%), fatigue in 50 (63%), cough in 24 (30%), peripheral oedema in 24 (30%), agitation/confusion in 17 (22%) patients. Sixty-three (79%) patients were perfectly aware about their disease and 13 (17%) about their terminal condition. Seventy-four families (94%) were fully informed about the disease and 71 (90%) about the imminent fatal outcome. SimC support ended due to the following causes: death at home for 53 patients (67%), improvement of symptoms in 9 patients (10%), admission to the palliative care ward in 13 patients (16%). Five patients (6%) were hospitalized for planned palliative procedures. Only one patient (1.2%) required A&E admission due to high fever from pneumonia. The questionnaire highlighted that 96% of patients had no pain in the last 24 hrs of life, 94% received analgesic treatment, and none of the patients underwent resuscitation manoeuvres. Death was not an unexpected event in 98%. The palliative care team had a contact with the family in the last 24 hours and was informed about death in 96% of patients. Conclusion: This study focused on SimC in MM. Data is still partial and we are working to retrieve it. The most relevant achievements are that the vast majority of patients (98.8%) followed within this program did not require any urgent admission to A&E Department and died at home according to their preference, with careful and assiduous support by the palliative care team, in an appropriate context of Public Health Service. Keywords: Psycological support, palliative care, Advanced mesothelioma, Simultaneous care MS13: GENOMICS AND DRUG SENSITIVITY TUESDAY, MAY 3, 2016 16:30 – 18:00 MS13.01: THE MEXTAG COLLABORATIVE CROSS: IDENTIFYING THE GENETIC BASIS OF MESOTHELIOMA Scott Fisher1, Kimberley Burton1, Willem J. Lesterhuis1, Bruce Robinson1, Grant Morahan2, Graeme Walker3 , Richard Lake1 School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, WA, AUSTRALIA, 2Centre For Diabetes Research. The University of Western Australia, Harry Perkins Institute of Medical Research., Perth, WA, AUSTRALIA,3Drug Discovery Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, AUSTRALIA 1 the genetic heterogeneity of disease as well as complications of environmental variation between cases and control groups (e.g. amount of carcinogen exposure, effect of smoking and diet). Thus, at least so far, the genes detected by GWAS have a minor impact on disease risk and it is not known where in the disease pathway they act, nor how they contribute to disease mechanisms. Here we outline a new strategy designed to rapidly identify the genes associated with risk of mesothelioma. To define mesothelioma susceptibility and resistance loci, this study combines the Collaborative Cross (CC) with our well-characterised MexTAg transgenic mouse model of mesothelioma. The CC is a powerful mouse resource specifically developed to rapidly identify genes associated with complex traits, while MexTAg mice rapidly, uniformly and predictably develops mesothelioma, but only after asbestos exposure. Methods: 1: Generate and expose CC-MexTAg mice to asbestos and assess mesothelioma development. The CC is a collection of 100 recombinant inbred mouse lines covering over 90% of the common allelic diversity of the mouse species. The genome sequences of each of the 100 CC lines are known. Each CC line will be crossed with MexTAg mice and the resulting CC-MexTAg progeny exposed to asbestos. Exposed mice will be monitored for overall survival, the time to disease onset and the time to disease progression. Disease will be confirmed by histological analysis. 2: Identify candidate modifier genes associated with mesothelioma latency and time to progression. Using our established informatics pipeline, we will rapidly identify alleles that 1) protect mice against, or sensitize to mesothelioma, and 2) influence the pathology and course of the disease.3: Validate the candidate modifier genes in the well‑defined Wittenoom cohort of asbestos-exposed subjects. Human orthologues of candidate genes will be validated in our mesothelioma GWAS dataset. Results: Breeding of CC-MexTAg progeny has begun and the first batch of asbestos exposure experiments are underway. Interim results will be presented at iMig 2016. Conclusion: This study will provide insight into the genetic factors underlying differences in mesothelioma development after asbestos exposure. We aim to identify and validate modifier genes that will lead to an improved understanding of the pathobiology of mesothelioma, identification of new druggable targets and ultimately provide the necessary data for the development of diagnostic tests to assess individual risk of developing mesothelioma after asbestos exposure. Such tests would identify the most at risk patients for further active monitoring and treatment, while reassuring other patients that mesothelioma is unlikely to develop. Keywords: mouse models, Collaborative Cross, MexTAg, genetics of mesothelioma Objectives: Mesothelioma development after asbestos exposure is highly variable: some people do not develop the cancer despite high level exposure for many years, while others get disease with no known history of contact. There is good evidence that at least part of the difference in susceptibility to mesothelioma is genetic, but the genes involved remain mostly unknown. Genome-wide association studies (GWAS) have been used to try and identify mesothelioma susceptibility genes, but the detection of significant associations in GWAS is hindered by iMig2016.ORG 57 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS13.02: TRANSLATIONAL CONTROL OF MPM: ROLE OF EIF6 AND MICRORNAS IN METABOLISM Stefania Oliveto1, Annarita Miluzio2, Pierluigi Gasparini3 , Roberta Alfieri2, Elisa Pesce2, Stefano Grosso4 , Sara Ricciardi2, Daniela Brina2, Luciano Mutti5, Bruno Murer6 , Carlo M. Croce3 , Stefano Biffo7 Molecular Histology And Cell Growth Unit, INGM - Fondazione Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milano, ITALY, 2INGM - Fondazione Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milano, ITALY, 3Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, UNITED STATES OF AMERICA, 4MRC - Toxicology Unit, Leicester, UNITED KINGDOM, 5School of Environment and Life Sciences, University of Salford, Manchester, UNITED KINGDOM, 6Azienda ULSS 12 Veneziana, Venezia, ITALY, 7INGM - Fondazione Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi” and University of Milan, Milano, ITALY 1 Objectives: Translation is a cellular process finely regulated during growth and development and it is deregulated in cancer cells. Molecular mechanisms which control mRNA translation and the protein synthetic machinery are constituted by steps potentially involved in tumorigenesis, pointing them as novel druggable targets for cancer therapy. It has been shown that eukaryotic Initiation Factor 6 (eIF6) is a limiting factor in tumorigenesis, in vivo, regulating the availability of active 80S subunit. A relationship between eIF6 activity and RISC complex has been suggested, but remains controversial. We evaluated the expression and activity of eIF6 in MPM, and its role in tumor growth and metabolism. Moreover we investigated microRNAs enriched on polysomes, and, among them, we focused on the role and sublocalization of miR-24-3p in MPM cells. Methods: The expression levels of eIF6 were measured by IHC, WB analysis and qRT-PCR. 2D-electrophoresis has been used to study the phosphorylation status of the protein.Cell proliferation was analysed by MTT assay and FACS analysis was used to determine cell cycle progression and apoptotis. Tumor growth, in vivo, has been analysed by xenograft tumor technique. Methionine incorporation assay and polysomal profiles were used to determine the translational status of cells.We showed metabolism impairment in eIF6 knockdown cells using lactate and ATP assays. Finally, we isolated RNA from polysomal profiles fractions of MPM cells and proceeded to microRNAs profiling. We also performed RNA seq analysis to identify targets of miR-24-3p. Results: We observe that Malignant Pleural Mesothelioma (MPM), a tumor characterized by 100% lethality at two years from diagnosis, exhibits high levels of eIF6 and differential subcellular miRNAs distribution. We show that MPM contains high levels of hyperphosphorylated eIF6 and that PKCβ inhibitor Enzastaurin (Ely-Lilly) induces eIF6 dephosphorylation in time-dependent manner. Treatment of mesothelioma cells, with either Enzastaurin or shRNA for eIF6 affects cell growth, in vitro, and causes reduced tumor growth and metastasis formation, in vivo. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells, evidencing less glycolysis and less ATP content in cells depleted for eIF6 or treated with Enzastaurin. Moreover, sucrose density gradient analysis of MPM cells identified miRNAs in RNA subpopulations: miRNAs distribution both in monosomes and active polysomes is characterized by high variability in miRNAs occupancy. We evidenced that polysome-bound miRNAs present a correlation with the cell cycle pathway and that miR-243p shows a significant polysomal localization. We found that in spite of being upregulated in most MPM cell lines, miR-24-3p displays a different expression between epitheliod and sarcomatous histosubtypes, and its inhibition has different effects. Conclusion: We propose that eIF6 is necessary for Malignant Mesothelioma growth, in vivo, and can be targeted by kinase inhibitors and we suggest a new translational role of mir243p in MPM, taking in account its localization and cell specific function. Cell specific miR-24-3p targets are characterized by RNA sequencing analysis. Keywords: Malignant Pleural Mesothelioma; Translation; eIF6; phosphorylation; PRKCB; miRNA MS13.03: BAP1 KNOCKOUT BY CRISPR-CAS9 GENOME EDITING IN MALIGNANT PLEURAL MESOTHELIOMA CELL LINES FOR ISOGENIC FUNCTIONAL STUDIES Julija Hmeljak, Lee Spraggon, Marc Ladanyi Human Oncology And Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA Objectives: BAP1 loss is the third most prevalent genetic alteration in malignant pleural mesothelioma (MPM). BAP1 is a multifunctional deubiquitinase involved in chromatin dynamics, DNA repair and cell cycle regulation. Current data suggest that the role of BAP1 inactivation via mutation or loss in MPM is complex. In order to elucidate the effect of BAP1 loss in MPM cells, we used the CRISPR-Cas9 system to genetically ablate BAP1 in BAP1 wild-type MPM cell lines. Methods: HMeso (biphasic MPM) and VAMT (sarcomatoid MPM) were transfected with a cocktail of three unique bifunctional CRISPR plasmids, each containing humanized Cas9 and a single guide RNA (gRNA) targeting the 5’ coding region of BAP1. We isolated single HMeso BAP1-/- and VAMT BAP1/ clones, which were confirmed to be negative for BAP1 protein expression and were screened at the genomic level to confirm the correct gene editing by CRISPR-Cas9. Heterozygous partial knockout clones (BAP1+/-) were also isolated and analyzed. Results: Utilizing these newly developed isogenic cell lines, we are performing extensive in vitro characterization, gene expression profiling, and assessing response to radiation in the context of growth delay and DNA damage. Conclusion: These isogenic cell line models will provide a powerful platform in which to further investigate the role of BAP1 in MPM biology. Keywords: BAP1, CRISPR, isogenic cell lines iMig2016.ORG 58 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Table 2: Effect of BAP1 MS13.04: BAP1 EXPRESSION AND IMPACT ON TREATMENT OUTCOMES IN MALIGNANT PLEURAL MESOTHELIOMA IN A PROSPECTIVE UK BASED CLINICAL TRIAL Neelam Kumar1, Krishna Kolluri1, Elaine Borg2, Elizabeth Sage3 , Zhi Zhou1, Mary Falzon2, Sam Janes1 Ucl Respiratory, Division of Medicine, University College London, London, UNITED KINGDOM, 2University College London Hospital, London, UNITED KINGDOM, 3University College London, London, UNITED KINGDOM 1 Objectives: Genomic studies of malignant pleural mesothelioma (MPM) have identified frequent mutations in BRCA Associated Protein 1 (BAP1). BAP1 is a nuclear deubiquitinase with important roles in regulating gene expression and DNA repair. Previous studies have identified 100% correlation between nuclear staining for BAP1 and wild type BAP1 status, pointing to immunohistochemistry (IHC) as a reliable technique to detect BAP1 molecular status. The objective of this study is to assess BAP1 expression and infer molecular status using IHC in a cohort of patients from a prospective UK based clinical trial (MSO1 trial). Furthermore, we aim to evaluate the effect of BAP1 status on treatment outcomes. This is the first assessment of BAP1 status in MPM in a UK patient cohort. Methods: BAP1 expression was evaluated by IHC in 79 tumour biopsies collected during the MSO1 trial by two consultant histopathologists. Cases were considered positive (wild type BAP1) if strong nuclear staining was present throughout the tumour and negative (mutant BAP1) if absent. Results: Assessment of BAP1 expression was concordant in 77 of 79 cases (97%). BAP1 expression was negative in 66 of these 77 cases (86%). Patient characteristics are in Table 1 and the effect of BAP1 expression on treatment outcomes in Table 2. Nuclear BAP1 IHC positive (N=11) Nuclear BAP1 IHC negative (N=66) p-value Gender (M=male) M: 100% M: 91% 0.30 Median age at diagnosis (years) 69.5 66.0 0.94 Table 1: Clinical characteristics Epithelioid 82% 89% Biphasic 18% 9% Sarcomatoid 0% 3% 0.94 Treatment Active symptom control (ASC) 36% 36% ASC + vinorelbine 36% 32% ASC + mitomycin, vinblastine, cisplatin 27% 32% p-value All 21.0 23.3 0.22 Active symptom control (ASC) 24.3 25.0 0.62 ASC + vinorelbine 12.8 22.8 0.11 ASC + mitomycin, vinblastine, cisplatin 15.7 19.4 0.69 Conclusion: BAP1 expression was negative in 86% of MPM tumours suggesting a high frequency of BAP1 mutations in this UK cohort. No significant differences in clinical characteristics or outcomes were noted between cases with positive or negative BAP1 expression overall. When analysed by treatment subgroup, there was a trend towards a survival benefit in cases with negative BAP1 expression (BAP1 mutants) in the ASC plus vinorelbine arm, but no statistically significant difference in outcomes within any treatment arm. We plan to further validate our findings by correlating BAP1 expression directly with BAP1 molecular status using laser capture microdissection and sequencing. Keywords: BAP1, mesothelioma MS13.05: RELATIONSHIP OF PD-L1 EXPRESSION AND PROGNOSIS IN EPITHELIOID MESOTHELIOMA Tohru Tsujimura1, Tomoo Kudo1, Yoshiyasu Shinohara1, Ayuko Sato2, Shigeki Shimizu2, Takashi Daimon2, Seiki Hasegawa2, Takashi Nakano2 Department of Pathology, Hyogo College of Medicine, Nishinomiya, JAPAN, 2Hyogo College of Medicine, Nishinomiya, JAPAN 1 0.57 Histology Nuclear Nuclear BAP1 BAP1 IHC IHC positive negative status on median overall survival from diagnosis (months) Objectives: Malignant pleural mesothelioma (MPM) is a refractory tumor with poor prognosis. The most common histological type of MPM is epithelioid mesothelioma (EM). Programmed cell death-1 ligand 1 (PD-L1), which participates in immune evasion of tumor cells, has been reported to be involved in progression and poor prognosis in various human tumors. The purpose of this study is to clarify the clinical/prognostic significance of PD-L1 in EM. Methods: We examined immunohistochemically PD-L1 expression in tumor cells (TCs) and tumor-infiltrating immune cells (ICs) of 42 EM patients who underwent extrapleural pneumonectomy. Associations of clinicopathological characteristics with PD-L1 expression were examined with the use of Fisher’s exact test. The relationship between PD-L1 expression and the patient’s survival was examined as follows. Overall survival curve was estimated by using the Kaplan-Meier method and was compared with the use of the log-rank test. Hazard ratios and their 95% confidence intervals were estimated with the use of Cox’s proportional-hazards model. iMig2016.ORG 59 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Results: Thirty (71%) TCs and 16 (38%) ICs were positive for PD-L1. Pathological stage (stage I/II vs III/IV) was significantly associated with PD-L1 expression in ICs. Overall survival was significantly shorter in EM patients with PD-L1-positive TCs and/or PD-L1-positive ICs than those with PD-L1-negative TCs and PD-L1-negative ICs. The 5-year survival rate was lower in EM patients with PD-L1-positive TCs (20.6%) than those with PD-L1-negative TCs (46.0%). Conclusion: These results indicate that PD-L1 expression in TCs and/or ICs of EM is associated with poor prognosis of patients. PD-L1 expression may have important therapeutic implications for the management of EM. Keywords: PD-L1, epithelioid mesothelioma, prognosis calculations were validated using literature searches and in vitro based experiments. The comparison of model simulations with genome wide microarray data demonstrated a significant rate of correct predictions derived when compared to various microarray profiles obtained from different cancel cells. Conclusion: In summary, we show that the use of systems biology approaches to generate dynamic logical models provides predictive value and better understanding of cancer development. Patient-specific microarray data will be integrated into these simulations: by assigning initial node states to observed patient-specific expression levels, personalised predictions will be generated to identify mutation drivers/abrogated pathways and novel druggable target. Finally, this approach will facilitate the continual personalisation of MPM patients’ treatment based on identifying shifts in signalling pathways that give rise to resistance to therapy for a particular tumour. Keywords: cancer, mesothelioma, p53, systems biology MS13.06: SYSTEMS BIOLOGY APPROACHES TOWARDS DEVELOPING PERSONALIZED CANCER THERAPIES FOR MALIGNANT PLEURAL MESOTHELIOMA (MPM) MS14:RADIOTHERAPY TUESDAY, MAY 3, 2016 16:30 – 18:00 Michelle Hussain1, Alice Guazzelli1, Jean-Marc Schwartz2, Luciano Mutti1, Marija Krstic-Demonacos1 School of Environment And Life Sciences, University of Salford, Salford, UNITED KINGDOM, 2Faculty Of Life Sciences, University of Manchester, Manchester, UNITED KINGDOM 1 Objectives: Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with no effective treatments and poor prognosis. Chemotherapy is a common treatment used to treat cancer patients, however, overall this treatment is often ineffective highlighting the needs for novel approaches. The overall aim of this research is to understand the MPM biology, the mechanism of resistance to therapy and facilitate patients stratification to improve survival. The knowledge of pathway changes will facilitate patient stratification and result in personalised, more effective therapeutic strategies. Numerous literature and large datasets have been accumulated about cancer causes and therapies, however systematic approaches with clear potential for clinical applications are lacking. Methods: Here we employ a systems biology approach including bioinformatics, text mining and logical modelling combined with in vitro laboratory based experiments to analyse pathways affected in MPM. One of the genes crucial for cancer development and treatment is the p53 tumor suppressor. Despite the 80,000 publications associated with the p53 in PubMed, the details of p53 function are still unclear due to the complexity of its interactions. Using a systematic approach we integrate this vast amount of information by constructing a large-scale logical model of the p53 interactome from databases and literature information Results: Our previously generated model containing 205 nodes representing genes or proteins, DNA damage input, apoptosis and senescence outputs, and 677 logical interactions was improved and adapted by addition of genes suggested as the drivers of MPM, to create a model consisting of 300 nodes and 860 interactions between them. Predictions from in silico knock-outs mimicking mutations, steady state analysis and dependency MS14.01: EXAMINING SIGNALING PATHWAY CROSSTALK IN MESOTHELIOMA PDT AND RT SENSITIVITY USING 2D AND NOVEL 3D TISSUE CULTURE MODELS Keith A. Cengel1, Sarah Hagan2, Edmund Moon3 , Charles B. Simone1 Radiation Oncology, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 2University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 3Division of Pulmonary, Allergy And Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA 1 Objectives: Photodynamic therapy (PDT) and external beam radiotherapy (RT) have been used as adjuvant therapies directed at increasing local control in patients undergoing surgical resection of malignant pleural mesothelioma (MPM). In patients undergoing radical pleurectomy and PDT for MPM, we have previously demonstrated that expression/activation of epidermal growth factor receptor (EGFR)/STAT3 signaling correlates with increased pleural recurrence rates and decreased overall survival. We have also shown that activation of STAT3 through EGFR pathway activation mediates resistance of lung cancer cells to both PDT and ionizing RT. Both EGFR and STAT3 are activated in the wound healing/inflammatory response to surgical injury, and EGFR/STAT3 activation leads to increased cox-2 expression. Therefore, we hypothesized that STAT3 might mediate crosstalk between inflammatory and growth factor signaling. Methods: To begin to evaluate this hypothesis, we transfected human mesothelioma cell lines derived from subjects enrolled on tissue acquisition studies at Penn (EMM, EMP, Ren), with iMig2016.ORG 60 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP a pTRIPZ expression vector designed to allow doxycycline-induced STAT3 or EGFR shRNA expression. We then performed clonogenic cell survival assays to assess the efficacy of PDT or RT with or without inhibition of inflammatory signaling by celecoxib (cox-2 inhibitor). After PDT or RT, cell death was quantitated using calcein/ethidium bromide fluorescent live/dead cell assays. Protein expression/signaling activation was measured by Western blot analysis of tumor nodule protein extracts. All assays and Western blot analyses were run in distinct biological triplicates. Results: These studies demonstrated that inhibition of EGFR/ STAT3 signaling pathways significantly enhance PDT-mediated cellular cytotoxicity. The addition of celecoxib was found to further enhance this effect. To evaluate the role of these pathways in a more clinically relevant in vitro model, we developed a novel 3D tissue culture model of human MPM cells in which shRNA expression vector transfected cells are implanted superficially on a matrigel pad and allowed to develop into tumor nodules measuring 100-150 micrometers in diameter. Preliminary results from experiments using this tumor nodule/gene expression assay system demonstrated significantly enhanced cytotoxicity following PDT in the presence of EGFR/STAT3 pathway inhibition. Enhanced cytoxicity with EGFR/STAT3 inhibition similarly was also seen following ionizing RT. Conclusion: The results using 2D tissue culture demonstrate that EGFR/STAT3 signaling pathway activation mediates resistance of MPM cells and tumor nodules both to PDT and RT. In addition, we have developed a novel 3D MPM nodule model with the ability to selectively inhibit gene expression using inducible shRNA and validated our findings from 2D tissue culture. Further work is underway to develop heterotypic MPM nodules using combinations of human fibroblasts, macrophages and lymphocytes to better mimic the complex cellular interactions in MPM. SYSTEMS Trial was the first prospective study of radiotherapy in MPM to use validated outcome measures for pain. This multicentre, single arm phase II study of conventional dose palliative radiotherapy (20Gy in 5#) recruited 40 patients in three centres over 18 months and demonstrated that approximately one third of patients experienced clinically meaningful improvements in pain with minimal toxicity. It is hypothesised that increasing the total radiation dose and the dose per fraction will result in a greater proportion of patients experiencing a clinically significant pain response. The objective of the SYSTEMS-2 Study is to compare a hypo-fractionated, dose escalated regime (36Gy in 6 fractions), with the standard dose (20Gy in 5 fractions). Methods: This study aims to recruit 112 patients with a diagnosis of MPM, in whom radiotherapy is indicated for pain control. Patients should have a worst pain score of >/= 4/10 (measured by the Brief Pain Inventory, BPI) after analgesia optimisation. Recruitment will take place in 8-10 centres across the UK. Randomisation will occur after completion of radiotherapy planning, but prior to the first treatment and plans must be acceptable for both dose/fractionation regimes. Doses to organs at risk (e.g. spinal cord) can be minimised using advanced planning techniques such as Intensity Modulated Radiotherapy (IMRT), however IMRT availability will not be an essential requirement for participating centres. If there is concern regarding proximity of the tumour to an organ at risk, the final fraction of the dose escalated arm can be omitted. Keywords: 3D tissue culture models, photodynamic therapy, radiation therapy, signal transduction MS14.02: SYSTEMS-2:RANDOMISED PHASE II TRIAL OF STANDARD VERSUS DOSE ESCALATED RADIOTHERAPY FOR PAIN IN MALIGNANT PLEURAL MESOTHELIOMA Miranda J. Ashton1, Anthony Chalmers2, Nicholas Macleod3 , Noelle O’Rourke3 , Barry Laird4 Beatson West of Scotland Cancer Centre, Glasgow, UNITED KINGDOM, 2Institute of Cancer Sciences, University of Glasgow, Glasgow, UNITED KINGDOM, 3Beatson West of Scotland Cancer, Glasgow, UNITED KINGDOM, 4Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UNITED KINGDOM 1 Objectives: Pain is one of the most common symptoms associated with malignant pleural mesothelioma (MPM) and is often poorly responsive to analgesia. Palliative radiotherapy is a recognised component of standard treatment for MPM-associated pain; however, there is no consensus on optimal dose, fractionation or technique, and very little efficacy data. The Results: Primary endpoint will be pain assessed at 5 weeks measured by BPI, with a fall of >/=2 points on the BPI constituting a significant response. Secondary endpoints will be assessed using validated tools and will include acute toxicities, radiological response, overall survival and quality of life. Exploratory endpoints will include change in strong opioid use and potential predictive and response biomarkers. Conclusion: It is anticipated that this study will provide robust and accurate symptom response data for palliative radiotherapy iMig2016.ORG 61 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP in MPM and help to establish the optimal dose and fractionation. This will guide clinical practice and should aid more effective palliation for patients with MPM-associated pain. Keywords: Pain, radiotherapy, palliation, dose-escalation MS14.03: OVERCOMING RADIATION RESISTANCE OF MESOTHELIOMA BY ACTIVATING TUMOUR SPECIFIC CELL DEATH Saurabh Dayal1, Lesley Gilmour1, Marcel Verheij2, Anthony Chalmers3 University of Glasgow, Glasgow, UNITED KINGDOM, 2Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 3Institute of Cancer Sciences, University of Glasgow, Glasgow, UNITED KINGDOM 1 Objectives: The incidence of mesothelioma is increasing and current treatments are ineffective. While advances in technical radiotherapy are increasing its potential clinical application, intrinsic radiation resistance of mesothelioma remains an important barrier. Defects in the apoptosis pathway are a likely cause of radioresistance and treatment with Tumour necrosis factor-Related Apoptosis Inducing Ligand (TRAIL) has potential to overcome this. Methods: Radiation and TRAIL (iso-leucine zippered form) were tested alone and in combination in human mesothelioma cell lines MSTO-211H, H2052 and H226 to determine effects on cell viability, clonogenic survival and apoptosis (measured by caspase-3/7 activity and Annexin-V/PI analysis). Synergy was assessed by isobologram analysis. Mechanisms underlying interactions between radiation and TRAIL were probed by measuring cell surface and total levels of the death receptors DR4 and DR5 using immunoblotting, flow cytometry and immunofluorescence and by documenting effects of death receptor knockdown and specific caspase inhibitors on apoptosis and cell viability. TRAIL/radiation combinations were evaluated in vivo using subcutaneous MSTO-211H xenografts. Results: Radiation and TRAIL exhibit schedule-dependent synergy. TRAIL treatment 24 hours after radiation was associated with significant increases in apoptosis and reductions in cell viability and clonogenic survival in all cell lines tested. Consistent with this, radiation caused upregulation and externalisation of DR4 & DR5 with maximum effects 24 hours after treatment. We hypothesised that radiation induced DR4/5 upregulation and externalisation enables activation of the extrinsic apoptotic pathway by TRAIL. This was verified by showing that inhibition of the extrinsic apoptotic pathway blocked the cytotoxic effects of the radiation/TRAIL combination whereas inhibition of the intrinsic pathway did not. Furthermore, siRNA knockdown of DR5 abolished the radiosensitising effect of TRAIL. Effects of radiation/TRAIL combinations in vivo will be presented. Conclusion: Addition of TRAIL overcomes radioresistance exhibited by mesothelioma cells by activating the extrinsic apoptotic pathway. The synergistic combination of TRAIL and radiation has therapeutic potential in mesothelioma. Keywords: mesothelioma, TRAIL, apoptosis, radiotherapy iMig2016.ORG 62 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS14.04: SYNERGISTIC EFFECT OF LOCAL RADIATION THERAPY AND IMMUNOTHERAPY IN A MOUSE MODEL OF MPM Luis De La Maza-Borja1, Matthew Wu1, Licun Wu1, Zhihong Yun1, Marc De Perrot2 Thoracic Surgery Research, University Health Network, Toronto, ON, CANADA, 2Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Center, Toronto, ON, CANADA 1 Objectives: Our group developed a new approach focusing on Surgery for Mesothelioma After Radiation Therapy (SMART), with encouraging results in a phase I/II clinical trial. We believe that radiation is important to achieving activation of the immune system and may contribute to the benefits observed in patients. Objective: To develop a mouse model to analyze the immunogenic effect of Local Radiation Therapy (LRT), its impact on immune cell recruitment and the effect of adjuvant immunotherapy in the context of MPM. We hypothesized that LRT administered to a tumor before surgery is immunogenic and that adjuvant immunotherapy is beneficial and contributes to tumor free survival. Methods: Mice were inoculated subcutaneously in the flank with the MPM cell line AB12 and AE17-OVA and were treated with LRT in three 5Gy fractions. Radiation and untreated tumors were analyzed for CD8+ T cell tumor infiltration. Furthermore, tumor infiltrating lymphocytes (TILs) were analyzed with flow cytometry using H-2Kb tetramer SIINFEKL as wells as activation markers. To assess the effect of adjuvant immunotherapy, tumor bearing mice were treated with anti-PD1, anti PD-L1 and anti-CTLA-4 alone or in combination with LRT. To assess protective memory, AE17-OVA tumor bearing mice were treated with LRT and radical surgery and compared to radical surgery alone. Cured mice were then rechallenged in the opposite flank and tumor growth was followed. Results: Tumor growth was decreased in mice treated with LRT and showed a significant increase in the number of infiltrating CD3+CD8+ cells compared to untreated tumors. Radiated tumors also showed a greater proportion of tetramer specific CD8+ T cells. Furthermore, infiltrating tetramer-specific CD8+ T cells showed significant upregulation of the activation marker 4-1BB and significant downregulation of the exhaustion marker PD-1. Combination of LRT and immunotherapy showed an important synergistic effect in mice treated with anti CTLA-4 and only a modest effect in mice treated with anti PD-1 and anti PD-L1.In the rechallenge experiment, mice treated with LRT and radical surgery showed significant deceleration in tumor growth after rechallenge compared to radical surgery alone, moreover, 3 out of 10 mice in the LRT and radical surgery group completely rejected the tumor compared to 0 out of 10 mice in the radical surgery group. MS14.05: THE SMART TRIAL - AN RCT OF PROPHYLACTIC RADIOTHERAPY IN PREVENTING PROCEDURE TRACT METASTASES IN MESOTHELIOMA Nick Maskell1, Amelia O. Clive2 Academic Respiratory Unit, University of Bristol, Bristol, UNITED KINGDOM, 2Respiratory Research Unit, North Bristol NHS Trust, Bristol, UNITED KINGDOM 1 Objectives: The role of prophylactic radiotherapy to prevent the development of procedure tract metastases (PTM) in patients with malignant pleural mesothelioma has been subject to intense debate. We examined its efficacy in preventing this complication with a suitably powered, randomised controlled trial. Methods: We randomly allocated patients with histo-cytologically proven mesothelioma, who had undergone a large bore pleural intervention in the previous 35 days to immediate radiotherapy (21 Gray in 3 fractions) or deferred radiotherapy (given if a PTM developed). Patients were followed up for 12 months. The primary outcome was the rate of PTM until death or 12 months. Secondary outcomes included chest pain, quality of life, analgesic requirements, health care utilisation and safety (including radiotherapy toxicity). Results: Two hundred and three patients were randomized from 22 UK centres. The mean age was 71 (SD 8.1), 181/203 (89%) of patients were male, 142/203 (70%) had epithelioid histology. The baseline characteristics of the treatment arms were comparable. No significant difference was identified in the rate of PTM between the immediate and deferred radiotherapy groups (9/102 (8.8%) vs 16/101 (15.8%) respectively; OR 0.51 (0.19, 1.32); p =0.141). There was no difference identified in the quality of life, chest pain, analgesia requirements or survival of the two groups. Conclusion: Among patients with mesothelioma, routine use of prophylactic radiotherapy after large bore thoracic interventions does not confer benefits in terms of PTM rate, symptom control or quality of life when compared to careful clinical follow up and deferred radiotherapy should a PTM develop. (Funded by a Research for patient benefit award from the National Institute of Health. ISRCTN72767336) Keywords: randomised controlled trial, radiotherapy, mesothelioma Conclusion: Local radiation therapy induced proliferation and activation of specific anti-tumor CD8+ T cells. These specific anti-tumor T cells may be responsible for rejection of the tumor after rechallenge. Combination of radiation and immunotherapy showed a synergistic effect in controlling tumor growth. Activation of the immune system secondary to LRT was further improved with immunotherapeutic drugs. Keywords: Radiation, CTLA4, Immunotherapy, Surgery iMig2016.ORG 63 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS15:MULTIMODALITY TUESDAY, MAY 3, 2016 16:30 – 18:00 MS15.01: COMBINED MODALITY TREATMENT USING EXTRAPLEURAL PNEUMONECTOMY FOR MALIGNANT PLEURAL MESOTHELIOMA: A SINGLE CENTRE EXPERIENCE Philippe Nafteux1, Stephanie Peeters2, Johnny Moons1, Yolande Lievens3 , Melanie Dekeyser1, Christophe Dooms4 , Johan Vansteenkiste4 , Paul De Leyn1, Kristiaan Nackaerts4 Thoracic Surgery, KU Leuven-University of Leuven, University Hospitals Leuven, Leuven, BELGIUM, 2Radiotherapy, KU Leuven-University of Leuven, University Hospitals Leuven, Leuven, BELGIUM, 3UGhent-University of Ghent, University Hospital Ghent, Ghent, BELGIUM, 4Respiratory Diseases, KU Leuven-University of Leuven, University Hospitals Leuven, Leuven, BELGIUM 1 (n=52) were: 12,8%, 22.1% and 15.3% respectively. Subsequently, median disease-free survival of epithelial MPM pts was better than for non-epithelial MPM pts, 21.5 and 13.5 months, respectively (p=0.0037), even reaching 34.9 months for pN0 patients (n=33). Cox proportional hazards model showed a significantly lower DFS in non-epithelial MPM pts (HR=4.24, 95% CI=1.81-9.98; p=0.001) and in node positive patients (pN1 pts: HR=4.55, 95% CI=1.09-19.00; p=0.038 and pN2 pts: HR=2.57, 95% CI=1.06-6.23; p=0.036). None of the other examined covariates (laterality, pT- nor R-status) reached significance. Conclusion: This study demonstrated that CMT with EPP for MPM pts is feasible and safe, with an acceptable surgical mortality rate, in a tertiary referral centre setting. Careful patient selection (staging and physical performance) is of highest importance, given that only half of all ‘eligible’ pts will finish CMT. Recurrence of MPM is mostly observed in pts with non-epithelial MPM subtype and with nodal disease. Median disease-free survival for epithelial MPM pts who complete CMT looks promising, although unfortunately not yet validated in proper randomised-controlled trials. Keywords: radiotherapy, induction chemotherapy, extrapleural pneumonectomy, combined modality treatment Objectives: Combined modality treatment for MPM patients (pts) remains a matter of debate, especially regarding the choice of surgery between extrapleural pneumonectomy (EPP) or pleural decortication (P/D). Methods: Our combined modality treatment (CMT) protocol, starting in 2003, consisted of induction chemotherapy (IC), followed by EPP and thoracic radiotherapy (RT). Eligibility criteria of candidates (inclusion criteria: age ≤ 70 years, WHO ≤1, medically fit for pneumonectomy, MPM staging cT2N2M0 or less for all histologic subtypes) were discussed at the weekly multidisciplinary round. IC consisted of 3 cycles of cisplatin (75mg/m² D1 q3wks) and pemetrexed (500mg/m² D1). If non-progressive, EPP was performed followed by hemithoracic RT (most frequently intensity-modulated radiotherapy, IMRT; dose 54Gy/1.8Gy ± boost). Survival was calculated from histological confirmation of MPM diagnosis and analysed by Kaplan-Meier. Results: From March 2003 till December 2014, in total 197 MPM pts were discussed of which 97 pts started CMT. Histologic subtypes: epithelial (n=79), non-epithelial or mixed (n=18). Clinical TNM staging IA/IB/II/III: 9/8/57/23 pts. After IC, 13 pts had “progressive disease”, 5 pts were deemed irresectable and 3 pts refused surgery. Response rate of IC: CR/PR/SD/PD in 3%/30%/53%/14% of pts. A total of 76 pts underwent surgery: EPP in 56 pts, exploratory thoracotomy in 20 pts (inoperable chest wall invasion). Surgical (in-hospital) mortality was 3.6% (2/56 pts). After EPP, 5 pts were not referred for RT because of: unique kidney(1), postoperative empyema(1), multidisciplinary decision(1), SAKK 17/04 trial inclusion(2). Two pts did not complete radiotherapy (bone metastases development and intercurrent respiratory failure). Finally, 52 pts received CMT, of which 47 pts trimodality and 5 pts IC + EPP. Only slightly more epithelial MPM pts (43/79, 54%) completed CMT compared to non-epithelial MPM pts (9/18, 50%). Intent-to-treat median survival (n=97) and median survival of those who fully completed CMT (n=52) were 22.4 months and 33.1 months, respectively. Intent-to-treat overall 5-year survival (n=97), overall and disease-free 5-year survival in MPM pts who fully completed CMT MS15.02: OUTCOME OF TRIMODALITY THERAPY INCLUDING INTRACAVITARY HYDROGEN PEROXIDE TREATMENT IN MALIGNANT PLEURAL MESOTHELIOMA Mir A. Hoda1, Thomas Klikovits1, Viktoria Laszlo1, Clemens Aigner2, Georg Lang1, Shahrokh Taghavi1, Sabine Zöchbauer-Müller3 , Karin Dieckmann4 , Balazs Dome1, Walter Klepetko1 Division of Thoracic Surgery, Medical University of Vienna, Vienna, AUSTRIA, 2Thoracic Surgery, Ruhrlandklinik - University of Essen, Essen, GERMANY, 3Oncology, Medical University Vienna, Vienna, AUSTRIA, 4Radiation Oncology, Medical University Vienna, Vienna, AUSTRIA 1 Objectives: Malignant pleural mesothelioma (MPM) is an aggressive malignancy related to asbestos exposure. Trimodality therapy (TMT) involving macroscopic complete resection either by extrapleural pneumonectomy (EPP) or pleurectomy/ decortication (P/D) with neoadjuvant or adjuvant chemotherapy and adjuvant radiotherapy is a widely accepted treatment protocol with curative intent. Recently a combination of TMT with intracavitary treatment strategies has been reported to be beneficial. In this study we investigated the impact of TMT in combination with intraoperative hydrogen peroxide treatment in patients with MPM. Methods: All MPM patients who were referred for surgical therapy within a TMT protocol between 2000 and 2012 were enrolled in this study. Data was collected retrospectively until 2005 and prospectively from 2006 from patients who underwent at least 3 cycles of induction chemotherapy followed by EPP and intraoperative hydrogen peroxide treatment and postoperative intensity modulated radiotherapy up to 58 Grays. In order to investigate the effect of hydrogen peroxide in vitro on iMig2016.ORG 64 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MPM cell growth, MPM cell lines (N=10) were treated with different concentrations of hydrogen peroxide and sulforhodamine B and clonogenic assays were performed. Results: 30 patients completed TMT and intraoperative hydrogen peroxide treatment during the observation period. There were 24 males and 6 female with a mean age of 61 years at the time of diagnosis. Median follow-up was 18.5 months. Histological subtypes were epitheliod MPM in 23, biphasic MPM in 6 and sarcomatiod MPM in 1 patient. Eighteen patients were in late stages whereas 12 patients were in early stages at the time of diagnosis. Four (13.3 %) patients experienced major postoperative complications. These complications requiring re-thoracotomy were: bleeding , patch rupture, bronchopleural fistula. Overall median survival (Kaplan-Meier) was 31 months (95% confidence interval: 12–48 months). One-year survival was 80%, 2-year survival was 55% and 3-year survival was 45%. 30 day mortality was nill. In vitro, hydrogen peroxide inhibited the growth of MPM cells in short- and long-term viability assays at already low concentrations after 5 minutes of treatment. Conclusion: In our experience, EPP in combination with intraoperative hydrogen peroxide treatment within a TMT protocol is a well-tolerated and feasible treatment approach. Compared to reported classical TMT protocols trials, morbidity and perioperative mortality rates are lower and median survival is equal or better. Furthermore we were able to show that hydrogen peroxide inhibited MPM cell growth in vitro after short exposure. Keywords: Surgery, multimodality treatment, intraoperative treatment MS15.03: CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRATHORACIC CHEMOTHERAPY FOR TREATMENT OF PLEURAL MESOTHELIOMA: A 10-YEAR EXPERIENCE Pietro Bertoglio1, Marcello C. Ambrogi1, Antonio Chella2, Vittorio Aprile1, Stylianos Korasidis1, Marco Lucchi1, Paolo Dini1, Olivia Fanucchi1, Alfredo Mussi1 University Hospital Of Pisa, Division of Thoracic Surgery, Pisa, ITALY, 2University Hospital Of Pisa, Division of Pneumology, Pisa, ITALY 1 Objectives: The primary end-point of this retrospective 10-year study was to evaluate safety and feasibility of cytoreductive surgery followed by hyperthermic intrathoracic chemotherapy (HITHOC) perfusion for treatment of Malignant Pleural Mesothelioma (MPM). The secondary end-point was survival, disease free interval and analysis of possible risk-factors. Methods: The outcomes of all patients with MPM who underwent cytoreductive surgery followed by HITHOC, during the period 2005-2014, were analyzed. All patients were evaluated in a multidisciplinary setting. Selection criteria were histologically-proven epithelioid or biphasic MPM; clinical IMIG stage I-III disease; age 18-75 years; performance status < 3 according to Eastern Cooperative Oncology Group; absence of cardiac, neuropathic or renal disease; adequate medullary reserve; no con- comitant infection; no pregnancy status. Surgery consisted of resection of parietal and mediastinal pleura plus gross debulking of any disease on the diaphragm and the pericardium, which were routinely spared. After thoracotomy closure, HITHOC was run by the mean of the chest drains using a dedicated perfusion machine: Cisplatin (80 mg/m2) and Epirubicin (25mg/m2) perfusion lasted for 60 minutes at a target temperature of 42°C. Intra-operative and post-operative morbidity and mortality were recorded. All patients received at least three cycles of adjuvant chemotherapy, while prophylactic radiotherapy was administered according to the choice of the referring oncologist. Survival analysis (calculated from the day of surgery) was performed only on patients with a minimum follow-up of 12 months. Results: Among 49 patients, 41 were male. Median age was 68 years (35-76). Histology was epithelioid in 43 cases. Pathological stage I, II, III and IV was presented in 12, 14, 20 and 3 cases respectively. No intraoperative complications occurred and all procedures were successfully completed. No 30- and 90-day mortality were noticed. Morbidity consisted in anemia requiring blood transfusion in 11 cases (22,45%), prolonged air-leak (>5 days) in 4 cases (8,16%), wound dehiscence in 3 cases (6,12%) and one (2,04%) postoperative empyema, treated and resolved with medical therapy. Median hospital stay was 8 days (5-45). At a mean follow up period of 26 months, 12 patients were still alive and 4 of them have no clinical or radiological signs of disease. Actuarial median overall survival was 22 months and a 1, 2 and 5 year survival accounted for 79,6, 43,3 and 13,7% respectively. Median disease free survival was 12 months after surgery. Age over 65 years and sex did not showed to be significantly related to the survival, while biphasic histology had a significant worse prognosis compared to epithelioid (p=0,026). Stage were a predictor of prognosis: patients with stage I had a median survival of 46 months (p<0,001) and a median DFI of 18 months (p=0,004). Conclusion: Cytoreductive surgery associated to HITHOC and adjuvant chemotherapy is feasible and safe, with no mortality and low morbidity, allowing a good control of the disease and acceptable outcomes; its low invasiveness allows to extend indication for surgery also to patients who might not be fit for more invasive and detrimental procedures. Larger controlled studies are needed to confirm our promising results. Keywords: Malignant pleural mesothelioma, hyperthermic intrathoracic chemotherapy, cytoreductive surgery, partial pleurectomy MS15.04: RADICAL PLEURECTOMY AND HYPERTHERMIC INTRATHORACIC CHEMOPERFUSION FOR THE TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA Laura V. Klotz, Michael Lindner, Jürgen Sklarek, Rudolf A. Hatz Lungenfachklinik Gauting, Center for Thoracic Surgery Munich, Gauting, GERMANY Objectives: Radical pleurectomy and decortication (P/D) of the parietal and visceral pleura represents a surgical treatment iMig2016.ORG 65 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP approach for patients suffering from malignant pleural mesothelioma (MPM) without the possibility to undergo pleuropneumonectomy. For several years, we combine this procedure with hyperthermic intrathoracic chemoperfusion (HITHOC). Methods: Between 2009 and 2014, 70 patients with malignant pleural mesothelioma underwent radical P/D followed by HITHOC. Patients’ characteristics, tumor stage, intra- and postoperative complications and overall survival were evaluated retrospectively. Results: The median patient age was 68 years. Sarcomatoid compared to epitheloid MPM showed significant difference in median survival after P/D and HITHOC with 9,2 months for sarcomatoid and 18 months for epitheloid subtype. Concerning epitheloid MPM, median survival was significantly better for patients macroscopic complete resection (MCR) in contrast to patients after macroscopic incomplete resection with 34,4 months versus 12,3 months. Conclusion: Radical P/D in combination with HITHOC is a promising treatment option for selected patients with epitheloid MPM. Macroscopic complete resection is the most important prognostic factor for survival. events, hematological and renal toxicity were monitored using CTCAE grading. Quality of life was assessed with the SF36v2 questionnaire, physical component summary (PCS) score and mental component summary (MCS) score and were compared to pre-treatment values using the Wilcoxon signed rank test. Results: No dose limiting toxicity was observed. Major morbidity was observed in 4 patients (33%). 30day- and 90day-mortality was 0%. The median serum AUC0-24 in the highest dose level group reached 23 h*µg/g even after induction chemotherapy, which is still below the suggested renal toxicity risk level, 25 h*µg/g [Royer 2008]. Local tissue cisplatin concentration at 90 minutes varied from 12-133 (median: 36.5 µg/g). Serial chest wall biopsies of 2 patients showed cisplatin at day 74 and 204 after application. PCS score was significantly decreased initially but returned to baseline values at 8 months after application. The MCS score was never significantly different from pretreatment evaluation. The median follow-up after surgery was 17 months (range 11 – 36 months). Median freedom from recurrence was 8 months (95% confidence interval (CI): 4-12 months). In one patient with IMIG stage I, no sign of relapse was observed at 16 months after treatment (44 mg/m2 BSA). Median overall survival was 21 months (95% CI: 14-28). Keywords: pleurectomy, Malignant pleural mesothelioma, Surgery, hyperthermic chemoperfusion MS15.05: INTRACAVITARY CISPLATIN-FIBRIN APPLICATION FOLLOWING RESECTION OF MESOTHELIOMA Isabelle Opitz1, Olivia Lauk1, Mayura Meerang1, Martina Friess1, Michaela B. Kirschner1, Guillaume Wuilleret1, Cordelia Bommeli1, Alexander Jetter2, Beat Aeschlimann3 , Detlef Guenther3 , Rolf Stahel4 , Walter Weder1 Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 2Department of Clinical Pharmacology And Toxicology, University Hospital Zurich, Zurich, SWITZERLAND, 3Department of Chemistry And Applied Biosciences And Laboratory of Inorganic Chemistry, ETH Zurich, Zurich, SWITZERLAND, 4Clinic For Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 Objectives: Early local tumor relapse is very common after resection of malignant pleural mesothelioma (MPM). Intracavitary chemotherapy after tumor resection might improve local tumor control. The present clinical trial assesses intracavitary cisplatin-fibrin application after pleurectomy/decortication (P/D) for MPM patients. Methods: Twelve patients (75% IMIG stage III + IV) with a median age of 65 years underwent intracavitary cisplatin –fibrin application after P/D at 4 different dose levels of cisplatin (11, 22, 33 and 44mg/m2). Eight patients were previously treated with intravenous cisplatin/pemetrexed (100 mg/m2). To evaluate cisplatin pharmacokinetics, blood and chest wall tissue samples were taken at several time points. Cisplatin levels were measured by inductively coupled plasma sector field mass spectrometry. Besides adverse and serious adverse Figure 1: Serum cisplatin AUC (A), tissue/fibrin cisplatin concen- tration in serial biopsies from 2 patients (B). Conclusion: The administration of intracavitary cisplatin-fibrin as high as 44mg/m2BSA is safe after (e)P/D, also in combination with induction chemotherapy. Tissue cisplatin concentration was cytotoxic whereas no dose limiting toxicity due to iMig2016.ORG 66 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP systemic distribution was detected. Quality of life is normalized 8 months after treatment. A confirmation of the safety and evaluation of efficacy of the highest dosage, 44 mg/m2BSA, in a phase II trial is ongoing. Keywords: intracavitary treatment, phase I clinical trial, cisplatin MS15.06: PLEURECTOMY / DECORTICATION AND INTRAOPERATIVE INTRAPLEURAL HYPERTHERMIC CDDP PERFUSION FOR MALIGNANT PLEURAL MESOTHELIOMA were not reached in P/D group and 17 months in EPP group. Two and 3-year overall survivals were 90% and 68% in P/D group, respectively, and 30% and 30% in EPP group, respectively. Median disease free survivals were not reached in P/D group and 12 months in EPP group. Two and 3-year disease free survivals were 57% and 57% in P/D group, respectively, and 30% and 20% in EPP group, respectively. First relapse sites indicated that all 4 relapses were locoregional in P/D group, while 6 of 7 relapses were distant and the other was both local and distant in EPP group. Conclusion: P/D and intraoperative hyperthermic CDDP perfusion followed by systemic chemotherapy for resectable MPM was promising. Further study with more patient accrual is warranted. Keywords: pleurectomy / decortication, hyperthermia, intrapleural chemotherapy, multimodality treatment Kenichi Okubo, Hironori Ishibashi, Masashi Kobayashi, Chihiro Takasaki, Sachiko Kumazawa Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, JAPAN Objectives: The role of surgery in the treatment for resectable MPM is considered to be macroscopic complete resection. We examined our results of multimodality treatment including extended pleurectomy/decortication (P/D) for resectable MPM. MS15.07: HIPEC AS A TREATMENT FOR MALIGNANT PERITONEAL MESOTHELIOMA: ARE WE THERE YET? Methods: We have performed a treatment-protocol consisting of P/D with intraoperative hyperthermic intrapleural CDDP perfusion (42℃, CDDP 80mg/m2 in saline 2L, 1hr) and postoperative chemotherapy (CDDP+PEM, 4 cycles) for patients with MPM (cT1-3N0-2M0) since 2010. Our indication of P/D-protocol was patients with MPM who were intolerable for EPP until 2013, and all patients with MPM after 2014. There were 10 men and 2 women with a mean age of 66.9 years (55-76 years). Five patients had a right-side disease and 7 had a left-side disease. Histological subtypes were epithelioid in 9, biphasic in 2, and desmoplastic in 1, and pathological stagings were stage I in 4, stage II in 1, stage III in 6, and stage IV in 1. Eleven patients underwent a P/D and hyperthermic chemoperfusion initially, and one patient with secondary nephrotic syndrome received five cycles of preoperative chemotherapy. All parietal and visceral pleura were removed, and pericardium and/or diaphragm were resected when necessary. Concentrations of platinum in the perfusate were examined before and after perfusion in 7 patients. Acute surgical outcome, survivals and relapse patterns in P/D group were examined, and compared with 10 patients (EPP group) who received trimodality treatment consisting of extrapleural pneumonectomy, chemotherapy, and intensity modulated radiation therapy for entire hemithorax (50Gy) in our institute during 2010-2013. Gleneara E. Bates, Yaakov Bressler, Robert N. Taub Results: All patients obtained macroscopic complete resection in P/D and EPP groups. All but one in P/D group received multiple cycles of chemotherapy, and all in EPP group completed the trimodality treatment. Operation time was longer in P/D group; however, there were no differences in ICU stays or hospitalizations. Ten patients in P/D group and 7 patients in EPP group experienced postoperative complications; however, there were no operative mortality. EPP group suffered from cardiac complications and P/D group had prolonged airleak. Concentrations of platinum showed that 29% of CDDP was left in the pleural cavity after the chemoperfusion. Median survivals Medicine, Columbia University Medical Center, New York, NY, UNITED STATES OF AMERICA Objectives: Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is now advocated by numerous experienced mesothelioma specialists as part of the standard of care for malignant peritoneal mesothelioma (MPM).The earliest studies with use of hyperthermia alone and intraperitoneal chemotherapy alone in humans were conducted in the 1970’s. Since, there has been little systematic research conducted on how these two treatments may be optimally used in combination.This study investigates the largest single-institution cohort of MPM patients treated with surgical cytoreduction and HIPEC guided by a medical oncologist. Methods: Kaplan-Meier curves and univariate cox proportional hazards model were used to estimate survival and significant treatment and prognosis factors for 195 patients who underwent cytoreductive surgery and or HIPEC treatment between 1995–2014; patients were not excluded for bicavity disease or for unresectable disease. Results: The median survival time was 3.21 years with (95% CI: 2.38-5.53), with median follow-up of 3.44 years (SD=3.4, minimum=0.014 and maximum=16.752) years from first operation. The mean age at diagnosis was 54.8 years [HR: 1.027 (95% CI: 1.012-1.042)] with 111 men (57%) and 84 women (43.1), with female gender having favorable survival [HR: 0.442 (95% CI: 0.296-0.659)]. Asbestos exposure was reported in 77 patients (39.5%) with n=80 (41.0%) having no known asbestos exposure and no documented exposure in 38 patients (19.5%). Majority of patients had epithelioid histology (n=16, 82.6%), with the remainder biphasic/sarcomatoid (n=34, 17.4%), with increased risk of death with non-epithelioid histology [HR: 2.46(95%CI 1.59-3.82)], (P=0.001). Of the 195 patients who iMig2016.ORG 67 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP received cytoreductive surgery, 71 (36.1%) received 1 HIPEC treatment, while 124 (63.9%) received 2 HIPEC treatments, with completion of protocol having an associated favorable prognosis [HR: 0.161 (95%CI 0.109-0.237)] (p= 0.001). Of those who received a full treatment course of cytoreductive surgery and 2 HIPEC treatments, 66 (33.8% CI: 95%) were alive at the median follow-up. Conclusion: This large cohort illustrates that CRS and HIPEC may be an effective treatment for MPM. While the treatment continues to evolve, the future of HIPEC for MPM will depend largely on monitored multi-institutional collaborative randomized clinical trials to demonstrate whether HIPEC is the optimal treatment for MPM. There is much variation of technique for HIPEC among medical centers – parameters of such operations include: open or closed perfusion, chemotherapeutic agents, concentrations of agents, temperature range, and exposure time. Standardizing HIPEC for MPM patients would be an important contribution to the continued advancement of MPM treatments. Keywords: Peritoneal, Survival, HIPEC, mesothelioma MS16: NOVEL IMMUNE STRATEGIES TUESDAY, MAY 3, 2016 16:30 – 18:00 Technologies in the pIDT.SMART cloning plasmid. It was then subcloned into the previously described MigR1 retroviral vectors containing the CARs against human mesothelin (mesoCAR) (Riese et al., 2013) and murine fibroblast activating protein (FAPCAR) (Wang et al., 2014). Primary murine T cells were isolated and transduced with these retroviral particles. The mesoCAR and RIAD constructs were also subcloned into a lentiviral vector used to transduce human T cells undergoing anti-CD3/ CD28 bead activation. CAR vs. CAR-RIAD T cells were tested for tumor lytic and cytokine secretion function in the presence/ absence of PGE2 and adenosine. These T cells were also compared in murine models of established solid flank tumors. Results: After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, more cytokine release, and enhanced killing of tumor cells compared to CAR T cells. When injected into tumor-bearing mice, murine and human CAR-RIAD T cells demonstrated enhanced anti-tumor efficacy compared to CAR T cells due to increased T cell infiltration of established tumors, and attenuated tumor-induced hypofunction. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells in response to the chemokine CXCL10 and also adhered better to various matrices. Conclusion: Our data therefore show that the addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy should therefore be considered for clinical application in treating solid tumors. Keywords: T cells, tumor microenvironment, Immunotherapy MS16.01: BLOCKADE OF PROTEIN KINASE A (PKA) LOCALIZATION AUGMENTS TRAFFICKING AND ANTI-TUMOR EFFICACY OF CAR T CELLS Edmund Moon1, Kheng Newick1, Shaun O’Brien2, Jing Sun2, Albert Lo2, Steve Maceyko2, Steven Albelda2 Pulmonary, Allergy, And Critical Care, University of Pennsylvania, Philadephia, PA, UNITED STATES OF AMERICA, 2University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA 1 Objectives: In recent years, the adoptive transfer of T cells transfected with chimeric antigen receptor (CAR) genes has shown great promise in treating blood-borne tumors. However, in the case of solid tumors like mesothelioma, many factors exist that eventually render these CAR T cells ineffective. Two such factors include the presence of immunosuppressive mediators (such as prostaglandin E2 (PGE2) and adenosine), and poor T cell trafficking. Since PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T cell receptor (TCR) activation, we generated CAR T cells that expressed a small peptide called the “regulatory subunit I anchoring disruptor” (RIAD) that inhibits the association of protein kinase A (PKA) with ezrin; this interaction is required for the negative effects of PKA on TCR activation. We hypothesized that cloning the RIAD transgene into T cells expressing CARs would enhance their function within the tumor microenvironment and result in superior tumoricidal ability as compared to T cells with CAR alone. Methods: The RIAD construct into which myc and ddk (FLAG) tags were incorporated, was synthesized by Integrated DNA MS16.02: CHARACTERISING T-CELL RESPONSES AGAINST MUTATED MESOTHELIOMA NEOANTIGENS Jonathan Chee1, Shaokang Ma1, Jenette Creaney1, Bruce Robinson2 School of Medicine and Pharmacology, National Centre Of Asbestos Related Diseases, University of Western Australia, Nedlands, AUSTRALIA, 2School of Medicine and Pharmacology, National Centre Of Asbestos Related Diseases, University of Western Australia, Nedlands, WA, AUSTRALIA 1 Objectives: A feature of carcinogen-induced cancers is the accumulation of mutations in the cancer cell. Cytotoxic T lymphocytes (CTLs) respond to mutated proteins (neo-antigens), and in some experimental models, boosting CTL responses specifically against neo-antigens can cause tumour regression. High throughput sequencing such as RNA and exome sequencing has allowed us to interrogate mutations from different cancers. Application of algorithms on sequencing data allows us to predict mutated proteins in a cancer that can be potentially recognised by host immune cells such as cytotoxic CD8 T cells (CTLs). We have sequenced mouse mesothelioma (AB1/AB1-HA), and described the first mutated mesothelioma neo-antigens. Furthermore, we have demonstrated immune responses against iMig2016.ORG 68 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP one of the predicted neo-antigens: mutated Uqcrc2 (Uq2) in mesothelioma bearing animals. The objective of this study was to characterize further characterize T cell responses against neo-antigens in tumour bearing animals after different treatments that cause tumour regression in AB1 model. We hypothesize that treatments will increase the strength of responses to ‘existing’ neo-antigens such as Uq2, and could also lead to the detection of responses against other neo-antigens that would otherwise be undetectable without treatment. aims to induce an effective in vivo anti-tumor T-cell response. These T cells, however, are strongly suppressed by tumor associated macrophages (TAMs) within the tumor, thereby preventing an effective anti-tumor immune response from occurring. TAMs are known to be short-lived cells and are highly dependent on signaling via the colony stimulating factor 1 receptor (CSF1R). We investigated whether the efficacy of DC-therapy could be enhanced by depleting TAMs through CSF1R-blockade in a mesothelioma mouse model. Methods: Mice were inoculated subcutaneously with mesothelioma cell lines (AB1-HA). AB1-HA bearing animals were treated either with anti-CTLA4 antibody (checkpoint blockade immunotherapy), anti-GITR antibody (Treg modulation), gemcitabine (chemotherapy), neo-antigen vaccinations or depleted of Tregs (removal of immunosuppression). We tested T cell responses at the draining lymph nodes and tumours against predicted neo-antigens using different immunoassays such as IFNg ELISPOT, pMHC tetramers and flow cytometry. Methods: Four groups of six female wildtype Balb/c mice were injected intraperitoneally with a syngeneic mesothelioma cell line (AB1) on day 0, followed by suboptimal treatment with DC-therapy or PBS on day 10. DCs were cultured from wild-type Balb/c bone marrow cells, loaded with an AB1-cell line lysate and matured using a TLR9-agonist (CpG). Concurrently, mice were fed from day 10 onwards either with a CSF1R-inhibitor in chow (PLX3397) or control chow. Blood was obtained on day 15 and analyzed by flow cytometry to investigate peripheral immune activation. Mice were sacrificed when they presented with signs of severe illness or at the end of the experiment, 120 days post-tumor injection. End-stage tumors were investigated using flow cytometry and immunohistochemistry to determine the local immune composition. Results: The frequency of T cells specific for a single neo-antigen (Uq2) is low (<0.1%). ELISPOT was the only immunoassay tested that could detect responses against neo-antigens. Conventional pMHC staining and flow cytometry was not sensitive enough to detect a positive signal for low frequency T cells. Using the ELISPOT assay, we demonstrate the frequency of T cell responses to neo-antigen Uq2 was highly variable between mice after treatment, and showed a general trend of increase after checkpoint blockade immunotherapy, chemotherapy or Treg removal (compared to non-treated mice). Treatments did not increase T cell responses to 30 other predicted neo-antigens. Conclusion: The frequencies of neo-antigen specific T cells are low and restricted to only one or a few mutated neo-antigens. For effective translation, e.g. using neo-antigen vaccines, assays with increased sensitivities, or an additional T cell expansion step must be used to detect and phenotype neo-antigen specific T cells. We detected an increase in neo-antigen T cell responses after some treatments. Current studies include a detailed analysis of Uq2 and other response, including whether Uq2 or other neo-antigen responses are essential for an anti-tumour immune response. Keywords: Immunotherapy, tumour neo-antigens, T cells, tumour immunology MS16.03: CSF1R-BLOCKADE SYNERGIZES WITH DENDRITIC CELL IMMUNOTHERAPY IN A MESOTHELIOMA PRECLINICAL MODEL Floris Dammeijer, Lysanne Lievense, Menno Van Nimwegen, Koen Bezemer, Margaretha Kaijen-Lambers, Rudi Hendriks, Joost Hegmans, Joachim Aerts Results: Analysis of peripheral blood from day 15 during CSF1R therapy revealed no significant changes in CD4+ and CD8+ T-cell numbers and no additional increase in proliferation (Ki-67+) or effector markers (KLRG1) compared to DC-therapy alone. However, Ly6G+ granulocytes and Ly6C+ monocytes were decreased in numbers, accompanied by an increase in immature myeloid cells defined by a Ly6C/Ly6G intermediate phenotype. There was an increase in survival of mice treated with the combination therapy as 50% of mice survived for the duration of the experiment. In contrast, only one mouse survived when treated only with DC-therapy, and all mice had to be sacrificed in the CSF1R-monotherapy and PBS control groups. End stage tumors revealed a decrease in TAMs when mice were treated with the CSF1R-inhibitor, however, mice that progressed during treatment had surprisingly rare CD8-T-cell infiltrates. Coincidentally, these tumors were populated by dense infiltrates of GR1+ cells Conclusion: TAMs represent an abundant population in mesothelioma tissue. Using a CSF1R-inhibitor, we show that TAMs can be selectively depleted in a mesothelioma mouse model, and that CSFR1-blockade synergizes with DC-therapy. A subset of mice progressed during CSFR1-blockade, a finding which could be explained by the infiltration of GR1+ cells, indicating a possible redundancy between these cells and TAMs in the tumor. These findings pave the way for further experiments investigating the benefits of disabling local immune suppression together with potent T-cell induction by DC-therapy in malignant mesothelioma. Keywords: Tumor associated macrophages, Dendritic Cell Immunotherapy, Malignant mesothelioma, Combination Immunotherapy Dept. Of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, NETHERLANDS Objectives: Dendritic cell (DC)-based immunotherapy is a promising treatment for malignant mesothelioma. DC-therapy iMig2016.ORG 69 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS16.04: PROSTAGLANDIN E2-CAMP-ADENOSINE NEXUS IN MESOTHELIOMA; SELF AMPLIFYING IMMUNOSUPPRESSION? MS16.05: HETEROTYPIC 3D SPHEROID TUMOUR MODELING OF MESOTHELIOMA TO DETERMINE IMMUNE RESISTANCE Zsuzsanna Tabi Saly Al-Taei, Josephine Salimu, Zsuzsanna Tabi Division of Cancer And Genetics, Cardiff University, Cardiff, UNITED KINGDOM Division of Cancer And Genetics, Cardiff University, Cardiff, UNITED KINGDOM Objectives: ATP-release by damaged or dying cells represents a danger signal that contributes to the initiation of immune responses. On the other hand, the ATP-metabolite adenosine is well known for its extensive immunosuppressive effects and direct support of tumour growth. Cell surface expressed ectonucleotidases hydrolyse ATP in a sequential manner: CD39 hydrolyses ATP into ADP and 5’-AMP while CD73 hydrolyses AMP into adenosine. CD73 can be expressed by malignant cells, while CD39 by tumour stroma. Due to the combined activity of these two enzymes, adenosine levels are often elevated in the tumour tissue. Circulating human monocytes in healthy donors are CD39-positive but do not express CD73. We observed recently that monocytes in mesothelioma-associated pleural exudate express both CD39 and CD73. The aim of this study is to reveal the regulation and relevance of monocytic CD73 expression in mesothelioma. Objectives: Tumour modelling in vitro in the form of 3D spheroid cell culture provides a more accurate platform for assessing the benefit of potential new therapeutics, when compared to 2D culture. However, these homotypic tumour cell spheres still fail to capture the complexity of tumour tissue. We have an ongoing project to develop a complex 3D heterotypic tumour spheroid model incorporating the main tumour components; tumour, stromal and endothelial cells to more accurately mimic tumour tissue in vitro. This model will enable us to study the susceptibility of mesothelioma tumours to immune cell killing. We predict that the inclusion of fibroblasts and endothelial cells alongside the tumour will provide marked protection of tumour cells from T cell mediated killing. Methods: CD14+ myeloid cells in the pleural effusion and peripheral blood of patients and healthy donors were phenotyped by flow cytometry for the expression of CD39 and CD73. Healthy donor CD14+ cells were separated and exposed to the cell free fraction of pleural effusion (pleural fluid; PF) or to adenosine (in the form of NECA), prostaglandin E2 (PGE2) or forskolin to detect the induction of CD73 expression. PF treatment was also carried out in the presence of adenosine-receptor or PGE2-receptor inhibitors. Results: We found significant CD73 expression on CD14+ cells present in pleural exudate but not in peripheral blood of patients with malignant mesothelioma. The observed co-expression of CD39 and CD73 makes these tumour-associated monocytes uniquely capable of metabolising pro-inflammatory ATP to immunosuppressive adenosine. We also found that CD73 can be upregulated on normal CD14+ cells upon exposure to PF in a dose- and cell type-dependent manner, as this effect was not observed on T cells. Cyclic-AMP-inducers, forskolin and PGE2, as well as adenosine, were also able to induce CD73 expression. Inhibition of adenosine A2a receptor or PGE2-receptors EP2 and EP4 abolished CD73 induction by PF on monocytes, demonstrating a self-amplifying loop by adenosine via cAMP signalling in mesothelioma. Conclusion: Our findings point towards a cross-talk between adenosine, PGE2 and cyclic AMP in the regulation of CD73 expression on tumour-associated monocytes, potentially leading to sustained adenosine production. This may contribute not only to enhanced tumour growth but also to the immunosuppressive nature of mesothelioma and should be considered when designing new therapeutic approaches. Keywords: adenosine, immune cells, immunosuppression Methods: To construct this model we used a mesothelioma cell line generated in house from tumour tissue (#18), primary normal lung fibroblasts (AG-02603; which we anticipate will be ‘hijacked’ by the tumour to form tumour-promoting stroma) and primary endothelial cells (HUVECs). These cells were cultured in low-adherence 96 well U bottomed plates to aid spheroid formation. We assessed cell distribution within the spheroids 5 days after initial cell seeding by paraffin embedding, sectioning and subsequent H&E staining. Spheroid growth was determined using a 3H-thymidine incorporation assay to measure proliferation. Cytotoxic T cell killing assay measuring 51Chromium release was used to assess susceptibility of the spheroids to T cell mediated killing. Results: We have successfully generated tumour only (1 component), tumour and fibroblast (2 component) and tumour, fibroblast and endothelial cell (3 component) spheroids. After 5 days, 2 component spheroids assume a structure that is comparable to tumours in vivo. This includes a necrotic core, proliferating cells to the periphery of the sphere, mucin deposits and an outermost layer of secretory mesothelial cells. The 2 and 3 component spheroids had a growth advantage over the 1 component spheroids. We also found the 1 component spheroids to be sensitive to T cell killing. However, as predicted, the 2 component spheroids are significantly more resistant to T cell killing in comparison. Furthermore, this protection is further enhanced by the inclusion of endothelial cells in the 3 component spheres. The mechanism of this immuno-resistance, acquired by the tumour cells in 2 and 3 component spheroids, is currently the subject of further study. Conclusion: In conclusion, we have generated a 3D mesothelioma tumour model with a more accurate basis than current in vitro tumour models. We were able to mimic the growth and survival advantage conferred by stromal and endothelial cells and consequent resistance to immune attack. This model can be widely used to accelerate the screening of novel therapies that are of potential benefit to patients. Keywords: T cells, spheroids, immuno-resistance iMig2016.ORG 70 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP MS16.06: IMMUNE ESCAPE CORRELATES STRONGLY WITH AN INFLAMED PHENOTYPE IN MALIGNANT MESOTHELIOMA MS16.07: EXPLOITING IMMUNE CHECKPOINT BLOCKADE TO DEVELOP EFFECTIVE THERAPY FOR MALIGNANT MESOTHELIOMA Yi-Hung Carol Tan1, Arun Khattri2, Zhixiang Zuo2, Aliya Husain3 , Hedy Kindler2, Tanguy Y. Seiwert2 Scott Fisher1, Jessica Solin1, Thomas Casey1, Willem J. Lesterhuis1, Sally M. Lansley2, Bruce Robinson1, Richard Lake1 Medicine, The University of Chicago, Chicago, AL, UNITED STATES OF AMERICA, 2Medicine, The University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 3Department of Pathology, The University of Chicago, Chicago, IL, UNITED STATES OF AMERICA 1 1 Objectives: Malignant mesothelioma (MM) is commonly associated with an inflammatory reaction, although the specific patterns of immune escape remain incompletely understood. We used emerging, high-fidelity gene expression data from the TCGA mesothelioma cohort to interrogate subgroups based on expression of immune related genes, and determined associated immune escape mechanisms. Methods: RNA-seq data from 25 MM were analyzed using gene signatures representative of T-cells, NK-cells, neutrophils, and dendritic cells/macrophages, as well as genes associated with immune escape (immune checkpoints and cellular immune escape). The cellular de-convolution algorithm CiberSorter was also applied. Using this unsupervised gene set, hierarchical clustering was performed to identify intrinsic immune subgroups. Groups correlated with T-cell inflammation (Kindler, ASCO 2014), based on the 12-gene inflammation signature (Harlin/Gajewski, CR 2009). Results: MM tumors readily clustered into two large groups: inflamed and non-inflamed. 35% of tumors demonstrated high levels of inflammation (group 1), presence of all four immune cell components, and 80% of tumors had a TCIP-high phenotype. Non-inflamed tumors (group 2) showed low immune cell related gene expression and were 85% non-T-cell inflamed. Prominent immune escape was present in all group 1 tumors, including expression of PD-1/PD-L1, CTLA4, LAG3, and FOXP3 (however not B7H3). Inflammation strongly correlated with presence of immune escape (functional immune response) in group 1 while group 2 tumors exhibited neither infiltration with immune cells nor immune escape (immunological ignorance). There was no correlation of PD-L1 expression with either macrophage infiltration or degree of CD8 T cell infiltration, suggesting primarily tumor based PD-L1 expression, which was confirmed using multi-color immunofluorescence imaging. Conclusion: MM can be classified into inflamed/group 1 and non-inflamed/group 2 tumors. Group 1 tumors show simultaneous infiltration with multiple immune cell components and prominent immune escape. Inflamed and non-inflamed tumors may require different treatment strategies for immunotherapy. Keywords: gene signatures, mesothelioma, RNA-seq, Immunotherapy School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, WA, AUSTRALIA, 2Pleural Medicine Unit, Institute for Respiratory Health, Perth, WA, AUSTRALIA Objectives: Immune checkpoint blockade (ICPB) is effective against melanoma and is now being applied to other cancers, including mesothelioma. ICPB therapies work by using antibodies to block molecules that negatively regulate T cell function, thus promoting and prolonging anti-tumour immunity. Current ICPB therapies are mostly focused on two key checkpoint molecules; CTLA-4 and PD‑1 and dual blockade appears superior to single agent. However, at least 22 other checkpoint molecules have been identified and the best combinations for each cancer have yet to be defined. Using our well established preclinical mesothelioma models, this study aims to characterise the expression profile of a subset of checkpoint molecules on immune cells present within mesothelioma tumours to identify the best combination of checkpoint blockade antibodies for effective therapy against mesothelioma. Methods: Tumours harvested from mice inoculated with AB1 and AE17 mesotheliomas were assessed by multiparameter flow cytometry to characterise expression of immune checkpoint molecules (CTLA-4, OX40, TIM-3, GITR and PD-1) on immune cell subsets within the mesothelioma tumour microenvironment. Based on these data, tumour bearing mice were treated with antibodies either alone or in combination to identify the best therapies for anti-tumour immunity against mesothelioma in two mesothelioma tumour models. Results: OX40 and CTLA-4 are highly expressed on tumour resident regulatory T cells (Treg) compared to tumour infiltrating lymphocytes (CD4 and CD8 TILs). Conversely, increased PD-1 expression was observed for non-Treg CD4 and CD8 TILs compared to Treg, while broad TIM-3 expression was observed on both effector and regulatory T cells. We observed a significant delay in tumour growth and associated improvement in overall survival in mice that were treated with either αCTLA-4 or αGITR alone, but not in mice treated with αOX40, αPD-1 or αTIM-3. Combining αCTLA‑4 with αOX40 provided no additional benefit in tumour growth delay over CTLA-4 alone. Conversely, a small delay was observed when PD-1 and TIM-3 were combined, suggesting that the dose/scheduling of this combination treatment warrants further investigation. These combinations are currently being tested in an orthotopic (intrapleural) mesothelioma mouse model. Conclusion: Immune checkpoint blockade is a significant breakthrough, offering promise for the treatment of many solid tumours including mesothelioma. Data from our pre-clinical mouse models suggest that immune checkpoint molecules are highly expressed on tumour infiltrating immune cells and that immunotherapies that target these molecules can delay mesothelioma development and improve survival. We are continuing to refine our treatment protocols to ultimately identify which combination of immune checkpoint molecules are best iMig2016.ORG 71 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP for generating effective immunity against mesothelioma in both subcutaneous and orthotopic models. These findings will be fundamental to inform the rational design of future clinical trials that utilise ICPB for the treatment of mesothelioma. Keywords: Immunotherapy, immune checkpoint blockade, mouse models iMig2016.ORG 72 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP POSTER SESSIONS PP01: POSTER MIXER AND POSTER DISCUSSION SESSION 1 MONDAY, MAY 2, 2016 18:00 – 19:30 PP01.01: SYSTEMIC INFLAMMATION CONSISTENTLY PREDICTS ADVERSE OUTCOME BASED ON MULTIPLE BIOMARKERS IN PATIENTS WITH MESOTHELIOMA Michael Mcgettrick1, Selina Tsim2, Kevin Blyth2 Respiratory Department, Queen Elizabeth University Hospital, Glasgow, Glasgow, UNITED KINGDOM, 2Respiratory Department, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM 1 Objectives: Predicting survival in patients with Malignant Pleural Mesothelioma (MPM) is challenging. Inflammatory biomarkers including Neutrophil-to-Lymphocyte ratio (NLR), Platelet-to-Lymphocyte ratio (PLR) and the modified Glasgow Prognostic Score (mGPS), which integrates CRP (</>10mg/l) and Albumin (</>35g/l) into a 3-point score, have proven inconsistent prognostic tools in MPM. We compared the prognostic values of NLR, PLR and mGPS to established tools (histology, Performance Status (PS) and EORTC Prognostic Score (EPS)). Methods: 213/1250 patients with archived MPM tissue were identified retrospectively.743/1250 (diagnosed pre-2008, prior to electronic records), 213/1250 (from a different health-board) and 11/1250 (non-pleural MPM) were excluded. Relevant data were collected using electronic records. NLR and PLR were dichotomised using established cut-points. Kaplan-Meier survival methodology (log-rank or log-rank for trend) and hazard ratios (HR) were used to assess prognostic influence and quantify risks of death. Results: Mean age was 73 (±11) years, 81% were male. 63% had Epithelioid, 19% Sarcomatoid, 8% Biphasic and 10% not-specified sub-type. PS at diagnosis was 0-1 in 43%, 2-3 in 17%, 4 in 1% and not recorded in 40%. Mean NLR, computable in 95%, was 5.7 (±4.4). Mean PLR, computable in 95%, was 309 (±205). mGPS was 0 in 56/283 (20%), 1 in 87/283 (31%), 2 in 95/283 (33%) and not computable in 45/283 (16%). EPS was computable in 180/283 (63%) and high risk in 50/180 (28%). The prognostic significance of NLR, PLR and mGPS are summarised in Figure 1. Interestingly, the HR in patients with systemic inflammation (NLR >5, PLR > 300 or mGPS 1 or 2) relative to those without was similar (around 1.6). EPS predicted survival with similar weight to inflammatory indices (chi2 8.038, p=0.0046) and associated HR in high-risk patients (1.68 (1.16 – 2.3)). PS and histological subtype appeared more powerful predictors of outcome than any inflammatory index (chi2 113.1, p ≤0.0001, HR in PS 4 and PS 2-3, 28.3 and 1.84, relative to PS 0-1 respectively and chi2 17.75, p=0.0005, HR in Sarcomatoid and Biphasic, 2.22 (1.51 – 3.28) and 1.65 (1.08 – 3.23), relative to Epithelioid MPM respectively). Conclusion: Systemic inflammation is consistently associated with survival disadvantage in MPM, when measured using different biomarkers. Although the strength of this association is modest it appears similar to EPS, a validated prognostic tool. PS and histology are more strongly associated with outcome. It is not clear from the current data whether the association between inflammation and outcome relates to co-morbidities or tumour biology. This merits further study. Keywords: Biomarkers, Inflammation iMig2016.ORG 73 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.02: AN UPDATE ON DIAPHRAGM: A PROSPECTIVE, MULTI-CENTRE STUDY OF FIBULIN-3 AND SOMASCAN AS BIOMARKERS IN MESOTHELIOMA Selina Tsim1, Caroline Kelly2, Laura Alexander2, Ann Peek2, Jim Paul2, Rosemary Woodward3 , John E. Foster3 , Kevin Blyth1 Respiratory Medicine, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM, 2Cruk Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, UNITED KINGDOM, 3Clinical Research Imaging Facility, Queen Elizabeth University Hospital, Glasgow, UNITED KINGDOM 1 Objectives: Diagnostics in Malignant Pleural Mesothelioma (MPM) remain difficult and accurate non-invasive biomarkers to guide invasive histological sampling are required. SOMAscan is a 13-protein serum classifier with encouraging diagnostic performance (AUC 0.95) in a retrospective surgical series but this has not been assessed prospectively. Fibulin-3 is measured by ELISA in plasma and has shown similar promise (AUC 0.99), but these results have not been replicated in subsequent retrospective series. The primary objective of DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is to prospectively assess the diagnostic and prognostic value of these biomarkers, relative to Mesothelin and volumetric tumour assessment using Magnetic Resonance Imaging. Methods: A prospective multi-centre observational study is currently being conducted in 20 centres across the U.K. and Ireland, all of whom have evolved pleural diagnostic services. The primary end-point is the sensitivity and specificity of SOMAscan and Fibulin-3 for MPM. The study is powered based on available results in 120 patients with MPM, requiring recruitment of a projected 600 patients with Suspected Pleural Malignancy (SPM), assuming a 20% Mesothelioma incidence rate. This reflects the study design, which requires biomarkers to be drawn prior to pleural biopsy, pleurodesis or other intervention that might affect results, which also mirrors the probable timing of sampling for a tumour marker in clinical practice. Inclusion criteria are SPM and informed written consent. Exclusion criteria are insufficient fitness for diagnostic sampling or an inter-costal chest drain in-situ or within the preceding 3 months. Neither asbestos exposure nor pleural plaques are inclusion criteria, given the significant incidence of MPM in patients without these features. 109 asbestos-exposed controls (AEC) are also being recruited in Glasgow and the study includes extensive sample banking for future testing of MPM biomarkers. Results: The first recruiting centre (Glasgow) opened to recruitment on 31st December 2013. Since then, 428 patients have been recruited to the SPM arm (71% of original target) and 73 recruited (67% of target) to the AEC arm. An interim, blinded statistical review indicates that the incidence rate of MPM so far, is lower than predicted (20%), with a current rate of 13%. Significant progress has been made with the development of quantitative volumetric MRI methods and further validation of Early Contrast Enhancement, a recently reported and novel perfusion-based MRI biomarker of PM. Biomarker results will be compared with Mesothelin, the current best performing test, and volumetric assessment of tumour burden. The lower incidence of MPM recorded will require a study extension for 12 months, allowing completion in December 2016. The banking of prospectively collected, well-phenotyped samples of serum, plasma, whole blood (and pleural fluid in a proportion) will create a valuable resource for future MPM biomarker validation and/or discovery. Keywords: Biomarkers, Diagnostics PP01.03: EXAMINATION OF THE SERUM SOLUBLE MESOTHELIN-RELATED PEPTIDE (SMRP) LEVEL IN PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA Taiichiro Otsuki, Eisuke Shibata, Koji Mikami, Takayuki Terada, Kozo Kuribayashi, Takashi Nakano Respiratory Medicine, Hyogo College of Medicine, Nishinomiya Hyogo, JAPAN Objectives: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy of the mesothelium. MPM is difficult to detect in the early stages, as most cases are already at an advanced stage on diagnosis. This study aimed to evaluate serum soluble mesothelin-related peptide (SMRP) levels as a diagnostic marker for MPM . Methods: Serum SMRP levels were measured in 99 patients with MPM at the Hyogo College of Medicine between April 2013 and December 2015. Results: A total of 84 men and 15 women were included in the study. The histologic types (n) were: epithelioid (75), sarcomatoid (9), biphasic (10), and desmoplastic (5). Regarding clinical stage, 17 patients had Stage I disease, 28 had Stage II, 22 had Stage III, and 32 had Stage IV. The median serum SMRP level was 2.2 nmol/L (range, 0.2–81.4 nmol/L). There were 63 positive patients (64%) when we set a reference value of 1.5 nmol/L. Based on histologic type, the median SMRP levels for epithelioid, sarcomatoid, biphasic, and desmoplastic MPM were 2.6, 3.2, 0.95, and 0.9 nmol/L, respectively. Patients with epithelioid MPM had significantly higher SMRP levels than patients with non-epithelioid MPM (P=0.02). However, the patient with the higher levels had sarcomatoid mesothelioma. Conclusion: We examined serum SMRP levels in malignant pleural mesothelioma patients. In our analysis, we found that serum SMRP levels is a useful marker for the diagnosis of MPM. Conclusion: DIAPHRAGM has been designed to rigorously assess the diagnostic performance of SOMAscan and Fibulin-3 in patients presenting with suspected PM who could have MPM. iMig2016.ORG 74 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.04: PI3-KINASE PATHWAY AND MET INHIBITION IS EFFICACIOUS IN MALIGNANT PLEURAL MESOTHELIOMA Rajani P. Kanteti, Jacob J. Riehm, Immanuel Dhanasingh, Frances E. Lennon, Hedy Kindler, Ravi Salgia Medicine, University of Chicago, Chicago, UNITED STATES OF AMERICA Objectives: Malignant pleural mesothelioma (MPM), an aggressive cancer commonly associated with prior asbestos exposure has poor prognosis. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/ mTOR dual inhibitor, GDC-0980, in MPM. Methods: The MPM cells were treated with crizotinib, BKM120, or GDC-0980 alone or in combination. Relative levels of downstream signaling molecules were determined by immunoblotting and cell viability by Alamar Blue assay. The mechanism of inhibition was further studied using apoptosis assays and cell cycle analysis. Cell motility was studied using Boydon chamber migration assays. The effect of crizotinib, BKM120 and their combination on in vivo tumor growth was determined using a PDX mesothelioma model. Results: Cell viability results demonstrated that both pleural and peritoneal mesothelioma cell lines were highly susceptible to the inhibitory effects of crizotinib and BKM120 when used individually. Furthermore, the combination of crizotinib with either BKM120 or GDC-0980 was synergistic in suppressing growth of pleural mesothelioma cells (CI<1). Migration assays demonstrated that treatment of MPM cells with crizotinib, BKM120, or GDC-0980 significantly decreased MPM cell migration, while the combination of crizotinib with either BKM120 or GDC-0980 was synergistic. In addition, treatment of MPM cells with BKM120 alone or in combination with crizotinib induced G2/M arrest and apoptosis. The degree of apoptosis in MPM cells was much greater with BKM120 treatment compared to crizotinib and their combination elicited the maximum effect. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT, and ribosomal S6 kinase. In vivo studies using a PDX mouse model showed that crizotinib and BKM120 together acted synergistically in inhibiting tumor growth. PP01.05: EARLY DIAGNOSIS BY CYTOLOGY IMPROVES SURVIVAL Sulaf A. Own1, Gunnar Hillerdal2, Katalin Dobra1, Anders Hjerpe1 Dept Of Laboratory Medicine / Pathology, Karolinska University Hospital, Huddinge, SWEDEN, 2Dept Of Pulmonary Diseases, Karolinska University Hospital, Solna, SWEDEN 1 Objectives: A conclusive diagnosis of MM can be based on effusion cytology, using the guidelines now approved by IMIG [1]. This makes an earlier diagnosis possible, which in turn may influence the effect of chemotherapy [2]. Methods: During 2008-2013 a total of 91 patients were diagnosed with MM at the Karolinska University Hospital in Stockholm. The first diagnosis was obtained by histology in 48 cases and by cytology in 43 cases. In 14 of the latter cases a subsequent biopsy was obtained, verifying the diagnosis. All diagnoses were supported by clinical findings, including CT scans. Cases with sarcomatoid MM, secondary primaries and a case lost to further treatment were excluded, studying the importance of time for diagnosis in 77 cases of epithelioid and mixed type MMs. Clinical data, including evaluation of responses, were retrieved from hospital archives and survival data were obtained from the Swedish population data base. Results: Results The median time for diagnosis was 1 month less for cytology compared to histology. Chemotherapy was given somewhat more often following a histological diagnosis. Still the overall survival and the proportion of patients surviving 3 years was significantly better following a diagnosis based on effusion cytology; among treated patients 9/26 (38%) versus only 1/23 (4%), the median survival being 23 months and 14 months, respectively. The rate of initial responses to chemotherapy (stable disease + partial response) was slightly better in the cytology group Conclusion: Both our in vitro and in vivo findings suggest that dual inhibition of PI3K and MET pathway may be a much more effective strategy in treating MPM as compared to a single agent. Keywords: Mesothelioma, MET, PI3K, Crizotinib Fig. Survival after chemotherapy of MM diagnosed by cytopath- logy vs histopathology Conclusion: The earlier MM diagnosis obtained with effusion cytology improves the overall survival after chemotherapy. With fewer rotal numbers of malignant cells, the risk that resistance to therapy develops with time might then be less [2]. Our findings show the importance of the cytological diagnosis and encourage the initiation of treatment as soon as the diagnosis iMig2016.ORG 75 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP is obtained. References 1. Hjerpe A, Ascoli V, et al: Guidelines for Cytopathologic Diagnosis of Epithelioid and Mixed Type Malignant Mesothelioma. Complementary Statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology. Acta Cytol. 2015;59(1):2-16. Also published in: Diagn Cytopathol. 2015;43(7):563-76, Cytopathology. 2015;26(3):142-56, and CytoJournal, 2015;12(1): 26-40. 2. DeVita Jr. The James Ewing lecture. The relationship between tumor mass and resistance to chemotherapy. Implications for surgical adjuvant treatment of cancer. Cancer 1983;51:12091220 Keywords: prognosis, Early diagnosis, Effusion cytology PP01.06: LOW MERLIN EXPRESSION AND HIGH SURVIVIN STAINING INDEX ARE INDICATORS FOR POOR PROGNOSIS OF MALIGNANT MESOTHELIOMA PATIENTS Mayura Meerang1, Karima Bérard1, Martina Friess1, Byron K.Y. Bitanihirwe1, Alex Soltermann2, Bart Vrugt2, Emanuela Felley-Bosco3 , Raphael Bueno4 , William Richards5, Burkhardt Seifert6 , Rolf Stahel7, Walter Weder1, Isabelle Opitz1 Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 2Institute of Surgical Pathology, University Hospital Zurich, Zurich, SWITZERLAND, 3Department of Molecular Oncology, University Hospital Zurich, Zurich, SWITZERLAND, 4Brigham and Women’s Hospital, Boston, MA, UNITED STATES OF AMERICA, 5Brigham and Womens Hospital, Boston, MA, UNITED STATES OF AMERICA, 6Department of Biostatistics, Epidemiology, Biostatistics, And Prevention Institute (ebpi), University of Zurich, Zurich, SWITZERLAND, 7Clinic For Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 Objectives: Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein-1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Results: Kaplan-Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre-induction CTX tissues of cohort 1 with shorter PFS and OS (figure 1A, 1B). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post-CTX tissues (available from cohort 1 only) was associated with short PFS (p=0.04) and OS (p=0.05). High nuclear Survivin labeling indices in both preand post-CTX tissues of cohort 1 was associated with shorter PFS (figure 1C, 1D). In cohort 2, this was associated with both PFS and OS (p=0.046 and p=0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for short PFS of cohort 1 [HR (95% CI): 0.5 (0.3-0.9); p=0.001] and OS [HR (95% CI): 0.5 (0.3-1); p=0.04]. High Survivin labeling index was an independent prognostic factor for short PFS in patients from cohort 1 [HR (95% CI): 3.4 (1.7-6.8); p=0.006] and short OS in patients from cohort 2 [HR (95% CI): 2.35 (1.27-4.33); p=0.006]. (See next page.) Methods: Tissue microarrays comprised of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in both nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre- and post-CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/ or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H-score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and progression free survival (PFS). iMig2016.ORG 76 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Conclusion: Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. Keywords: Survivin, NF2, Merlin, Hippo pathway, Prognostic biomarkers iMig2016.ORG 77 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.07: MICRORNAS IN BLOOD AS BIOMARKER OF PLEURAL MALIGNANT MESOTHELIOMA Valentina Bollati1, Tommaso Cavalleri2, Chiara Favero1, Laura Dioni1, Carolina Mensi3 , Claudia Bareggi4 , Lorenzo Bordini3 , Alessandro Palleschi5, Aldo Todaro3 , Dario Consonni3 , Angela C. Pesatori1 Epiget, Department of Clinical Sciences And Community Health, Università degli Studi di Milano, Milan, ITALY, 2Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research, Rozzano, ITALY, 3Department of Preventive Medicine, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, ITALY, 4Unit Of Medical Oncology, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, ITALY, 5Thoracic Surgery Unit, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, ITALY 1 Objectives: Malignant Pleural Mesothelioma (MPM) is an aggressive cancer refractory to current therapies caused almost exclusively by asbestos. New specific diagnostic markers for early MPM diagnosis are needed. MiRNAs are single stranded noncoding that post-transcriptionally regulate gene expression by triggering mRNA cleavage or repressing translation. Changes in the expression of miRNAs have been implicated in several diseases and cancers, including MPM. miRNAs are stable molecules that can be easily investigated in different specimens (e.g. blood), and used as a disease biomarker. Our aim was to determine if a specific miRNA signature in plasma may help to discriminate between malignant pleural mesothelioma patients (MPM) and healthy subjects with a Past Asbestos Exposure (PAE). Methods: We investigated a group of 23 MPM patients and 19 healthy subjects with Past Asbestos Exposure (PAE). In this study population we screened 754 miRNAs in blood by TaqMan™ OpenArray® Human MiRNA Panel. Than we selected for validation, in the same groups of subjects, the top-23 differential miRNAs. RNU48 was used as endogenous control. We used multiple linear and logistic regression models adjusted for age, sex, BMI, and smoking habits to compare miRNAs profiling between MPM and PAE subjects. Results: After miRNA screening, we identified 29 differential miRNAs in plasma. Among the top 23 differential miRNAs, 19 were validated by Real time PCR and were able to discriminate between MPM and PEA subjects. In receiver operating characteristic (ROC) curve analysis, the three best miRNAs were miR-103 (area under curve, AUC=0.82), miR-98 (AUC=0.82) and miR-744 (AUC=0.81). Conclusion: The identified signature was useful for MPM diagnosis. Further studies are needed to verify if they can be of help for early MPM diagnosis and/or to detect high risk groups. Keywords: microRNA, epigenetics, mesothelioma diagnosis, Asbestos exposure PP01.08: SEPTIN-7, LIPOMA PREFERRED PARTNER AND TRANSALDOLASE DISCRIMINATE NEOPLASTIC FROM PRENEOPLASTIC MESOTHELIAL CELLS Daniel L. Pouliquen1, Alice Boissard2, Béatrice NawrockiRaby3 , Joëlle Nader1, Philippe Birembaut3 , Marc Grégoire1, Olivier Coqueret2, Catherine Guette2 UMR 892 INSERM / 6299 CNRS, Nantes, FRANCE, 2UMR 892 INSERM / 6299 CNRS, Angers, FRANCE, 3UMRS-903 INSERM, Reims, FRANCE 1 Objectives: Quantitative proteomic analyses, which allow to distinguish invasive and less aggressive stages of some cancers, has helped to identify new diagnostic or pronostic biomarkers. To date, applied to mesothelioma, this approach has poorly been investigated. In this study we used a biocollection of preneoplastic and neoplastic mesothelial cell lines established from F344 rats induced with crocidolite to determine proteomic signatures specific of each stage. Methods: The cell lines used in this study belong to a biocollection established in 2011 from a group of F344 rats, after 136 to 415 days of induction with crocidolite administered intraperitoneally. Nine cell lines, including 4 neoplastic cell lines (which produce tumors after orthotopic injection to syngeneic rats), and 5 preneoplastic cell lines (not producing tumors) representing different stages of the epithelial-to-mesenchymal transition (EMT) according to previous transcriptomic analysis of their expression profile, were selected for the study. Proteomic analyses were conducted using a LC-MS/MS approach with iTRAQ labeling on 4 x 106 cells of each cell line, in comparison with a reference cell line from the biocollection showing a typical epithelioid cobblestone morphology comparable to normal mesothelial cells and presenting the highest expression of Cdh1 and the lowest expression of the Acta2 and Tgfb1 genes. The in vitro invasive properties of the four neoplastic cell lines were also assessed using a modified Boyden chamber assay, in comparison with preneoplastic cells. Results: Among the 950 detected, 57 proteins of interest were identified, characterized by a significant increase or decrease relative to the reference cell line. Three of the 4 neoplastic cell lines, characterized by their invasive properties both in vitro in the Boyden chamber assay, and in vivo after transplantation to syngeneic rats, showed significant higher levels of transaldolase (taldo1). Conversely, all preneoplastic cell lines and the fourth, non-invasive, neoplastic cell line, M5-T2, were characterized by a significant higher level of septin-7 (sept-07) and lipoma-preferred partner homolog (Lpp). The peculiar case of M5-T2 was also associated with the highest level of Lpp. Finally, among the three invasive neoplastic cell lines, the maximum decrease in the content of Lpp and sept-07, and the highest level of taldo 1, was observed for the M5-T1 cell line, which showed the highest capacity of migration in the Boyden chamber and the highest metastatic potential in vivo. Conclusion: These preliminary results obtained on 9 cell lines open up interesting prospects for complementary studies on the whole biocollection, with the aim to characterize the proteomic signature of the different stages of mesothelial carcinogenesis. iMig2016.ORG 78 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Keywords: Preneoplastic, Neoplastic, Quantitative proteomic analyses, Cell lines PP01.10: PROGNOSTIC SIGNIFICANCE OF MITOTIC ARREST DEFICIENT 2-LIKE PROTEIN 1 IN MALIGNANT MESOTHELIOMA Aaron S. Mansfield1, Tobias Peikert2, Justin Moser3 , Anja Roden4 PP01.09: COL3A1, A NEW POTENTIAL IMMUNOHISTOLOGICAL MARKER FOR THE DIAGNOSIS OF MALIGNANT PLEURAL MESOTHELIOMA Charly Liddell1, Fabien Gueugnon2, Jean-Michel Nguyen2, Christine Sagan1, Laurent Cellerin3 , Marc Grégoire2, Christophe Blanquart 2 Pathology, CHU de Nantes, Nantes, FRANCE, 2INSERM UMR 892 / CNRS 6299, Nantes, FRANCE, 3Pneumology, CHU de Nantes, Nantes, FRANCE 1 Objectives: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The diagnosis is performed by immunohistology. However, in some cases the differential diagnosis of MPM from lung adenocarcinoma (ADCA) remains difficult. Using a transcriptomic approach, we identified Col3A1 as a new potential biomarker for MPM. The aim of this study was to validate Col3A1 for the differential diagnosis of MPM from lung ADCA by immunohistology Methods: We first studied the higher mRNA expression of Col3A1 in MPM compared with lung ADCA using our biocollection of cell lines established from pleural fluids of patients. We performed immunofluorescence experiments to confirm the mRNA results. Then, Col3A1 labeling was performed on 14 MPM and 15 lung ADCA tumor slides to evaluate the diagnostic value of this biomarker. Results: Col3A1 mRNA expression was demonstrated to be specific for cells of mesothelial origin. We showed that the mRNA expression of Col3A1 is as effective as that of WT1 (error rate (ER): 0.0526) and better than calretinin (ER: 0.263), podoplanin (ER: 0.2105) and keratin 5 (ER: 0.3157) in differentiating MPM cells from lung ADCA cells. The diagnostic potential of Col3A1 to differentiate MPM from lung ADCA was confirmed by immunohistology, with a specificity of 92.85% and a sensitivity of 93.30% for the percentage of stained cells. Conclusion: This study validates Col3A1 as a new potential MPM biomarker for immunohistology. Thus, this biomarker could be included in the panel of biomarkers currently used for MPM diagnosis after independent validation. Keywords: diagnosis, mesothelioma, biomarker, immunohistology Medical Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA, 2Pulmonary And Critical Care Medicine, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA, 3Internal Medicine, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA, 4Laboratory Medicine And Pathology, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA 1 Objectives: Mitotic Arrest Deficient 2-Like Protein 1 (MAD2L1) is a critical component of the spindle assembly checkpoint, which delays mitosis until all kinetochores are attached to a mitotic spindle ensuring appropriate segregation of sister chromatids. Overexpression of MAD2L1 results in stabilization of Securin and Cyclin B, delays exit from mitosis and promotes aneuploidy through nondisjunction events. MAD2L1 mutations are rare, but overexpression of MAD2L1 is common in human malignancies. Recently, MAD2L1 expression has been identified as a potential therapeutic target in malignant mesothelioma (MM) and a prognostic marker in early stage lung cancer. We sought to characterize the expression of MAD2L1 in MM and to determine its prognostic significance. Methods: We developed a tissue microarray (TMA) with 160 cases of MM with 0.6mm cores in triplicate. Immunostaining was performed at Mayo Clinic’s Pathology Research Core using the Leica Bond RX stainer. The MAD2L1 antibody (Bethyl Laboratories IHC-00412 rabbit, polyclonal) was diluted 1:75 in Background Reducing Diluent (Dako) for 30 minutes. The detection system used for MAD2L1 was the Envision Flex System (Dako). Percent expression was scored as 0 (none), 1 (1-25% tumor cell expression), 2 (26-50%), 3 (51-75%) or 4 (76-100%); the intensity was scored as 0 (negative), 1 (weak), 2 (moderate) or 3 (strong). The average H-score (percent expression score multiplied by intensity score) for the three cores was determined for each case. Survival was estimated with Kaplan-Meier curves by quartiles and compared with a log-rank test. All but 25 subjects were followed until death. Results: 109 males (68%) and 51 females (32%) had a median age of 66 years (interquartile range, 58-73). The cases were epithelioid (n=99, 62%), biphasic (n=26, 16%), sarcomatoid (n=25, 16%) or not further specified (n=10, 6%). A broad range of MAD2L1 expression was noted (median H-score=8, interquartile range 5-9, range 0-12). Kaplan-Meier estimates demonstrated similar survival of cases with the three highest quartiles of MAD2L1 expression. Therefore, these cases were grouped together and their survival was compared to that of cases in the lower quartile. The survival of patients with the lowest quartile of MAD2L1 expression (n=39, median=13 months, mean=37 months) was significantly greater than that of patients with the three highest quartiles of MAD2L1 expression (n=121, median=10 months, mean=17 months; p=0.05); with most of the difference seen in the tails of the curves (Figure 1). Conclusion: Increased MAD2L1 expression is a negative prognostic marker in MM. The therapeutic modulation of MAD2L1 is being explored. iMig2016.ORG 79 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP significantly higher in the BPD group than in MPD or MPM patients (p<0.0001). At the opposite, pleural BDNF were significantly higher in MPM patients vs. MPD patients or BPD patients (p=0.0002). Conclusion: Plasma fibulin-3 and BDNF seemed of little interest for MPM diagnosis, showing some discrepancies with previous published results for fibulin-3. Pleural fibulin-3 level might have a prognostic value in pleural diseases. Increased levels of BDNF in pleural effusions are associated with malignancy and more particularly with MPM for highest BDNF levels. Keywords: biomarker, BDNF, fibulin-3, mesothelioma Keywords: prognosis, mesothelioma, mad2l1 PP01.12: TARGET TRIAL Duneesha De Fonseka1, Louise Allen1, Nick Maskell2 PP01.11: BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND FIBULIN-3 AS BIOMARKERS FOR DIAGNOSIS OF MALIGNANT PLEURAL MESOTHELIOMA (MPM) Sarah Benziane1, Patrick Smeele2, Sophie Deshayes3 , Anne-Laure Chéné4 , Camille Munck1, Marie C. Willemin1, Eric Wasielewski1, Arnaud Scherpereel1, Marc Grégoire2, Christophe Blanquart2 Pulmonary and Thoracic Oncology Department, Hospital of the University (CHU) of Lille, Lille cedex, FRANCE, 2Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm U892, Nantes cedex, FRANCE, 3Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm U892, Nantes cedex , FRANCE, 4Digestive and Thoracic Oncology Department, Laënnec Hospital, CHU of Nantes, Nantes, FRANCE 1 Objectives: MPM is a rare tumor with poor prognosis, usually associated with previous asbestos exposure. Its diagnosis, usually based on histology, obtained by invasive procedures, may be tricky. To date, no diagnostic biomarker was validated in routine. In this study, we aimed at evaluating two potential biomarkers, BDNF and fibulin-3. Methods: observational, retrospective study in 2 French centers. Plasma and pleural effusion samples were collected from 3 different groups : patients with « benign pleural diseases » (BPD), patients with malignant pleural diseases excluding MPM (MPD), or MPM patients. Biomarker levels were determined using ELISA assays (Human BDNF DuoSet (R&D Systems) and FBLN3 (USCN)). Results: 310 patients (76 BPD, 108 MPD, 126 MPM) were recruited. Plasma fibulin-3 levels were significantly higher in the BPD group than in MPD or MPM patients (p<0.0001), and in MPM vs. MPD patients (p=0.0056). There was no difference between the 3 groups for pleural fibulin-3 levels. However, patients with highest pleural fibulin-3 levels at the time of diagnostic tend to have a shorter survival (p=0.06), suggesting a possible prognostic value. Plasma BDNF levels were also Academic Respiratory Unit, North Bristol NHS Trust, Bristol, UNITED KINGDOM, 2Academic Respiratory Unit, University of Bristol, Bristol, UNITED KINGDOM 1 Objectives: TARGET trial is a randomised controlled trial designed to compare the diagnostic yield of PET-CT guided pleural biopsy versus CT-guided pleural biopsy in suspected pleural malignancy, where patients have already had one non-diagnostic biopsy. Diagnosis of pleural malignancy, particualrly mesothelioma can be challenging in the absence of pleural fluid to perform a thoracoscopy for direct visualisation and biopsy of the pleura. Computed Tomography (CT) or Ultrasound (US) guided biopsy of the pleura are two of the commonest techniques used in this situation but the diagnostic rate is low. Diagnostic imaging in pleural malignancy remains a significant challenge. PET-CT scanning has proven itself a useful tool in diagnosing and staging lung cancer. It identifies areas of high metabolic activity, which is a feature of malignant disease, by highlighting areas of uptake of the radio labelled glucose analogue Fluorodeoxyglucose (FDG). We hypothesise that targeting the CT guided biopsy to these highlighted areas on PET-CT may increase the diagnostic yield of pleural biopsies. Methods: This multi-centre randomised controlled study conducted in the UK will recruit patients from 10 respiratory departments over a 24 month period or until 78 patients have been recruited. Patients will be randomised either to receive a PET targeted biopsy or a standard CT guided biopsy using an online randomisation tool. The experimental group will undergo a PET scan which will be reviewed by a local radiologist to identify the most suitable area for biopsy, then a CT guided biopsy targeted to the afore highlighted area. The standard CT group will have a repeat CT and a biopsy from a site identified as per the local radiologist. Standard Operating Procedures (SOP) will be in place to minimise variation. All patients will be followed-up for a 12 month period from randomisation. The study is NIHR (Research for Patient Benefit) funded. Results: The trial opened to recrutiment in September at North Bristol NHS Trust and is currently in the set-up phase of 5 other UK trusts. Results of this study will be due to in 2019. iMig2016.ORG 80 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Conclusion: If this superiority study is proven successful, it would shorten the patient’s cancer journey and reduce the number of invasive investigations they undergo. An early diagnosis may allow more patients to have life prolonging chemotherapy that they may not be able to have at a later stage in disease if they are too unwell. Mesothelioma patients have a very poor survival and often some of this time may be spent in hospital. An early diagnosis would allow patients more time to enjoy the financial benefits of the compensations they receive following a diagnosis of mesothelioma. Keywords: pleural mesothelioma, PET-CT scan, CT guided biopsy Fig. Effects of Carboplatin (C), Pemetrexed (P) on a primary isolate of malignant mesothelioma. In this case both drugs cause arrest in early S-phase when compared to the untreated control. This effect is masked when the two drugs are combined, instead resulting in a broader G0/1 peak. PP01.13: EX VIVO EFFECTS OF PEMETREXED AND CARBOPLATIN ON MALIGNANT MESOTHELIOMA CELLS Carl-Olof Hillerdal1, Rita Ötvöss1, Tände Szatmari1, Katalin Dobra1, Anders Hjerpe2 Dept Of Laboratory Medicine / Pathology, Karolinska Institutet, Huddinge, SWEDEN, 2Dept Of Laboratory Medicine / Pathology, Karolinska University Hospital, Huddinge, SWEDEN 1 Objectives: The combination pemetrexed and carboplatin is the standard treatment for malignant mesothelioma worldwide. Malignant mesotheliomas have an objective response rate of 40% to this combination. The ex vivo analysis of the sensitivity to these drugs could be helpful in predicting the effects of individual tumours, and thereby provide a basis for future personalized choice of therapy. However, when testing mesothelioma cell lines, 48 hours’ drug exposure to pemetrexed had no effect when evaluating with a live/dead assay based on remaining mitochondrial activity, while the S-phase resulting arrest could be traced by cell cycle analysis. Methods: Tumor cells were isolated from pleural effusions obtained from patients with malignant mesothelioma and grown as short-term cultures in IMDM medium, supplemented with 20% FCS. These cultures were then incubated for 48 or 72 hours, with pemetrexed, carboplatin and their combinations added to the culture medium. The effects of these exposures were analysed with a cell cycle assay based on flow cytometry. For comparison the development of apoptosis was monitored with a flow cytometer annexinV/PI assay and cell survival with a mitochondrial activity assay. Results: Exposure of mesothelioma cell isolates to pemetrexed during 48 hours regularly caused an increased proportion of cells in early s-phase. A similar effect could in some isolates also be obtained after incubation with carboplatin alone. While in some cases carboplatin caused an increased proportion of apoptotic cells and a corresponding decrease in cell survival, no such effect could be seen after incubation with pemetrexed, even when the exposure time was prolonged to 72 hours. Interestingly, when the two dugs were combined, the effects were masked, probably due to confluence of G0/1 and S-phase peaks. Conclusion: All cytotoxic drugs have a unique modus operandi. At difference with many other cytotoxic drugs the relatively short 48 hours’ incubation in medium containing pemetrexed will not result in apoptosis and decreased cell survival. The estimation of sensitivity to this drug ex vivo is best performed as a cell cycle analysis, without simultaneous exposure to carboplatin. We now correlate this effect on S-phase progression with the actual responses to given therapy. Keywords: chemotherapy, Ex vivo analysis, prediction, mesothelioma PP01.14: DIAGNOSING MESOTHELIOMA VIA CHEST WALL MOTION ANALYSIS TECHNOLOGY Ghazi Elshafie1, Prem Kumar2, Andrea Aliverti3 , Madava Djearaman1, Babu Naidu1 Heartlands Hospital, Birmingham, UNITED KINGDOM, 2University of Birmingham, Birmingham, UNITED KINGDOM, 3Politecnico di Milano, Milano, ITALY 1 Objectives: Mesothelioma carries a poor prognosis. . Differentiating benign from malignant pleural disease can be challenging, and may require invasive surgery. We aim to evaluate the effects of benign and malignant pleural disease on chest wall motion using OEP, this may constitute a useful tool in the diagnostic pathway. Methods: Optoelectronic plethysmography (OEP) was used to measure chest wall motion of 16 patients recruited to this study. The measurements were performed before any pathological diagnosis. Pathological diagnosis was obtained via surgical pleural biopsy. After the pathological diagnosis, they were divided into 3 groups. A pleural disease-free (n=4), an empyema group (n= 6) and a mesothelioma group (n=4). A radiological assessment was performed in all patients. Results: The relative contribution of the diseased part of the pulmonary ribcage motion to the overall pulmonary ribcage motion was significantly lower in the mesothelioma group, 19 iMig2016.ORG 81 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP +/- 17 % compared the control and empyema group 50 +/- 3 % and 44 +/- 7 % (p 0.01 and p 0.01) respectively (figure 1). The radiological diagnosis matched the pathological diagnosis in only 30% of all patients. When the diseased side of the chest contributed ≤ 36% of the overall chest wall motion all patients had a pathological diagnosis of mesothelioma. Conclusion: This is the first data to describe the effect of empyema and malignant mesothelioma on chest wall mechanics, and proved that OEP, is more predictive than conventional radiology, and could be used in clinical practice to diagnose those diseases. analyzed by C4d immunohistochemistry. We compared the correlation of C4d levels with the clinicopathological characteristics of the MPM patients. Results: We found no evidence of C4d labeling on tumor cells in the MPM tissue specimens. However, germinal centers of lymphoid structures within the tumor stroma showed C4d positivity. Circulating levels of C4d were not significantly increased in MPM patients when compared to healthy controls or patients with non-malignant pleural diseases. Importantly, after dividing the patient cohort by using the cutoff of 1.5µg/mL, patients with low C4d levels at diagnosis showed a very strong tendency towards longer overall survival. C4d levels following induction chemotherapy were remarkably higher in patients with stable disease or progressive disease (SD/PD) when compared to patients with minor or major positive chemotherapeutic response (MR) (SD/PD: 1.94±0.34 µg/mL, MR: 0.70±0.51 µg/mL; p=0.026). Interestingly, several inflammation-related prognostic markers including fibrinogen, CRP and albumin showed no significant correlation with chemotherapeutic response. Conclusion: Circulating plasma level of C4d is a potential new prognostic biomarker in MPM patients. Since prediction of response after induction chemotherapy in MPM patients is a challenging task, our data suggest that measuring circulating C4d levels may help to risk-stratify patients following induction chemotherapy. Keywords: complement activation, response evaluation, prognostic biomarker Keywords: Chest Wall, mesothelioma, Optoelectronic plethysmography PP01.15: CIRCULATING LEVEL OF THE COMPLEMENT COMPONENT 4D (C4D) CORRELATES WITH CHEMOTHERAPEUTIC RESPONSE AND SURVIVAL IN MPM PATIENTS Thomas Klikovits1, Paul Stockhammer1, Julia Kodnar2, Viktoria Laszlo1, Yawen Dong1, Mir A. Hoda1, Walter Klepetko1, Balazs Dome1, Rudolf Oehler2, Balazs Hegedus1 PP01.16: VOC ANALYSIS IN HEADSPACE AIR OF MESOTHELIOMA AND LUNG CANCER CELL LINES: A COMPARATIVE LITERATURE STUDY Sabrina Lagniau1, Kevin Lamote2, Karim Y. Vermaelen2, Jan P. Van Meerbeeck3 Internal Medicine, Ghent University, Ghent, BELGIUM, 2Respiratory Medicine, Ghent University Hospital, Ghent, BELGIUM, 3Thoracic Oncology, Antwerp University Hospital, Edegem, BELGIUM 1 Objectives: Circulating levels of the degradation product of C4 (C4d) were found to be prognostic in lung adenocarcinoma patients. Since there is limited information available about the role of complement activation in the progression of MPM we analyzed the circulating and tissue levels of C4d in a cohort of MPM patients. Objectives: Early detection of malignant pleural mesothelioma (MPM) and lung cancer is important in order to improve the disease’s management. Research has focused on volatile organic compounds (VOCs) in breath to serve as early screening tools. Although several VOCs have been identified, it is not yet clear which VOCs arise from the neoplastic cells themselves or from the host response. The analysis of headspace air of mesothelioma and lung cancer cell lines can therefore be useful. The goal of this study was to perform a literature search in order to compare different methods for headspace analysis and to identify tumour-specific VOCs which could serve as interesting biomarkers. Methods: Plasma samples from MPM patients (n = 56) were measured by ELISA for C4d levels. Additionally, healthy volunteers (n = 19) and patients with non-malignant pleural diseases (n = 14) were also included. In order to investigate local C4d expression, FFPE tissue specimens from 38 MPM patients were Methods: MEDLINE (PubMed) and Web of Science were searched for studies concerning headspace analysis in lung cancer and mesothelioma cell lines until January 2016. The following keywords have been applied: “headspace analysis” AND “lung cancer”, “headspace analysis” AND “lung cancer” Division of Thoracic Surgery, Medical University of Vienna, Vienna, AUSTRIA, 2Anna Spiegel Center for Translational Research, Department of Surgery, Medical University of Vienna, Vienna, AUSTRIA 1 iMig2016.ORG 82 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP AND “cell line”, “headspace analysis” AND “mesothelioma” and “headspace analysis” AND “mesothelioma” AND “cell line”. After removal of duplicates and manual selection of relevant articles, 9 articles remained and are compared in Table 1. Results: Table I: Summary. Conclusion: A plethora of VOCs is released or consumed by cancerous cell lines, which makes these interesting to use as biological markers in the diagnosis of lung cancer or mesothelioma. Nevertheless, no single VOC can presently be used as stand-alone biomarker. Furthermore, the studies are not comparable due to the use of different cell lines. This literature study shows that in the headspace air of cancerous cell lines the concentration of certain aldehydes (acetaldehyde), ketones (2-butanone, cyclohexanon) and alkanes is significantly decreased or increased in comparison with the headspace of non-cancerous cell lines or the headspace of medium. The most frequently used method in the studied articles is GC-MS. Because of the small number of studies and large interstudy differences, further translational research is necessary in order to determine which VOCs are tumour-specific, to optimize the sampling techniques and to gain information about real tumour-specific VOCs. It will also give information about the tumour’s metabolism. Finally, this literature study shows that analysis of VOCs in the headspace of cancer cell lines is promising and can be further explored for the development of biomarkers for early disease detection. Keywords: headspace analysis, Lung cancer, volatile organic compounds, mesothelioma iMig2016.ORG 83 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.17: PROGNOSTIC BIOMARKERS IN A LARGE COHORT OF PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA - A RETROSPECTIVE TWO-CENTER STUDY PP01.18: CHANGES IN MONOCYTE COUNT AND LYMPHOCYTE-TO-MONOCYTE RATIO DURING INDUCTION CHEMOTHERAPY CORRELATE WITH CLINICAL OUTCOME Thomas Klikovits1, Pietro Bertoglio2, Marcello C. Ambrogi2, Paul Stockhammer1, Yawen Dong1, Balazs Dome1, Balazs Hegedus1, Viktoria Laszlo1, Walter Klepetko1, Alfredo Mussi2, Mir A. Hoda1 Paul Stockhammer, Yawen Dong, Thomas Klikovits, Walter Klepetko, Balazs Dome, Balazs Hegedus, Mir A. Hoda Division of Thoracic Surgery, Medical University of Vienna, Vienna, AUSTRIA, 2Division of Thoracic Surgery, University Hospital of Pisa, Pisa, ITALY 1 Objectives: The aim of this study was to identify and validate prognostic biomarkers in a large cohort of patients with malignant pleural mesothelioma (MPM). Methods: We performed a retrospective chart review and included all patients with histologically confirmed MPM, treated at two specialized centers between 1994 and 2014. The effect of different clinical and pathological characteristics and laboratory values on patient outcome was investigated. Results: Two-hundred ninety-one patients were identified (222 males and 69 females). Mean age at diagnosis was 64 years (range 27-91 years). Main histological subtype was epitheloid (n=199, 68%). Multimodality treatment, defined as macroscopic complete resection combined with chemotherapy and/or radiation therapy and/or intracavitary treatment, was performed in 134 (46%) patients. Median overall survival in the whole cohort was 17.7 months from diagnosis; 1-, 3- and 5-year survival rates were 65%, 28% and 19%, respectively. When using univariate analyses, following variables were associated with a poor prognosis: advanced age (≥70 years, p=0.001), non-epithelial histological subtype (p =0.003), fibrinogen at diagnosis (HR 1.002, p=0.001), albumin at diagnosis (HR 0.963, p=0.001), haemoglobin at diagnosis (HR 0.874, p=0.001), platelets at diagnosis (HR 1.003, p=0.001), leucocytes at diagnosis (HR 1.116, p=0.001), neutrophils to lymphocytes ratio (NLR) at diagnosis (HR 1.063, p=0.006) and platelets to lymphocyte ratio (PLR) at diagnosis (HR 1.001, p=0.001). In the multivariate cox regression analysis, leucocyte count, fibrinogen, histological subtype and age remained as significant co-factors. Conclusion: Leucocyte count and fibrinogen at diagnosis were independently prognostic in a large cohort of MPM patients. These findings suggest that these inflammatory based prognostic markers can be utilized for improved patient selection with regard to different therapeutic modalities. Keywords: Biomarkers, prognostic value, therapeutic decision Division of Thoracic Surgery, Medical University of Vienna, Vienna, AUSTRIA Objectives: Lymphocyte-to-monocyte ratio (LMR) and monocyte count have previously been found to be prognostic in MPM patients. In order to validate these findings and to investigate the clinical significance of monocyte and lymphocyte count changes associated with induction chemotherapy, we followed the changes in the leukocyte subpopulations during chemotherapy in a cohort of MPM patients. Methods: Pre- and postchemotherapeutic levels of leukocytes, lymphocytes and monocytes were collected retrospectively from 113 patients with histologically confirmed MPM. 76 of these patients had a positive response after chemotherapy, 37 patients had a radiologically confirmed disease progression. We compared the data with the clinicopathological characteristics of the MPM patients. Results: We could confirm the prognostic relevance of LMR (LMR ≥2.74: median 50.8 months versus 17.9 months; p = 0.035) and absolute monocyte count at time of diagnosis (≥510 cells/µL: median 17.9 months versus 35.6 months; p = 0.013) in our MPM patient cohort (n = 113) using cut-offs established in the previous studies. In terms of chemotherapy, total leukocyte count showed a significant decrease after chemotherapy regardless to the response to treatment (Leukocyte count - 95% CI: -0.50 to -1.92 ×109/L; p = 0.001). Relative lymphocyte count as well as relative monocyte count showed a strong tendency for increasing after chemotherapy (Relative lymphocyte count - 95% CI: +0.0% to +5.5%; p = 0.05; relative monocyte count - 95% CI: 0.2% to 1.8%; p = 0.01). LMR and absolute monocyte count did not change after chemotherapy. When comparing patients with progressive disease and patients with positive response to chemotherapy, we found that in each group there was a strong tendency for a leukocyte count decrease after induction treatment. Relative lymphocyte count as well as absolute monocyte count did not correlate with chemotherapeutic outcome. However, patients with a positive response after chemotherapy had a significantly reduced LMR (95% CI: -0.17 to -1.11 ×109/L; p <0.01), whereas patients with progressive disease had an elevated LMR (95% CI: -0.17 to +2.28 ×109/L; p = 0.09). Furthermore, patients with a positive response had a highly significant increase in the relative monocyte count (95% CI: +1.2% to +2.9%; p <0.0001) whereas patients with disease progression showed a tendency for a decrease in their relative monocyte counts (95% CI: +0.4% to -2.5%; p = 0.15). Conclusion: LMR and circulating monocyte count are prognosticators in MPM patients. Furthermore, positive response to chemotherapy is associated with a significant increase in the relative monocyte count as well as with a LMR decrease. Monitoring monocyte count and LMR during chemotherapy may provide a tool to identify patients with a positive response. Keywords: induction chemotherapy, Monocyte count, Lymphocyte-to monocyte ratio, White blood cells iMig2016.ORG 84 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.19: COMBINING CELL-FREE MICRORNAS AND SMRP: A MULTI-BIOMARKER SIGNATURE WITH IMPROVED DIAGNOSTIC ACCURACY Michaela B. Kirschner1, Marissa Williams2, Sjaak Burgers3 , Mir A. Hoda4 , Catharina M. Korse3 , Daan Van Den Broek5, Thomas Klikovits4 , Balazs Hegedus4 , Balazs Dome4 , Michael Grusch4 , Walter Weder1, Isabelle Opitz1, Walter Klepetko4 , Nico Van Zandwijk2, Glen Reid6 Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 2Asbestos Diseases Research Institute, Sydney, AUSTRALIA, 3Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 4Medical University of Vienna, Vienna, AUSTRIA, 5Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 6Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA Conclusion: Data from two independent validation series confirms the previously observed diagnostic potential of increased miR-625-3p in blood from MPM patients. However, higher miR625-3p levels observed in NSCLC patients show that elevation of the level of this microRNA in plasma/serum is not restricted to MPM. The combination of cell-free microRNAs with SMRP showed an improved diagnostic accuracy highlighting the need for further investigation of multi-biomarker signatures. Keywords: cell-free microRNAs, SMRP, diagnosis 1 Objectives: Definitive diagnosis of malignant pleural mesothelioma (MPM) is difficult and in most cases requires a tissue biopsy of sufficient size. As a biopsy is not always feasible, the identification of an accurate biomarker easily measured in blood would represent an important step forward. The aim of this study was to investigate the diagnostic accuracy of combinations of soluble mesothelin-related protein (SMRP) and cell-free microRNAs. Methods: The study used two independent series of serum/ plasma samples: series 1 consisted of serum samples from 73 MPM patients, 69 healthy volunteers and 64 non-small cell lung cancer (NSCLC) patients collected at the Netherlands Cancer Institute between 1994 and 2013, and series 2 consisted of plasma samples from 36 MPM patients and 33 healthy volunteers collected at the Medical University of Vienna and the National Koranyi Institute of Pulmonology Budapest between 2011 and 2013. Cell-free miR-625-3p, and miR-126, previously shown to have diagnostic potential were measured by RT-qPCR. Additionally levels of soluble mesothelin-related protein (SMRP) were assessed (ELISA) in the samples of series 1. Results: Confirming previously published data, serum/plasma miR-625-3p was found to be able to discriminate between MPM and healthy controls with area under the ROC curve (AUCs) of 0.82 (95% CI: 0.75-0.89) in series 1 and 0.74 (95% CI: 0.630.86) in series 2. In addition, series 1 showed an AUC of 0.75 (95% CI: 0.67-0.84) for distinguishing NSCLC from healthy controls and an AUC of 0.46 (95% CI: 0.47-0.66) for discriminating MPM and NSCLC. For miR-126 AUCs in series 1 were at best 0.56 (95% CI: 0.47-0.66) for MPM vs healthy, while the same comparison in series 2 resulted in an AUC of 0.76 (95% CI: 0.64-.088). Assessment of SMRP in series 1 revealed AUCs of 0.69 (95% CI: 0.59-0.78) differentiating MPM from healthy individuals and 0.65 (95% CI: 0.54-0.75) separating MPM from NSCLC, and an AUC of 0.64 (95% CI: 0.55-0.72) for the comparison MPM vs all non-MPM. Aiming to improve the diagnostic accuracy, we evaluated the performance of combinations of two or three of the tested biomarkers in series 1. This analysis revealed the best performing combination for any comparison to be miR-625-3p + SMRP which achieved AUCs of 0.87 (95% CI: 0.81-0.92, MPM vs healthy), 0.63 (0.54-0.72, MPM vs NSCLC) and 0.76 (0.69-0.82, MPM vs all non-MPM), respectively. Adding miR-126 to this combination did not improve diagnostic accuracy. PP01.20: TUMOR-INFILTRATING LYMPHOCYTES AND BAP-1, VEGFR-2, IGF-1R EXPRESSION IN MALIGNANT PLEURAL MESOTHELIOMA Luca Ampollini1, Letizia Gnetti2, Matteo Goldoni3 , Nicoletta Campanini2, Luigi Ventura1, Michela Solinas1, Cesare Braggio1, Luigi Rolli1, Marcello Tiseo4 , Michele Rusca1, Paolo Carbognani1, Antonio Mutti3 , Enrico Maria Silini2 Department of Surgical Sciences, Thoracic Surgery, University Hospital of Parma, Parma, ITALY, 2Pathological Anatomy and Histology, University Hospital of Parma, Parma, ITALY, 3Department of Clinical and Experimental Medicine, University Hospital of Parma, Parma, ITALY, 4Medical Oncology, University Hospital of Parma, Parma, ITALY 1 Objectives: Malignant pleural mesothelioma (MPM) is a rare disease strongly related to asbestos exposure. MPM is frequently associated with a prominent inflammatory reaction. In this study, we investigated whether there was any relationship between survival and the presence of tumor infiltrating lymphocytes (TILs). The expression of BAP-1 (BRCA1-Associated Protein 1), VEGFR-2 (vascular endothelial growth factor receptor 2) and IGF-1R (Insulin-Like Growth Factor 1 Receptor) in tissue samples was also assessed. Methods: Forty-four cases of MPM were identified. All the biopsies used were obtained at the time of diagnosis. There were 24 males; mean age was 69 years. Twenty-six patients were smokers and 26 had a certain history of asbestos exposure. All histological slides were revised for the study; there were 28 epithelioid subtypes, 8 biphasic subtypes and 8 sarcomatoid subtypes. The presence of TILs was scored as absent, weak, moderate and strong according to a quantitative assessment on hematoxylin and eosin slides. The expression of BAP-1, VEGFR-2 and IGF-1R was analyzed by immunohistochemistry. The impact of asbestos exposure, tobacco consumption and histological subtypes on survival were also assessed. The survival analysis was analyzed by Kaplan Meier curve. Results: TILs were present in 89% of cases (weak 18%, moderate 36%, strong 34%) and were found to be a favorable prognostic factor (p=0.05). Median survival in TILs and non-TILs patients was 21 months and 4 months, respectively (Figure 1). Epithelioid MPM was characterized by an increased expression of VEGFR-2, both in tumor cells (p=0.04) and TILs (p=0.05) and more frequent inactivation of BAP1 (75%, p=0.05) than biphasic and sarcomatoid subtypes. IGF-1R was overexpressed in 57% of the tumors (14 epitheliods and 11 sarcomatoids) and in 23% iMig2016.ORG 85 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP of TILs (7 epitheliods and 3 sarcomatoids). The expression of VEGFR-2, BAP1 and IGF-1R was not significantly related with survival. Tobacco (p=0.93) and asbestos (p=0.62) exposures were also not significantly correlated with survival. Histology had no effect on survival (p=0.23) although epithelioid MPM fared better than sarcomatoid and biphasic tumors with a median survival of six months. work better in low-stage disease. Screening of asbestos exposed individuals by non-invasive methods is a desired path to increase the rate of early detection and cure in the future. Methods: Serum samples from the HUNT3 biobank, Levanger, Norway were profiled with Magnetic Resonance Spectroscopy (MRS metabolomics) and microRNA sequencing (Illumina). The sample included mesothelioma cases collected 1-3 years before diagnosis, along with age and sex-matched non-cancer individuals; the never smokers to ever-smokers ratio was 1:2. The produced data were analyzed with ad hoc bioinformatics pipelines. Results: There were six cases of pleural mesothelioma with pre-diagnostic serum, three females and three males. Only one was a never smoker while there was only one current smoker. Among the controls there were seven never smokers, two current and three former smokers. All cases versus all controls showed two metabolites significantly different by MRS, that was overexpressed and down-regulated respectively (Fold change 1.33/0.62, False Discovery Rate adjusted p=0.01/0.001). MicroRNA sequencing showed four significantly expressed microRNAs in serum, two overexpressed and two downregulated (False Discovery Rate adjusted p‹0.05). However this signature could not separate the groups completely. A 10-microRNA signature did separate the two groups (Figure 1) Conclusion: The presence of TILs favorably affects survival of MPM. Epithelioid MPM is characterized by longer survival, higher BAP1 loss and increased VEGFR-2 expression. Histological markers may improve the prognostic assessment of MPM and provide mechanistic clues for new therapeutic strategies. Keywords: VEGFR-2 (vascular endothelial growth factor receptor 2), IGF-1R (Insulin-Like Growth Factor 1 Receptor), tumor infiltrating lymphocytes, BAP-1 (BRCA1-Associated Protein 1) Conclusion: In this relatively small pilot study we identified both metabolites and microRNAs that were significantly differentially expressed in serum of mesothelioma patients 1-3 years prior to diagnosis. Importantly, we found that a 10-microRNA signature could differentiate the mesothelioma and non-cancer group. These are preliminary results whose validation in a larger cohort is still pending. There is hope that significant biomarkers can soon be discovered for early detection of mesothelioma within the metabolomics and microRNA molecular spectre. PP01.21: SERUM BIOMARKERS IN MESOTHELIOMA 1-3 YEARS BEFORE DIAGNOSIS: A PILOT STUDY Robin Mjelle1, Maria Markaki2, Trygve Andreassen3 , Vincenzo Lagani2, Ioannis Tsamardinos2, Tone F. Bathen3 , Pål Sætrom4 , Kristian Hveem5, Oluf D. Røe1 Department of Cancer Research And Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NORWAY, 2Department of Computer Science, University of Crete, Heraklion, GREECE, 3Department of Circulation And Medical Imaging, Norwegian University of Science and Technology, Trondheim, NORWAY, 4Department For Computer And Information Science, Norwegian University of Science and Technology, Trondheim, NORWAY, 5Department of Public Health And General Practice, Norwegian University of Science and Technology, Trondheim, NORWAY 1 Keywords: biobank, prospective study, early detection, pre-diagnostic serum Objectives: Early detection of mesothelioma could increase survival and curation rate as low stage and low tumor burden are positive prognostic factors. Moreover, emerging treatments as immunotherapy and other biological treatments seem to iMig2016.ORG 86 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.22: ROLE OF EPHA2 IN MALIGNANT MESOTHELIOMA Yi-Hung Carol Tan1, Christopher Villaflor2, Brian M. Won1, Rajani Kanteti1, Kyle Szeto2, Qudsia Arif3 , Aliya Husain3 , Wickii T. Vigneswaran4 , Hedy Kindler1, Ravi Salgia5 Medicine, The University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 2University of Illinos at Urbana-Champaign, champaign, IL, UNITED STATES OF AMERICA, 3Department of Pathology, The University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 4Loyola University Health System, Maywood, IL, UNITED STATES OF AMERICA, 5City of Hope, Duarte, CA, UNITED STATES OF AMERICA 1 Objectives: Overexpression of the ephrin-A1 ligand receptor EPHA2 has been reported in many cancers and is associated with tumor growth and metastatic potential. The role of EPHA2 in malignant mesothelioma (MM) remains unknown. We therefore investigated the expression and biology of EPHA2 in MM to assess whether it could be an appropriate target for therapy. Methods: To study the expression of EPHA2 in MM, immunohistochemistry and immunoblotting were performed on MM patient samples and cell lines. Polymerase chain reaction (PCR) and real-time PCR were used for gene mutation and amplification analysis, respectively. Doxazosin, a small molecule agonist of the EphA2 receptor tyrosine kinase and cisplatin were used in cell proliferation assay to study cell viability and wound healing assay was used for cell migration analysis. Results: EPHA2 was over-expressed in 66.7% (4/6) of MM cell lines. EPHA2 mutations were found in 28% (11/39) of MM patients. EPHA2 gene amplification occurred in 10.3% (4/39) of MM patient samples and in 33% (2/6) of MM cell lines. We observed over-expression of EPHA2 in 64% (48/75) MM tumor tissues with IHC staining score greater than 2+. Cells with EPHA2 mutations had more cell proliferation and migration than EPHA2 wild-type or normal controls. EPHA2 mutated cells had greater resistance to cisplatin than EPHA2 wild-type cells and one specific EPHA2 mutation showed resistance to both doxazosin and cisplatin. Conclusion: EPHA2 overexpression or mutation increased cell proliferation and migration. EPHA2 mutation confers resistance cisplatin. EPHA2 is a potential biomarker in this disease and may be an appropriate target for MM therapy. Keywords: EPHA2, target, biomarker, mesothelioma PP01.23: ENOX2-BASED EARLY DETECTION OF MALIGNANT MESOTHELIOMA Jenette Creaney1, B Hosteler2, Dj Taggart2, Dm Morre2, Arthur W. Musk3 , Bruce Robinson1, Dj Morre2 School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, WA, AUSTRALIA, 2MorNuCo Inc, Purdue University Research Park, West Lafayette, IN, UNITED STATES OF AMERI1 CA, 3Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, WA, AUSTRALIA Objectives: ENOX2 (Ecto-Nicotinamide Adenine Dinucleotide Oxidase Disulfide-Thiol Exchanger 2) is a member of a family of cell surface proteins that oxidize reduced pyridine nucleotides [NAD(P)H] and are essential for cell enlargement and growth. Recently specific isoforms of this protein have been found in the serum of cancer patients before diagnosis. In this study we explored if ENOX2 could be detected in mesothelioma patients sera. Methods: Archived serum samples from individuals exposed to asbestos and who developed either benign disease or malignant mesothelioma as determined from the Wittenoom Cancer Surveillance Program were assayed for the presence of mesothelioma-specific ENOX2 transcript variants using the ONCOblot Tissue of Origin Cancer Detection Test, which employs 2-D gel immuno- blot analysis of ENOX2 transcript variants in serum. Results: Two mesothelioma-specific ENOX2 transcript variants were detected in the serum of asbestos-exposed individuals 4 to 10 years prior to clinical diagnosis of malignant mesothelioma (average 6.2 years). Either one or both ENOX2 transcript variants indicative of malignant mesothelioma were absent in 14 of 15 subjects diagnosed with benign pleural plaques either with or without accompanying asbestosis. Conclusion: In a population of asbestos-exposed subjects who eventually developed malignant mesothelioma, ENOX2 transcript variants characteristic of malignant mesothelioma were present in the serum 4 to 10 years in advance of clinical symptoms. Keywords: biomarker, ENOX2, early detection, serum PP01.24: PROGNOSTIC MICRORNAS IN TISSUES FROM MALIGNANT PLEURAL MESOTHELIOMA PATIENTS RECEIVING MULTIMODALITY THERAPY Michaela B. Kirschner1, Bart Vrugt2, Martina Friess1, Mayura Meerang1, Peter Wild2, Nico Van Zandwijk3 , Glen Reid3 , Walter Weder1, Isabelle Opitz1 Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 2Institute of Surgical Pathology, University Hospital Zurich, Zurich, SWITZERLAND, 3Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA 1 Objectives: In a recent study using two cohorts (N=48 and N=43) of surgical specimens from malignant pleural mesothelioma (MPM) patients, we identified several microRNAs with prognostic potential. A combination of six of these microRNAs, which we termed the miR-Score, provided the best prognostic accuracy for identifying patients with a survival of >20 months following surgery. The purpose of the current study is to further evaluate these microRNAs in surgical and diagnostic tumor specimens of an independent cohort of MPM patients receiving multimodality treatment. Methods: We identified a cohort of 140 MPM patients who iMig2016.ORG 87 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP received chemotherapy followed by extrapleural pneumonectomy (EPP) between 1999 and 2014 at the University Hospital Zurich. At present microRNA analysis has been carried out in a small subset of 25 EPP (all chemo-pretreated) and 13 matching diagnostic (chemo-naïve) specimens. RNA was isolated from microdissected tumor tissue, and then subjected to microRNA specific RT-qPCR for the six microRNAs of the miR-Score. Kaplan-Meier log rank analysis was performed to determine association of the microRNAs with survival. Related-samples Wilcoxon Signed Rank Test was employed to determine differences in microRNA expression between diagnostic and surgical specimens. Results: For five of the six signature microRNAs Kaplan-Meier analysis in both EPP and diagnostic specimens showed similar associations between expression levels and survival as previously published. However, miR-21, the microRNA previously most significantly associated with prolonged survival, did not reach statistical significance in the current subset (p=0.764). As a result of the analysis of the individual microRNAs, also the combined miR-Score was not significantly associated with survival. This is most likely attributable to the small number of samples currently available. To evaluate whether chemotherapy might affect microRNA levels, we compared expression before and after chemotherapy in 13 matched sample pairs. While this analysis did not show significant differences in the median expression between pre- and post-chemotherapy tissue for any of the microRNAs, on the sample-by-sample investigation showed reduction in expression of miR-21 after chemotherapy. For all other microRNAs, while individual samples did show strong differences between pre- and post-chemo expression, no conclusive trend regarding the effect of chemotherapy could be observed. Conclusion: Preliminary data from an independent series of MPM specimens (diagnostic and post chemotherapy) show that despite the small number of investigated samples, the majority of microRNAs with prognostic potential could be validated. Our data also suggest that miR-21 levels may be affected by chemotherapy. Ongoing investigation in a larger number of samples is needed to validate the miR-Score and to provide more insight into the effect of chemotherapy on microRNA expression, and how this might be associated with response to therapy. Keywords: multimodality treatment, prognosis, microRNA PP01.25: CHEMOTHERAPY AND CHEMOTHERAPY PLUS TALC PLEURODESIS IN TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA: A RETROSPECTIVE ANALYSIS Guntulu Ak1, Muzaffer Metintas1, Huseyin Yildirim1, Selma Metintas2, Ulku Yilmaz3 , Cansel Atinkaya Ozturk4 , Isa Dongel5, Gokturk Findik6 , Senay Yilmaz1, Akın Ozturk7, Elcin Ersoz4 , Derya Kızılgöz3 , Pınar Akın Kabalak3 , Tuba Inal Cengiz3 Lung And Pleural Cancers Research And Clinical Center And Medical Faculty Department of Chest Diseases, Eskisehir Osmangazi University, Eskisehir, TURKEY, 2Lung And Pleural Cancers 1 Research And Clinical Center And Medical Faculty Department of Public Health, Eskisehir Osmangazi University, Eskisehir, TURKEY, 3Pulmonary Oncology Unite, Ataturk Chest Diseases and Chest Surgery Training and Educational Hospital, Ankara, TURKEY, 4Department of Chest Surgery, Sureyyapasa Chest Diseases and Chest Surgery Training and Educational Hospital, İstanbul, TURKEY, 5Medical Faculty Department of Chest Surgery, Suleyman Demirel University, Isparta, TURKEY, 6Department of Chest Surgery, Ataturk Chest Diseases and Chest Surgery Training and Educational Hospital, Ankara, TURKEY, 7Department of Pulmonary Oncolgy Unite, Sureyyapasa Chest Diseases and Chest Surgery Training and Educational Hospital, İstanbul, TURKEY Objectives: Surgery combined with radiotherapy and/or chemotherapy have been reported to improve median survival in patients with malignant pleural mesothelioma (MPM). However, since the majority of patients are ineligible for or refuse surgery, chemotherapy represents the only therapeutic modality in such cases. There has been a recent interest in the use of therapeutic options that can be used as adjunct to chemotherapy in MPM patients. Among those, talc pleurodesis administered in to pleural fluid for palliative purposes has been proposed to improve MS in MPM. The present study aimed at retrospectively assessing the effect of talc pleurodesis on MS in a group of MPM patients undergoing chemotherapy. Methods: A total of 248 patients ineligible for or refusing surgery who were treated with chemotherapy and who were followed-up for a minimum duration of 12 months between January 1991 and June 2015 were included. Age, gender, tumor cell type, disease stage, treatments administered, time of diagnosis and initiation of treatment, response to chemotherapy, KPS, outcome of pleurodesis, treatment related side effects, and death certificates were retrieved from the medical database. Patients with missing data or with a follow up duration of less than 12 months were excluded. Patients were divided into the two following groups: “chemotherapy alone” or “chemotherapy plus talc pleurodesis”. The two groups were compared with respect to factors that may have an influence on the prognosis of MS such as age, gender, stage, KPS, tumor histology, and treatment modality. Results: Of the 248 total participants, 134 were male and 114 were female with a mean age of 61.3 years (60.7 in males, and 62.2 in females). Chemotherapy alone was administered in 152 patients, while talc pleurodesis was given additionally in 96. Histological diagnoses were epithelioid, myxoid, and sarcomatoid in 193, 33, and 10 patients, respectively, while histological type could not be ascertained in 12 patients. There were 19, 42, 96, and 91 patients with stage 1, 2, 3, and 4 disease, respectively. A total of 155 patients had a KPS of ≤ 80, while 93 had a KPS > 80. The treatment groups were comparable in terms of gender (p=0.578), distribution of histological cell types (p=0.604), stage (p=0.669), and KPS (p=0.224). The MS in the overall patient group, i.e. 248 patients, was 12 months, while the corresponding figures were 13 and 9 months for epithelioid and non-epitheloid tumors, respectively (p<0.001 ). Again MS in stage 1, 2, 3, and 4 patients were 16, 15, 13, and 9 months respectively (p<0.001). Duration of MS was 10 months and 17 months in those with a KPS of ≤ 80 and > 80, respectively (p<0.001). Chemotherapy alone and chemotherapy plus talk-pleurodesis were associated with respective MS of 11 and 13 months (p=0.8884). Logistic regression analysis showed that male gender (p=0.034), advanced stage (p=0.002), non-epitheloid histology (p=0.001), and low KPS (p<0.001) were assoiMig2016.ORG 88 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP ciated with a poorer MS, with no effect of the addition of talk pleurodesis to chemotherapy on MS (p=0.391). When considering patients with epithelioid tumors only, stage (p=0.007) and KPS (p<0.001) emerged as significant predictors of MS, while addition of talc pleurodesis did not appear to have an effect on MS (p=0.660). In both treatment groups, the side effects were generally tolerable and no treatment-associated deaths were observed. Conclusion: In this retrospective analysis of a limited number of patients, addition of talc pleurodesis to chemotherapy did not result in a significant improvement in MS in patients MPM, although the survival difference between the two groups was 2 months. Thus, a prospective randomized study conducted by the Turkish Mesothelioma Working Group is currently underway to further assess the role of talc pleurodesis in these patients. *This study is supported by General Directorate of Health Researches, Republic of Turkey, Ministry of Health. Keywords: prognosis, mesothelioma, Talc pleurodesis, chemotherapy PP01.26: INITIAL RESULTS OF THE MULTICENTRIC TURKISH MALIGNANT PLEURAL MESOTHELIOMA DATABASE* Hasan Batirel Thoracic Surgery, Marmara University Faculty of Medicine, Istanbul, TURKEY Objectives: Malignant Pleural Mesothelioma (MPM) is a disease with poor prognosis. Environmental and occupational asbestos exposure are the main factors for MPM. We started an online MPM database in 2014. In this study we analyzed the initial results of this database. Methods: During 2014-2015, cases with a histologic diagnosis of MPM were recorded in an online MPM database by the Turkish Mesothelioma Study Group. 301 cases were recorded. Dual submissions, patients without a date of diagnosis, followup data and date of diagnosis earlier than 1.1.2013 were excluded. Eventually 204 cases were evaluable. Demographic, histologic, clinical and pathologic stage, treatment and survival data were analyzed. Kaplan-Meier survival and uni-, multivariate analyses were performed. Results: Average age was 62 ± 11 (76 females). Histologies were epithelioid (n=136), biphasic (n=34), sarcomatoid-desmoplastic (n=24) and subtype not identified (n= 9). Clinical T and N stage was available in 124 and 52 patients respectively. Pathologic T and N stage was available in 54 and 36 patients respectively. 80 patients underwent treatment that included surgery. Mean follow-up was 12.4 ± 8.1 months. Overall median and 2 year survivals were 14.6 months and 35% respectively. Clinical M1 disease patients (n=18) had a median survival of 7.1 months. There was no difference in median survival due to gender or side (Male/Female 14.6/14.5 months, p=0.92; Right/Left 13.4/18.5 months, p=0.51). Survival comparisons are shown in Table 1. Histology, Clinical T and N stage and treatment were significant (p<0.001, p=0.005, p=0.002 and p<0.001 respectively). Multivariate analyses showed histology (p=0.003, OR 8.7) and type of treatment (p=0.002, OR 9.5) as significant factors. Criteria (n) Median Survival (months) 2-yr Survival (%) p-Value Epithelioid (136)/ Biphasic (34)/ Sarcomatoid (24) 18.5/13.3/ 7.1 42/22/0 <0.001 Asbestos History Present (n=106) /Absent (n=98) 12.9/18.5 Clinical T1(n=8)/2(n=44) /3(n=36) /4(n=36)/ X(n=80) 12.9/19.8/ 18.8/8.8/ 16.8 29/37/ 42/11/43 0.005 Clinical N0(n=32) /2(n=20)/X(n=152) 24.9/8.1/ 14.3 56/0/33 0.002 Pathologic T1(n=5)/2(n=15)/ 3(n=27)/4(n=7) 16.9/16.1/ 21.2/NR Treatment Including Surgery (n=80)/ Without Surgery (n=91)/ Supportive (n=27) 19.8/12.4/ 4.2 46/28/19 <0.001 Surgery with MCR (n=51)/ Without MCR(n=29 21.2/15.8 50/47 0.58 32/40 0.093 0.39 Conclusion: Turkish MPM cohort which is mainly based on patients with environmental asbestos exposure with similar demographic characteristics and survival rates as in literature. Treatments that include surgery were associated with a prolonged survival which is likely due to a selection bias. Histologic subtype identification is very important for prognostic stratification. Turkish Mesothelioma Working Group Contributors: Muzaffer Metintas, Hasan Fevzi Batirel, Sedat Altin, Cansel Atinkaya Ozturk, Berna Oksuzoglu, Ulku Yilmaz, Figen Deveci, Adil Zamani, Adnan Sayar, Nazan Sen, Serdar Berk, Ufuk Yilmaz, Dilek Ernam, Pınar Akin Kabalak, Volkan Kara, Derya Ozaydin, Mehmet Ali Bedirhan, Tuba İnal Cengiz, Ibrahim Dincer, Isa Dongel, Talat Kilic, Zehra Seyfikli, Mehmet Bayram, Erdogan Cetinkaya, Ali Kadri Cirak, Gamze Kirkil, Celalettin Kocaturk, Muzaffer Metin, Berna Akinci Ozyurek, Umran Toru. * This study was was supported by General Directorate of Health Researches, Ministry of Health, Republic of Turkey. Keywords: chemotherapy, Survival, Surgery, mesothelioma iMig2016.ORG 89 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.27: FOURTH LINE CHEMOTHERAPY WITH DOCETAXEL FOR MALIGNANT PLEURAL MESOTHELIOMA (MPM) PP01.28: PHASE I TRIAL OF LENTIVIRAL CARTMESO CELLS IN PROGRESSIVE MALIGNANT PLEURAL MESOTHELIOMA (MPM) Jens B. Sørensen, Vinicius De Lima Andrew R. Haas, Gabriela Plesa, Drew A. Torigian, Edmund Moon, Mark O’Hara, Gregoary Beatty, Janos L. Tanyi, Annemarie Nelson, Naseem Kerr, Maureen Mcgarvey, Simon Lacey, Jos Melenhorst, Steven Albelda, Carl June Dept. Oncology, Finsen Centre/National University Hospital, Copenhagen, DENMARK Objectives: Docetaxel has revealed activity in malignant pleural mesothelioma (MPM) with response rates from 5%-23% when used as 1st line treatment (Vorobiof DA et al. 2002, Belani CP 2004, Sørensen JB 2008). There are no well-defined 3rd- or even 4th-line treatments for advanced MPM, but we use routinely carboplatin/gemcitabine/liposomized doxorubicin (CCG regimen) as 3rd line because of the activity previously reported (de Lima, 2015. Hence, Docetaxel was explored as a possible 4th line in MPM. Methods: Patients had histologically verified MPM, progression after 1st line platinum-pemetrexed, 2nd line vinorelbine, and 3rd line carboplatin/gemcitabine/liposomized doxorubicin (CCG regimen), and PS 0-2. The explored 4th line regimen was docetaxel 75 mg/m2 day 1 q3wks, maximum 6 cycles. CT-scans were done after every second cycle. Results: Out of 564 MPM patients who received 1st line platinum/pemetrexed 2010-2015 13 patients (2.3%) received later 4th line docetaxel. These 13 patients had median age 65 years, 92% were males, 15% PS 2, 46% epitheloid subtype and 54% biphasic, and all had stage IV disease. Median time from diagnosis to start of 4th line docetaxel was 21.5 months. 31% of patiens had previous palliative radiotherapy and 39 had palliative pleurectomy. Median treatment duration was 2 cycles (range 1-6 cycles). Treatment was postponed due to hematologic toxicities in 8% and dose reduction was necessary in 5 paatients (39%)(3 pts due to hematologic toxicity, one due to neutoxicity and one of other causes). A total of 4 CTC grade 3 events occurred (allergic reactions 2 cases, anemia 2 cases) and one grade 4 event (neutropenia). No toxic deaths occurred. There were no objective responses and disease control rate (DCR) was 23%. Medians of progression free survival (PFS) and OS were 1.5 and 4.6 months from start of 4th line treatment, respectively. Conclusion: 4th line treatment with docetaxel could be safely administered to heavily pretreated advanced MPM starting nearly 2 years after initial diagnosis. However, docetaxel did not have noteworthy activity in this late stage of the disease. More efficacious salvage regimens are sorely needed. Keywords: Docetaxel, 4th line treatment, chemotherapy University of Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA Objectives: Epithelial MPM expresses the tumor antigen mesothelin. Due to mesothelin’s limited expression profile in normal tissues, it is a potential ideal target for mesothelin-directed cellular-based immunotherapies. We performed a phase I clinical trial of lentiviral CART-meso cells in patients with progressive MPM. Methods: Five patients with epithelial MPM underwent a 10 liter apheresis for peripheral blood mononuclear cell isolation. Ex vivo transfection with a lentiviral chimeric anti-mesothelin immunoreceptor SS1 fused to the 4-1BB and CD3ζ signaling domains was performed. In a standard 3+3 phase I dose escalation format, patients received 1e7 or 1e8 CART-meso cells intravenously without or with 1.5 gm/m2 cyclophosphamide as a conditioning regimen two to four days prior to CART-meso cell infusion. Safety was assessed via standard CTCAE patient assessment and biochemical evaluation. A variety of immunologic and biologic correlates were assessed including CART-meso cell persistence and trafficking, human anti-mouse/CAR antibody (HAMA/HACA) development, and modified RECIST criteria response. Results: CART-meso cells without or with cyclophosphamide were administered without any evidence of on-target off-tumor toxicity to pleura, peritoneum or pericardium. One serious adverse event occurred in the cyclophosphamide group due to neutropenic fever requiring hospitalization for intravenous antibiotics. By Q-PCR, CART-meso RNA peaked between day 10-14 then trended toward undetectable by day 28. As expected, a nearly 10-fold higher CART-meso RNA level was detected at day 10-14 at 1e8 cells compared to 1e7 cells. Moreover, at both 1e7 and 1e8 cells, cyclophosphamide increased RNA level 10-fold over the dose without cyclophosphamide. One of the 5 patients infused with CART-meso cells had malignant ascites which was tapped post CART-meso cell infusion. CART-meso construct was detected in the ascites at days 9 and 17, but not day 28. Interestingly, this patient also had the highest level of mesothelin surface and cytoplasmic expression. Low level HAMA expression was present in one patient and interestingly the patient with malignant ascites had detectable HACA in their peritoneal fluid. By modified RECIST criteria, 4 of 5 patients had stable disease at one month, but all patients had progressive disease by 3 months. The patient with malignant ascites remains alive 10 months post CART-meso infusion on gemcitabine therapy. Conclusion: We were able to demonstrate the safety of a lentiviral murine CART-meso cellular therapy without and with cyclophosphamide in MPM patients. CART-meso cells demonstrated expansion and persistence that was enhanced with cyclophosphamide conditioning and trafficking was detected in the one patient. Despite no dramatic responses, these results demonstrate safety regarding no on-target off-tumor toxicity and a fully human CART-meso construct is in development iMig2016.ORG 90 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP and awaits a phase I trial to evaluate safety, biocorrelates and efficacy. Ultimately, combinatorial therapies to improve trafficking and to modify the tumor microenvironment may further enhance CART cell therapies in MPM and other solid tumors. Keywords: Cyclophosphamide, T cells, chimeric antigen receptor, phase I trial PP01.30: MESOTHELIOMA MORTALITY IN AUSTRALIAN AND ITALIAN-BORN WORKERS EXPOSED TO BLUE ASBESTOS AT WITTENOOM, WESTERN AUSTRALIA Nicholas De Klerk1, Alison Reid2, Enzo Merler3 , Susan Peters4 , Peter Franklin4 , Vittoria Bressan3 , Arthur W. Musk4 Telethon Kids Institute, University of Western Australia, Subiaco, WA, AUSTRALIA, 2Curtin University, Perth, WA, AUSTRALIA, 3Mesothelioma Register of the Veneto Region, Padua Local Health Unit, Padova, ITALY, 4School of Population Health, University of Western Australia, Perth, WA, AUSTRALIA 1 PP01.29: DOES MALIGNANT PLEURAL MESOTHELIOMA WITH METASTASES AT FIRST PRESENTATION REALLY BENEFIT FROM CHEMOTHERAPY? Hala Aziz Shokralla1, Mohamed Rahouma2 Medical Oncology, national cancer institute, cairo, EGYPT, 2Surgical Oncology, national cancer institute, cairo, EGYPT 1 Objectives: Our study aims to evaluate different clinico-pthological characteristics of metastatic cases of MPM at presentation and the possible benefits from active therapy from a single Institution practice data. Methods: We retrospectively analyzed patients with locally advanced or metastatic MPM, treated at the Department of Medical Oncology –national cancer institute in Egypt. Data on age, gender, smoking history, asbestos exposure, performance status, tumor stage, histology, type of treatment (Raltitrexed-Bortezomib-Gemcitabine-Vinorelbine with platinum containing agents), response to treatment and routine laboratory tests including complete blood count panel, date of death or censored status were collected. Mean Progression free survival and overall survival were estimated. Results: 114 patients had MPM. Fifteen cases present as metastatic disease (13%). Nine patients (60%) were men. The median age of patients was 52 years (range; 19-73) and mean pre-treatment weight was 72.6 kg. All cases were in performance status –I at presentation apart of five cases (two with PS-II and three with PS-III). Thirteen (87%) patients reported asbestos exposure. Dyspnea and Chest pain were the most prevalent symptoms (94%). Only one case had no pleural effusions at presentation, thickening was obvious in all cases, five cases had no mediastinal nodes (~34%) Eight cases had osseous deposits, five had hepatic focal lesions, two had contralateral lung metastasis, only one case had axillary nodes and another one had malignant ascites. Twelve cases received platinum containing combination, eight cases experienced progressive disease (~67%). The mean overall survival (OS) and Progression free survival (PFS) were 13.6 months and 7.8 months, respectively. Conclusion: Our results suggest that mesothelioma may present rarely with wide spread disease; most of them didn’t respond to platinum containing therapy. Further studies may confirm possible benefit of chemotherapy compared to supportive therapy alone. Objectives: To compare mortality from malignant mesothelioma and other diseases among Italian-born and Australian-born workers employed at Wittenoom, Western Australia, using rates from the general Western Australian and Italian populations. Methods: The minesite operated from 1943 and 1966 and work histories were based on employment records from Australian Blue Asbestos (ABA) who operated the Wittenoom mine. There were over 50 different nationalities recorded with Italians forming the largest migrant group. British and Australians were similarly recorded and not distinguishable from each other. Italians were identified both through company records and subsequent verification of all records and attribution on the basis of full name. Follow-up from 1943 to 2009 was done in both Australia and Italy for death and cancer incidence. Asbestos exposure was based on duration of employment and various industrial hygiene surveys which allocated specific levels to different jobs. No information on overtime or extra work periods was available. SMRs were based on both Australian and Italian rates and Cox regression models were used to examine the separate and combined effects of exposure and ‘nationality’ on mesothelioma mortality. Results: The mesothelioma mortality rate, per 100,000, was higher among the Italian-born workers (181.4, 95%CI 145.7225.8) than the Australian/UK-born workers (119.6, 95%CI 103.2-138.5). Within both groups of workers the risk of mesothelioma increased with an increasing level of cumulative exposure. Comparing the risk between Italian and Australian/UKborn workers by category of exposure showed a greater than twofold increased risk of mesothelioma among Italian workers in the lowest exposure category (<10 f/ml years), compared with Australian/UK-born workers. The risk of mesothelioma was not statistically different between Italian or Australian/UK-born workers in either the medium (10-50 f/ml years) or high (>50 f/ ml years) exposure categories. Conclusion: 30% of Italian immigrants who left Wittenoom have returned to Italy, most after at least two years of migration. Their time at Wittenoom has deeply affected their health with high risks for asbestos-related disease. Mortality from asbestos disease was significantly more marked in the Italians than in the British/Australians, and is perhaps indicative of discrimination against migrants. Keywords: crocidolite, migrant health, Malignant mesothelioma Keywords: metastatic-MPM-presentation-therapy iMig2016.ORG 91 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.31: PRELIMINARY REPORT OF AN OBSERVATIONAL CLINICAL REGISTRY ON MALIGNANT PLEURAL MESOTHELIOMA (MPM) IN ITALY (REGCLIN) Federica Grosso1, Annalisa Roveta2, Paolo Pedrazzoli3 , Francesco Valentino3 , Daniela Degiovanni4 , Alessandra Bearz5, Federico Rea6 , Francesco Cognetti7, Armando Santoro8 , Tiziana Cena9, Alberto Muzio10, Gianmauro Numico1, Carmine Pinto11, Massimo D’Angelo12, Giorgio V. Scagliotti13 , Corrado Magnani9 Oncology Unit, SS. Antonio e Biagio e C. Arrigo, Hospital, Alessandria, ITALY, 2Ssa Sviluppo E Promozione Scientifica, SS. Antonio e Biagio e C. Arrigo, Hospital, Alessandria, ITALY, 3Oncology Unit, Fondazione IRCCS Policlinico S. Matteo, Pavia, ITALY, 4Ss Hospice Monsignor Zaccheo/ Uocp, Santo Spirito, Hospital, Casale Monferrato, ITALY, 5Oncology Unit, Centro Riferimento Oncologico IRCCS, Aviano, ITALY, 6Divisione E Cattedra Di Chirurgia Toracica E Centro Trapianto Di Polmone, Azienda Universitaria Ospedaliera, Padova, ITALY, 7Oncology Unit, Istituto Nazionale Tumori IRCCS Regina Elena, Roma, ITALY, 8Oncology Unit, Istituto Clinico IRCCS Humanitas, Rozzano, ITALY, 9Medicina Traslazionale, Università degli Studi del Piemonte Orientale, Novara, ITALY, 10 Oncology Unit, Santo Spirito, Hospital, Casale Monferrato, ITALY, 11Oncology Unit, Azienda Ospedaliera Arcispedale - IRCCS Santa Maria Nuova, Reggio Emilia, ITALY, 12Centro Sanitario Amianto, Azienda Sanitaria Locale AL, Casale Monferrato, ITALY, 13Dipartimento Di Oncologia Medica, Università di Torino-San Luigi Hospital, Torino, ITALY Acknowledging the current incompleteness of the data it can be currently extrapolated that, a high proportion of patients received active treatment and a significant percentage of them was included in experimental studies. The overall survival compares favorably with historical data. While continuing to register new cases, we are now planning to expand this project also through the integration with the epidemiological registry ReNaM (Registro Nazionale Mesotelioma). Keywords: Malignant pleural mesothelioma, Registry, Database, Observational study 1 Objectives: The present study, supported by an Italian CCM (Centro per il Controllo delle Malattie) project , provides information about recruitment, clinical characteristics, treatment modalities, and outcomes of a large series of MPM patients included in the Italian observational protocol REGCLIN. Data were collected in a web-based registry of patients treated in 10 participating referral Institutions. Here we report on the preliminary analysis of the data collected so far. Methods: The most relevant clinical and treatment related variables for each patient were registered in the web database from each participating center. The collected data was then analyzed using SAS (9.2 v.). Results: Since January 2010 to November 2015, 359 MPM patients, 249 males (69%) and 110 females (31%), with a median age 70 (IQR 64-77; range 29-90) were included. Hystology was epithelioid in 261 (73%), biphasic in 49 (14%), sarcomatous in 36 (10%) cases and missing in 13 (3%). Diagnosis was obtained through pleuroscopy/thoracoscopy in 304 (85%) and through CT guided biopsy in 31 (9%), and through other modalities in 24 (6%) cases. Data about treatment modalities were available for 277 (77%) patients: 262 (94%) received chemotherapy, representing the only treatment modality for 163 (59%). Surgery was performed in 71 (26%) patients, always associated with chemotherapy; of these, 37 (13%) received multimodal approaches including also radiotherapy. Sixty-nine patients (25%) were treated in the context of clinical trials. The follow-up analysis is ongoing: it is currently available for 258 (72%) patients and, to date, overall survival (OS) is 15,7 months (IC90 13,8 – 18,3). Conclusion: This study demonstrates the feasibility of a webbased multi-institutional clinical and pathological registry that allows data sharing about diagnosis and treatment of MPM. PP01.32: SLOWLY PROGRESSIVE MALIGNANT PLEURAL MESOTHELIOMA IN AGED PATIENTS Mizue Hasegawa1, Asako Okabayashi1, Akitoshi Sato1, Naoko Yokohori1, Hideki Katsura1, Toshiko Kamata2, Eitetsu Koh2, Yasuo Sekine2, Di Wu3 , Kenzo Hiroshima3 Respiratory Medicine, Tokyo Women’s Medical University, Yachiyo Medical Center, Yachiyo, JAPAN, 2Thoracic Surgery, Tokyo Women`s Medical University, Yachiyo Medical Center, Yachiyo, JAPAN, 3Pathology, Tokyo Women`s Medical University, Yachiyo Medical Center, Yachiyo, JAPAN 1 Objectives: Malignant pleural mesothelioma (MPM) predominantly affects men aged 50-70 years. Without treatment, it is associated with a poor median survival, ranging from 4 to 12 months. Management for the aged patients is not fully elucidated since invasive examinations or treatments may be intolerable. We retrospectively evaluated the clinical and pathological features of MPM in aged patients diagnosed at our institution. Methods: Two patients were diagnosed as MPM over the age of eighty from March 2010 to December 2015 at our institution. Medical records were analyzed retrospectively. Results: Case 1; A 90 year-old man admitted to our hospital for fatigue and appetite loss. Chest X-ray and computed tomography (CT) revealed massive right pleural effusions and bilateral pleural plaques without remarkable thickening of pleura or mass lesion. Examination of pleural effusion showed elevation of hyaluronic acid with 170,000ng/ml, but cytological examination could not address diagnosis of MPM. After drainage of pleural effusion, palliative care was continued without assertive examination or treatment. After 8 months, patient died of pneumonia without increase of pleural effusion or progression of pleural lesions. Autopsy revealed slightly thickened pleura without obvious mass lesion. Microscopic findings of pleura revealed proliferation of round to oval cells with acinar formation. Immunohistochemical stainings were positive for CAM5.2, carletinin, D2-40, and negative for CEA, TTF-1.Final diagnosis was epithelioid MPM. Case 2; An 87 year-old man admitted to our hospital with hydro-pneumothorax. Chest CT revealed right hydro-pneumothorax with minimal pleural thickening or mass. Cytological examination of pleural effusion could not address diagnosis of MPM. Video-assisted thoracic surgery was performed for the treatment of refractory pneumothorax. Pathological findings of pleura revealed proliferation of round to oval cells with tubulopapillary pattern. Immunohistochemical iMig2016.ORG 92 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP stainings were positive for carletinin, D2-40, and negative for CEA, TTF-1. Final diagnosis was epithelioid MPM. Palliative care was continued until 5 months after when he died of pneumonia without marked progression of MPM lesions. and 31/12/2005, therefore MPM account for a total of 0.19% of all cases. It seems that second and third lines are useless. New studies and/or new drugs are mandatory for this disease category. Conclusion: We presented 2 cases of MPM in aged. Both patients were epithelial type with slow progression of MPM lesions and died of disease other than MPM. Invasive examination or treatment may not be helpful for aged patients with suspect or under diagnosis of MPM. Keywords: mesothelioma, asbestos Keywords: mesothelioma, aged, slow progression PP01.34: BRAIN METASTASES IN MALIGNANT PLEURAL MESOTHELIOMA PP01.33: A COHORT OF MALIGNANT PLEURAL MESOTHELIOMA TREATED AND FOLLOWED IN THE LAST TEN YEARS AT INSTITUTO ONCOLÓGICO HENRY MOORE Mariana Abal, Ernesto Gil Deza, Claudia Acuña, Carlos Garcia Gerardi, Gabriela Malcervelli, Dario Niewiadomsky, Flavio Tognelli, Eduardo Morgenfeld, Felipe Gustavo Gercovich Instituto Oncologico Henry Moore, Buenos Aires, ARGENTINA Objectives: The main objective of this paper is to analyze the clinical features and outcome of pt diagnosed with MPM who were treated at our institution during the last 10 years. Methods: We reviewed the clinical records of 50 pt diagnosed with MPM between 2005 and 2015. All the pt were treated and followed at our institution from the diagnosis. We reviewed the occupational exposure to asbestos, personal and family history, comorbidities, tumor stages, PS at presentation, pharmacological and/or invasive interventions. The tumor response was evaluated according to RECIST 2.0. Overall survival was registered from diagnosis until death or to the last pt’s visit. Results: Fifty pt were studied, the average age was 65 years old (range 44-85). Sex: male 28 pt (56%) / female 22 pt (44%). Occupational asbestos exposure was confirmed in 3 pt and suspected in 9 pt. No pt had a history of relatives diagnosed with MPM. Smoking was present in 22 pt. Stages: I: 3 pt (6%) , II: 7 pt (14%) , III: 18 pt (36%) and IV: 22 pt (54%). ECOG: 0-1: 27 pt (54%) , 2 : 20 pt (40%) , 3 :3 pt (6%) .In 45 pt (90%) there were no other concomitant neoplasias. The most frequent histologic subtype was Epithelioid in 36 pt (72%). Five pt underwent a surgical procedure (1 pt decortication ; 1 pt pleurectomy and pericardiectomy ; 1 pt tumor resection from chest wall and 2 pt pleurodesis ). Radiotherapy was indicated in 3 pt with palliative intent. Chemotherapy was the first therapeutic treatement in 40 pt (80%) . All pt received a first line of Platinum and Pemetrexed, 12 pt received a second line with gemcitabine or vinorelbine, only one pt received a third line. Eight out of 40 pt (20%) treated with the first line had a partial response and they had a median survival of 20 months (4-64) . No pt responded to the second line of treatment. Median overall survival for the total cohort was 11.3 months (range 1-64 m). Nobukazu Fujimoto1, Tomoko Yamagishi2, Yosuke Miyamoto2, Michiko Asano2, Yasuko Fuchimoto2, Sae Wada2, Shinji Ozaki2, Hideyuki Nishi2, Takumi Kishimoto2 Medical Oncology, Okayama Rosai Hospital, Okayama, JAPAN, 2Okayama Rosai Hospital, Okayama, JAPAN 1 Objectives: The brain is a rare site of metastasis in malignant pleural mesothelioma (MPM), and its clinical features and prognosis remain unclear. The aim of this study was to investigate the incidence, prognosis, and risk factors for brain metastases (BM) in MPM patients. Methods: The study included 150 consecutive patients with histologically proven MPM who were seen between July 1993 and October 2014 at Okayama Rosai Hospital, Japan. Baseline demographic and clinicopathological variables were collected retrospectively from patients’ medical records. These included age at initial diagnosis, gender, histological subtype, clinical stage, and baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS).Diagnosis of BM in MPM was based on magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) scans. Routine brain imaging was performed at the diagnosis but not during the follow-up period, unless BM was suspected. Leptomeningeal metastases were not included in the actuarial incidence of BM in this study. Results: The median follow-up time was 11 months (range 0–154.0 months). A total of eight patients (5.3%) developed BM during the course of their illness. Multivariate analysis identified age < 65 years (odds ratio [OR] = 5.83, p = 0.038) and International Mesothelioma Interest Group stage IV (OR = 1.69, p = 0.040) as independent factors related to increased risk of developing BM. The 1-and 2-year cumulative rates of BM were 4.0% (95% confidence intervals [CI] 1.4-8.5%) and 5.3% (95%CI 2.3–10.2%), respectively. Our study showed that the overall survival (OS) of patients with BM was worse than that of patients without BM (median OS 6.5 versus 11.0 months, p = 0.037). Conclusion: The prognosis for BM in MPM patients is poor. Clinicians should perform careful screening for BM, especially in patients with risk factors. Keywords: Brain metastases, Malignant pleural mesothelioma, asbestos Conclusion: The Instituto Oncológico Henry Moore in Buenos Aires, Argentina registered 26,734 new pt between 1/1/2005 iMig2016.ORG 93 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.35: MALIGNANT PLEURAL MESOTHELIOMA IN PATIENTS OLDER THAN 45 YEARS PP01.36: A MESOTHELIOMA CLUSTER AMONGST EXPERIMENTAL PHYSICISTS Fatma M.A. Aou El-Kasem1, Rabab M. Gaafar2, Hala Aziz Shokralla2, Abdel-Rahman M. Abdel-Rahman3 , Mohamed Rahoma3 Steven Kazan, William F. Ruiz Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2Medical Oncology, NATIONAL CANCER Institute, CAIRO, EGYPT, 3Surgical Oncology, National Cancer Institute, Cairo, EGYPT Kazan McClain Satterley & Greenwood, Oakland, CA, UNITED STATES OF AMERICA 1 Objectives: A cancer registry was analyzed to determine if the clinicopathologic characteristics, treatment modalities, and prognosis of malignant pleural mesothelioma (MPM) patients >45 years of age at diagnosis differ. Methods: Retrospective review of patients with MPM presented to medical oncology department, National Cancer Institute, Cairo University, Egypt;diagnosed between 2007 till 2012. Data regarding demographics, presentation symptoms, histology, tumor staging, treatment modality, and survival were obtained from all patients. Pearson’s chi(2) test and the Kaplan-Meier method with a log-rank test were used for statistical analysis. There were 114 cases of MPM diagnosed during this period 2007 and 2012. Among them, 56 patients were > 45 years old . These patients were selected for our study. Results: We found that lymph node metastasis (0.047), progression after initial response (0.009) and WBC (0.002) significantly affecting PFS of MPM patients older than 45 years. Median PFS= 8 months. Median OS=17 months. Median age was 55 years. PS was 0/ 1 in 39 (69%)cases. Thirty four (60%) cases were males. Fourty-three (76%) cases had asbestosis. Twenty-seven (48%) cases had chronic disease. Twenty-three (41%)cases were smokers. Dyspnea was presenting symptom in 52 (92%)cases. Fourty-nine(87%) cases were complaining of chest pain. Thirty-five (62%)were complaining of fatigue. Anorexia was present in 14 (25%) cases. Fourty-nine(87%) cases had effusion. Pleural thickening was documented in 53(94%) cases. Twenty-six (46%) cases had mediastinal lymph nodes. Nine (16%) cases had pulmonary metastasis. T1,2,3 represented in 45 (80%) cases. Fifty (89%) cases received platinum containing chemotherapy out of them 42 cases were responders. Thirty (53%) cases were epithelioid mesothelioma. Twenty-nine (51%)cases were grade 2&3 of differentiation. Conclusion: Lymph node metastasis (0.047), progression after initial response (0.009) and WBC (0.002) significantly affecting PFS of MPM patients older than 45 years. Early diagnosis and proper suitable treatment for old MPM patients are recommended. Bigger number of patient is recommended. Objectives: To determine the cause of mesothelioma in three renowned physicists who collaborated on experimental research during the 1960s and 1970s and died of mesothelioma between 2012 and 2015. Methods: Eugene Commins, Hyatt Gibbs and Melvin Simmons each hold doctoral degrees in physics, contributed substantially to their field and received numerous honors. The occupational and asbestos exposure information presented here was obtained from the public record including available death certificates,[1] obituaries and information obtained from Mr. Commins before his death. Results: Vital Statistics: Eugene Commins was born 1932. He obtained a Ph.D. in Physics from Columbia University in 1958. He worked as a physics professor for 57 years. He died in 2015 of Advanced Metastatic Malignant Mesothelioma, Biphasic, with Bone Metastasis. Hyatt Gibbs was born 1943. He obtained a Ph.D. in Physics from University of California – Berkeley in 1965. He worked as a research physicist for 43 years. He died in 2012 of Malignant Pleural Mesothelioma. Melvin Simmons was born 1943. He obtained a Ph.D. in Physics from University of California – Berkeley in 1968 and worked as a research physicist thereafter. He died in 2014 of Malignant Mesothelioma. Occupational Exposure Data[1]: Professor Commins was a doctoral-level physics professor at UC Berkeley from 1960-2010. A member of the National Academy of Sciences and the American Academy of Arts and Sciences and fellow of the American Association for the Advancement of Science and the American Physical Society, his students include Nobel laureate Steven Chu. Dr. Gibbs and Dr. Simmons were his students. Professor Commins and his students conducted experimental research that led to important advancements and publications in physics. During laboratory work during the 1960s and 1970s glass columns were used. Over time, the columns broke or became too thin for continued use. Researchers repaired and remade columns using glass blowing techniques. Asbestos paper and tape were soaked in water and wrapped around portions of the glass to allow handling. When the repairs were finished, the dried asbestos products were scraped into a trash can. Tongs with asbestos sleeves and asbestos gloves were used to handle hot glass and other high temperature materials. During circuit board soldering, transistors and other components were covered with torn-off asbestos tape to insulate the components. Conclusion: The subjects here were exposed to the same asbestos products in the same laboratory during the same time and died of mesothelioma within a three year period, five decades later. This data supports a prior mesothelioma cluster in an occupation not traditionally associated with asbestos exposure, and serves as a reminder that inhalation of asbestos fibers, not job title, increases mesothelioma risk. [1] Dr. Gibbs died in France; his death certificate was not obtained. [2] Professor Commins reported that he cut asbestos ceiling tile iMig2016.ORG 94 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP for two weeks in the 1950s, and repaired drywall at his home on two occasions in the 1960-70s. We found no information that Dr. Gibbs or Dr. Simmons had other occupational or non-occupational exposures to asbestos. with good PS. Keywords: mesothelioma, Physicists, laboratory asbestos exposure, cancer cluster PP01.37: SURVIVAL IN GOOD PERFORMANCE MALIGNANT PLEURAL MESOTHELIOMA PATIENTS; PROGNOSTIC FACTORS AND PREDICTORS OF RESPONSE M Rahouma1, Hala Aziz Shokralla2, Rabab M. Gaafar2, Galal Ghaly1, Abdelrahman Mohamed1 Surgical Oncology, National Cancer Institute, Cairo, EGYPT, 2Medical Oncology, National Cancer Institute, Cairo, EGYPT 1 Keywords: Malignant pleural mesothelioma (MPM), performance status, prognostic factors and predictors of response to chemotherapy Objectives: Malignant pleural mesothelioma (MPM) has a poor prognosis in general, we sought to evaluate prognostic factors and predictors of response to chemotherapy in good ECOG-performance status (PS=0-1) patients. Methods: We retrospectively reviewed our database and enrolled 82 patients with histologically confirmed MPM and PS=0-1 between 2012-2014 Age, weight, gender, smoking status, comorbidities, asbestosis, different symptoms, Tumor, Nodal(N)and Metastasis stages, response, different laboratory values, including pretreatment haemoglobin(Hb), neutrophil/ lymphocyte ratio and pathology. Survival was analyzed using Cox regression in univariate and multivariate analysis. Kaplan–Meier survival curves were obtained and compared by log–rank. Logistic regression was used to determine factors predicting response Results: Eligible patients were 82(Median age 45years, median body Weight 77 Kg, Hb=12 g/dl, platelets =372 x 109 /L , leukocyte=9.7x 103 /µL, neutrophils=6.1 cells/µL, lymphocytes=1.89 cells/µL, neutrophils-lymphocytes ratio (NLR)=3.6 pretreatment). Forty three were men, thirty cases were smoker, and 65 had asbestosis. twenty three present with chronic disease. all cases received platinum based chemotherapy;55(67.07%) were responder(whether SD or PR). Pathology were 49(59.8%) epithelial type, 17(20.7%) mixed type and 16(19.5%)sarcomatoid type. Median overall survival were 17 months (95%CI=14.1119.90). Median progression free survival(PFS) were 9 months(95%CI=6.97-11.03). Significant decrease in PFS were observed among advanced nodal (N) disease (median PFS in N0 and N+ were 10 and 5 months respectively), non-responders(p=0.012), lower NLR(p=0.026) and epithelial pathology type (p=0.062). Multivariate analysis(MVA) demonstrated that advanced N status (p=0.015), non-responder (p<0.001), lower NLR (p=0.015) and smoking (p=0.07) adversely affecting prognosis. Multivariate analysis shows only absence of metastasis(M0) (p=0.04) were the significant predictor of response Conclusion: In addition to previously recognized prognostic factors in MPM, better median survival is evident in patients PP01.38: NON-EPITHELIAL PLEURAL MESOTHELIOMA; CRITERIA, PROGNOSTIC FACTORS AND PREDICTORS OF RESPONSE Hala Aziz Shokralla1, M Rahouma2, Iman Loay3 , Rabab M. Gaafar1, Abdelrahman Mohamed2 Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2Surgical Oncology, National Cancer Institute, Cairo, EGYPT, 3Cancer Pathology Depatement, National Cancer Institute, Cairo, EGYPT 1 Objectives: Malignant pleural mesothelioma (MPM) has a poor prognosis in general. We conducted this study to evaluate prognostic factors and predictors of response to chemotherapy in non-epithelial MPM. Methods: We retrospectively reviewed our database and included patients with histologically confirmed non epithelial MPM 2012-2014. Age, weight, gender, smoking status, performance status(PS), comorbidities, asbestosis, symptoms, Tumor, Nodal(N)and Metastasis stages, response, laboratory values, including pretreatment haemoglobin(Hb), neutrophils/lymphocytes ratio(NLR), and pathology. Survival was analyzed using Cox regression in univariate and multivariate analysis. Logistic regression was used to determine factors predicting response. Kaplan–Meier(KM) survival curves were obtained and compared by log–rank. Results: Enrolled patients were 47(Median age 48years, Weight 80Kg, Hb=12 g/dl, platelets=343x109 /L, leukocytes=11x103 / µL, neutrophils=6.1 cells/µL, lymphocytes=1.10 cells/µL, NLR=5.25 pretreatment). Twenty eight were men from which 21 were smokers, 40 had asbestosis. Thirteen cases had chronic disease, 33(70.2%) were responders. Pathology were 25(53.2%) sarcomatoid type and 22(46.8%) mixed. Median iMig2016.ORG 95 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP overall survival(OS) were 17 months(95%CI=13.70-20.30). Median OS in N0(65.96%) versus N+(34.04%) were 19 months versus 9 months respectively(p=0.033) (figure 1). Median progression free survival(PFS) were 8 months(95%CI=5.61-10.39). Multivariate analysis(MVA) model included variables that had p value <0.20 on univariate analysis and involved weight, gender, smoking status, response and lymphocytes and revealed that high body weight [p=0.034(Hazard ratio(HR)=1.03, 95%CI=1.01-1.05)]and absence of response to chemotherapy(progressive disease) [(p=0.048 (HR=0.048,CI=0.24-0.99)] adversely affecting prognosis. There were no difference in OS(p=764) or PFS(p=0.676) between sarcomatoid and mixed pathology using unadjusted KM curves. Predictors of response, using Logistic regression, revealed that presence of asbestosis( p=0.038) was the only significant predictors of poor response to chemotherapy. Keywords: prognostic factors and predictors of response to chemotherapy, Asbestosis, Non-epithelial malignant pleural mesothelioma (MPM), Body weight PP01.39: DOES PRETREATMENT BODY WEIGHT HAVE ANY SIGNIFICANT IMPACT ON SURVIVAL IN PLEURAL MESOTHELIOMA IN YOUNG AGE GROUP? M Rahouma1, Hala Aziz Shokralla2, Rabab M. Gaafar2, Mohamed Kamel1, Abdelrahman Mohamed1 Surgical Oncology, National Cancer Institute, Cairo, EGYPT, 2Medical Oncology, National Cancer Institute, Cairo, EGYPT 1 Conclusion: Better OS in non-epithelial mesothelioma type was observed among N0 stage reflecting importance of early detection. Worse PFS was observed among those with heavy body weight suggesting disadvantages of overeating. Asbestosis carries a poor prediction to chemotherapy among our cohort. Multivariate analysis of PFS and MVA for predictors of response MVA of PFS P value HR 95% CI (Upper) 95% CI (Lower) Weight 0.034 1.03 1.01 1.05 Gender 0.154 2.01 0.77 5.27 Smoking status 0.369 1.56 0.59 4.12 Response 0.048 0.49 0.24 0.99 Lymphocytes 0.070 1.51 0.97 2.36 MVA for predictors of response P value OR 95% CI (Upper) 95% CI (Lower) PS 0.091 0.011 0.01 1.43 Asbestosis 0.038 0.05 0.01 0.85 Chest pain 0.080 0.09 0.01 1.35 Leukocytes 0.269 0.85 0.64 1.13 Objectives: Nutritional status has been associated with long term outcomes in cancer patients. We investigated whether the body weight (BW), as an indicator of the nutritional status, affects the survival in malignant pleural mesothelioma (MPM) patients in young age group. Methods: We retrospectively reviewed our database and enrolled patients with histologically confirmed MPM and aged 45 years or below in the period between 2012-2014 who received chemotherapy. Age, weight, gender, smoking status, presence of chronic diseases, asbestosis, different symptoms, Tumor(T), Nodal(N) and Metastasis(M) stages, response, different laboratory values, including pretreatment hemoglobin(Hb), neutrophils/lymphocytes ratio(NLR), and pathology. Survival was analyzed using Cox regression in univariate and multivariate analysis. Kaplan–Meier survival curves were obtained and compared by log–rank. Results: Eligible patients were 58 (Median age 39 years, median body Weight 77.5 Kg, pretreatment haemoglobin 12 g/dl, platelets 367 x 109 /L, leukocytes 10.7 x 103 /µL, neutrophils 6 cells/µL, lymphocytes1.25 cells/µL, NLR 4.5). Thirty-two cases (55.2%) were men, nineteen were smokers, 43 had asbestosis and only six cases presented with chronic disease. All cases received platinum based treatment; 17 cases (29.31%) were responder (whether stable disease or partial responders). Pathology were 37 (63.8%) epithelial type, 13(22.4%) were sarcomatoid type and only eight (13.8%) were mixed type. Median overall survival were 16 months (95% Confidence Interval (CI)=13.55-18.45). Median progression free survival (PFS) were 8 months(95%CI=6.17-9.84). PFS were adversely affected by Weight, as a continuous variable [p=0.025, Hazard Ratio(HR)1.02, CI:1.01-1.04] and advanced T stage (see figure). Conclusion: Although BW may reflects the nutritional status, that has been associated with long term outcomes in cancer patients, but it is associated with poor PFS in MPM. iMig2016.ORG 96 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP was applied. In 56 patients (54%) chemotherapy was applied (most common chemotherapy regiemens were pemetrexedcisplatin and gemcitabin-cisplatin). Radiotherapy was applied in 10 patients. Median overall survival (OS) was in all group of patients 11 months. Better OS was observed in epitheliod type compared to sarcomatoid type (11 vs 5,5 months). In patients with mixed type mean OS was 12,5 months. OS was significantly influenced by stage. OS was significantly better in stage III compared with stage IV (17,5 vs 9 months). Conclusion: Our data showed that surgery and radiotherapy are not preferd choice of treatment in our institution. Majority of patient were treated with chemotherapy alone. OS of our data showed comparable results with previously published data. Showing improvent in OS in stage III compared with stage IV patients. The study emphase need for earlier diganosis of MPM patients which could lead to better outcome in MPM patients. Keywords: prognostic factors and predictors of response to chemotherapy, Malignant pleural mesothelioma (MPM), Body weight PP01.40: MALIGNANT PLEURAL MESOTHELIOM: A SINGLE-CENTER EXPERIENCE IN CROATIA Marko Jakopovic1, Luka Brcic2, Tomislav Dujmovic3 , Goran Glodic3 , Anton Mazuranic3 , Branka Cucevic4 , Suzana Kukulj4 , Sanja Plestina4 , Mihovil Roglic4 , Zoran Janevski4 , Ivica Mazuranic4 , Silvana Smojver-Jezek4 , Sven Seiwerth3 , Miroslav Samarzija4 Department For Respiratory Diseases Jordanovac, University Hospital Center Zagreb, Zagreb, CROATIA, 2University of Graz, Graz, AUSTRIA, 3Zagreb Medical School, Zagreb, CROATIA, 4University Hospital Centre Zagreb, Zagreb, CROATIA 1 Objectives: Malignant pleural mesothelioma (MPM) is a rare malignancy usually caused by asbestos exposure. In this retrospective study, we aimed to analyse demographic, clinical, and pathological data and treatment-related outcomes in MPM patients diagnosed and treated in our institution. Methods: In this retrospective analysis we included 104 MPM patients diagnosed at Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, Croatia. Results: Between years 1999 and 2012, 104 patients were diagnosed with MPM (91 males, 13 females, mean age at diagnosis was 62). Epitehelial type was present in 74 patients (71%), sarcomatoid in 5 patients (4,8%), mixed type in 1 patient (1%), and in 21 (20%) the subype could not be determend. The disase was stage as IV in 70 patients (67%), stage III in 27 patients (26%), and as stage II in 4 patients (3%). The most frequent metastatic sites were mediastinum, thoracic wall, diaphragm and lungs. Out of 104 patients only 15 patients (14%) were surgically treated. Surgical procedures included decortication and pleurectomy. No extra-pulmonary pleurectomy was performed. In 36 patients (35%) onyl best supportive care Keywords: malignant pleural mesothelioma, overall survival, chemotherapy PP01.41: MESOTHELIOMA INCIDENCE IN LOMBARDY, ITALY: TIME PATTERNS AND FUTURE PROJECTIONS Dario Consonni1, Sara De Matteis2, Barbara Dallari1, Luciano Riboldi1, Pier Alberto Bertazzi1, Carolina Mensi1 Department of Preventive Medicine, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, ITALY, 2National Heart & Lung Institute, Occupational & Environmental Medicine, Imperial College London, London, UNITED KINGDOM 1 Objectives: Measuring malignant mesothelioma (MM) or pleural cancer incidence/mortality is a useful means to monitor asbestos-related diseases occurrence and to identify sources of asbestos exposure. Using data of the MM registry of the Lombardy Region, North-West Italy, the most populated and industrialised Italian region, we analysed asbestos exposure and time patterns in the period 2000-2012 and made future projections for the period 2013-2029. Methods: We selected all incident cases of MM with first diagnosis between 2000 and 2012. We examined time trends using standardised rates and Poisson regression. We fitted categorical Poisson age-cohort models using 5-year categories for age at diagnosis (reference: 70-74 years) and birth cohort (reference: cohort 1920-1924). The gender-specific age and cohort regression coefficients were then applied to population data to calculate projections of the numbers of MM cases and their 90% confidence intervals (CI) in the years 2013 to 2029. Data management and statistical analyses were performed with Stata 13. Results: In 2000-2012 we recorded 4,435 MM cases, 2,846 in men and 1,589 in women. Occupational asbestos exposure was more frequent in men (73.6%) than in women (38.2%). The average number of MM cases per year was still increasing (+2.6% in men, +3.3% in women). A maximum of 416 MM cases (266 men, 150 women) is expected in 2019. We forecast there will be iMig2016.ORG 97 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP 6,809 more cases (4,379 in men, 2,430 in women) in the period 2013-2029, for a total of 11,244 MM cases (7,225 in men, 4,019 in women) in 30 years. Conclusion: This study documented a high MM burden in both genders in the Lombardy Region, reflecting extensive occupational (mainly in men) and non-occupational (mainly in women) asbestos exposure in the past. Incidence rates are still increasing and a downturn of MM occurrence is expected to occur after 2019. Documenting mesothelioma occurrence may help to increase awareness of dangers of asbestos exposure in countries that still use it but where its health effects are still overlooked. Keywords: mesothelioma projections, mesothelioma incidence, asbestos, mesothelioma registry patients are recommended. Keywords: mesothelioma, young, clinicopathological,PFS PP01.43: INCREASING AGE AT DIAGNOSIS IN THE AUSTRALIAN MALIGNANT PLEURAL MESOTHELIOMA POPULATION: WHAT ARE THE POTENTIAL IMPLICATIONS? Matthew J. Soeberg1, James Leigh1, Tim Driscoll2, Bruce Armstrong2, Jane Young2, Nico Van Zandwijk1 Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA, 2Sydney School of Public Health, The University of Sydney, Sydney, NSW, AUSTRALIA 1 PP01.42: CLINICO PATHOLOGICAL CHARACTERISTICS OF YOUNG EGYPTIAN MALIGNANT PLEURAL MESOTHELIOMA PATIENTS Fatma M.A. Aou El-Kasem1, Abdel-Rahman M. Abdel-Rahman2, Mohamed Rahoma2 Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2Surgical Oncology, National Cancer Institute, Cairo, EGYPT 1 Objectives: A cancer registry was analyzed to determine if the clinicopathologic characteristics, treatment modalities, and prognosis of malignant pleural mesothelioma (MPM) patients < 45 years of age at diagnosis differ. Tables ,pictures, images are not applicable Methods: There were 114 cases of MPM diagnosed during this period 2007 and 2012. Among them, 58 patients were < 45 years old . These patients were selected for our study. Data regarding demographics, presentation symptoms, histology, tumor staging, treatment modality, and survival were obtained from all patients. Pearson’s chi(2) test and the Kaplan-Meier method with a log-rank test were used for statistical analysis Results: We found that weight , T4 and neutrophil lymphocytes ratio significantly affecting PFS of MPM patients younger than 45 years. Median PFS= 8 months. Median OS=16 months. Our patients’ age ranged from 19 to 45 years. PS was 0/ 1 in 43 cases. Thirty two cases were males. Six cases had Asbestosis. Nineteen cases were smokers. Dyspnea was symptom in 53 cases. Fourty-nine cases were complaining of chest pain ,Fourty-one were complaining of fatigue, anorexia was present in 21 cases, fifty one cases had effusion, Pleural thickening was documented in 57 cases, Twenty-four cases had mediastinal lymph nodes. Three cases had pulmonary metastasis, T1,2,3 represented in 50 cases. Fifty-two cases received platinum containing chemotherapy out of them 17 cases were responders. Thirty-seven cases were epithelioid mesothelioma, thirty-two cases were grade 2&3 of differentiation Objectives: Australia is known to have had one of the highest per-capita asbestos consumption rates, yet there are few contemporary reports on malignant mesothelioma trends. Methods: Data on 10,930 people with malignant pleural mesothelioma and 640 people with malignant peritoneal mesothelioma diagnosed in Australia during 1982-2009 were analysed. Observed incidence rate trends were quantified. Using age-period-cohort analyses, age-specific incidence rates were projected up to 2030 using observed incident cases during 1982-2012. Results: During 1982-2009, acceleration in malignant pleural mesothelioma age-standardised incidence rates were highest for women and those aged 75 years and above, with average annual percentage changes of +4.9 (95% CI 3.6, 6.2) and +7.2 (95% CI 5.4, 9.0) respectively. Age-standardised incidence rates for men with malignant pleural mesothelioma aged 0-64 years decelerated rapidly during 2003-2009, an average annual percentage change of -5.1% (95% CI -7.6, -2.5). Overall, male age-specific malignant pleural mesothelioma incidence rates in the 65-74 year age group during 2010-2030 are projected to decline with rates projected to increase for older men and women with malignant pleural mesothelioma. Conclusion: In Australia, there is a marked increase over time in people aged 75 years or more diagnosed with malignant pleural mesothelioma. In this presentation, we explore Australian and international data on malignant pleural mesothelioma case-series to investigate the potential treatment implications of this shift over time in malignant pleural mesothelioma age group distributions. Keywords: Australia; malignant pleural mesothelioma; incidence; trends Conclusion: Weight , T4 and neutrophil lymphocytes ratio significantly affecting PFS of MPM patients younger than 45 years.early diagnosis and agreesive treatment for young MPM iMig2016.ORG 98 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.44: STUDY ON THE EVOLUTION OVER TIME OF THE RISK OF MESOTHELIOMA AND LUNG CANCER AMONG FORMER ASBESTOS-EXPOSED WORKERS Corrado Magnani1, Laura Ancona2, Antonio Baldassarre3 , Vittoria Bressan4 , Tiziana Cena1, Elisabetta Chellini5, Francesco Cuccaro6 , Daniela Ferrante1, Patrizia Legittimo7, Ferdinando Luberto8 , Alessandro Marinaccio9, Stefano Mattioli7, Simona Menegozzo10, Enzo Merler4 , Lucia Miligi5, Dario Mirabelli11, Marina Musti3 , Enrico Oddone12, Venere Pavone13 , Patrizia Perticaroli14 , Aldo Pettinari14 , Roberta Pirastu15, Alessandra Ranucci1, Elisa Romeo2, Orietta Sala16 , Corrado Scarnato13 , Stefano Silvestri17 Dep. Translational Medicine, University Eastern Medicine, Novara, ITALY, 2Department of Epidemiology, Lazio Regional Health Service, Rome, ITALY, 3Interdisciplinary Department of Medicine, Occupational Medicine “B. Ramazzini”, University of Bari, Bari, ITALY, 4Mesothelioma Register of the Veneto Region, Padua Local Health Unit, Padova, ITALY, 5Occupational & Environmental Epidemiology Unit-Cancer Research & Prevention Institute (ISPO), Florence, ITALY, 6Azienda Sanitaria Locale BAT (Barletta, Andria, Trani), Unità Operativa Epidemiologia e Statistica, Barletta, ITALY,7Department Medical and Surgical Sciences, University of Bologna, and Unit of Occupational Medicine, S.Orsola-Malpighi University Hospital, Bologna, ITALY, 8Inter-institutional Epidemiology Unit, AUSL Reggio Emilia and Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia, ITALY, 9Italian Workers’ Compensation Authority (INAIL), Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Unit of Occupational and Environmental Epidemiology, Italian Mesothelioma Register, Rome, ITALY, 10National Cancer Institute IRCCS Fondazione Pascale, Napoli, ITALY, 11Unit of Cancer Epidemiology, CPO Piemonte and University of Turin, Torino, ITALY, 12Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, ITALY, 13Epidemiology Unit, Local Health Authority, Bologna, ITALY, 14Prevention Department, ASUR Marche, Senigallia, ITALY, 15Department of Biology and Biotechnologies Charles Darwin, Sapienza Rome University, Rome, ITALY, 16A.R.P.A. Emilia Romagna, Sezione Provinciale di Reggio Emilia, Reggio Emilia, ITALY, 17Cancer Prevention and Research Institute (ISPO), Firenze, ITALY 1 Objectives: According to the IARC, asbestos is carcinogenic to humans, and exposure to asbestos results in mesothelioma, lung cancer, ovarian and laryngeal cancer with sufficient evidence. It may also lead to gastric, colorectal or pharyngeal cancer with more limited evidence. The possible reduction in risk after cessation of exposure and after time since first exposure more than 40 years is still matter of debate. The cessation of the use of asbestos in Italy in 1992 has lead to a situation similar to a natural experiment that measures large-scale trends in the risk of disease among former asbestos-exposed workers. Methods: The study included a pool of Italian cohorts of asbestos exposed employed in plants located in different Italian regions that have already been the subject of epidemiological study. The follow up was updated up to 2010 or later. The main production sectors are: asbestos cement, construction and maintenance of rolling stock, shipbuilding. We computed SMRs for the major causes of death. The number of deaths expected in the cohort was estimated from age and sex-specific mortality rates of the participating Italian regions, provided by ISTAT (Rome, Italy) for the period 1970-2012. The incidence of mesothelioma will be detected using a record linkage to the National Mesothelioma Registry (ReNaM). A pooled analysis is performed in order to obtain information on the variation in the risk of malignant mesothelioma and the risk of death from other malignancies. In order to obtain a quantitative estimation of the exposure level to asbestos of the subjects of the cohorts, an index that takes into account the fraction of exposed to asbestos, direct or indirect use of asbestos and exposure level was computed. Information about these aspects has been provided for each cohort. Results: Pooled cohorts study includes 54,409 subjects, of which 14,743 have worked in the production of cement - asbestos. The dataset includes 48,355 men and 6,054 women. At the end of follow-up, 55.3% of the subjects were alive, 43.0% had died, and 1.7% were lost to follow-up or had moved abroad. The cause of death was known for the 94% of deceased subjects. Considering the follow up period after 1970, the cohorts contributed altogether about 1,430,000 person-years for men and 184,000 for women. Both genders showed increased mortality for all causes (p<0.001), all malignancies (p<0.01), pleural and peritoneal malignancies (both p<0.01) and lung cancer (p<0.01). In women, ovarian malignancies were more frequent than expected (p<0.05). No statistically significant increase was found for laryngeal cancer. Conclusion: In addition to the main objective of assessment of risk over time, it is expected that the study will allow further results, such as assessing the risk for those malignancies still under discussion and studying the risk for women. The working group: M.N.Ballarin4 , F.Barone-Adesi18 , C. Brentisci11, B.Cortini5, S.Curti7, M.Gangemi11, P.Girardi4 , F.Gioffrè4 , G.Gorini5, L.Mangone8 , F.Marinelli7, P.Marinilli13 , C.Panato4 , F.Roncaglia8 , C.Storchi8 , A.Stura11, S.Tunesi1, M.Vicentini8 , S.Verdi5, A.M. Nannavecchia19, L.Bisceglia20 1-17 as Authors’ affiliations 18Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy 19IRCCS Giovanni XXIII Oncologico Bari, Puglia, Italy 20 Agenzia Regionale Sanità Puglia, Bari, Italy Keywords: asbestos, mesothelioma, latency PP01.46: MORTALITY/HOSPITALIZATION FROM PLEURAL MESOTHELIOMA ASSOCIATED WITH ENVIRONMENTAL EXPOSURE TO FLUOROEDENITE IN BIANCAVILLA Susanna Conti1, Valerio Manno1, Giada Minelli1, Caterina Bruno2, Lucia Fazzo3 , Pietro Comba3 Unit Of Statistics, Istituto Superiore di Sanità, Rome, ITALY, 2Environment And Prevention, Istituto Superiore di Sanità, Roma, ITALY, 3Environment And Prevention Department, Istituto Superiore di Sanità, Roma, ITALY 1 Objectives: Fluoro edenite, a fibrous amphibole present in the sole and building materials of Biancavilla, a small town in Sicily (ITALY) was allocated in 2014 by the International Agency for Research on Cancer (IARC) to the Group 1 (“the agent is carcinogenic to humans”) as cause of mesothelioma. This evaluation was based on epidemiological studies coordinated by iMig2016.ORG 99 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Istituto Superiore di Sanità. The aim of our research is to study mortality and hospitalization from mesothelioma among residents in Biancavilla, using current data at the best of updating in Italy, available at the Unit of Statistics of Istituto Superiore di Sanità. Methods: The most recent national official mortality and hospitalization data (2006-2012) were analyzed. Mortality data are codified according to the International Classification of Disease (ICD), 10th Revision, which, introducing the morphology of malignant neoplasms, has specific codes for Pleural and Peritoneal Mesothelioma. Hospitalization data are yet codified according to the ICD Clinical Manifestation 9th Revision, which has only a topographic classification of neoplasms, therefore, hospitalizations due to malignant neoplasm of pleura/peritoneum were investigated. Standardized Mortality Ratio (SMR), Standardized Hospitalization Ratio (SHR) and their 90%Confidence Intervals (CI) were estimated by gender and age, being the population of Sicily the reference. To control confounding from social and economic factors, the SMRs and SHRs were adjusted by a deprivation index. Results: Among residents in Biancavilla there was a statistically significant death excess from Pleural Mesothelioma: SMR 632 (CI 409-978), based on 14 deaths during the study period, both among men and women. When SMR estimates were stratified by age, very high figures were shown in the younger age groups: SMR 1741, CI 576-5262 in subjects less than 50 years old and SMR 3229, CI 720-14474 in subjects less than 40 years old. The sex ratio (M/W) of deaths from pleural mesothelioma was 0.75 overall, 0.50 among younger subjects. Also hospitalizations due to malignant pleural cancer (18 cases) showed excesses, overall (SHR 399, CI 271-587) and in particular among younger persons (aged less than 50 years): SHR 1078, CI: 484-2400; the sex ratio was 1.25. Neither deaths nor hospitalizations from peritoneal mesothelioma were observed. Conclusion: The observed sex ratio (close/less than one) corroborates the hypothesis of an environmental exposure, rather than occupational; moreover, this may also reflect a high level of fiber exposure for women, who are often engaged in activities such as sweeping of floors, balconies and sidewalks located in front of the houses. The latency period of Pleural Mesothelioma caused by exposure to fluoro-edenitic fibres has not yet been studied, but if it were similar to the latency of Pleural Mesothelioma due to asbestos (20 - 40 years) the higher excesses of deaths and hospitalizations that we observed among young subjects would suggest early exposure, in teenage/childhood years. Major clean-up interventions were performed in Biancavilla after its recognition as a National Priority Contaminated site (2002) but our results suggest that particular attention should be paid on community needs in term of early diagnostic procedure and medical care, for both genders. PP01.47: SURVIVAL AND EXPECTED YEARS OF LIFE LOST OF MALIGNANT MESOTHELIOMA: ANALYSIS OF 105 CASES IN TAIWAN, 1977-2015 Lukas J. Lee1, Ting-Hui Wu2, Yu-Yin Chang1, Jung-Der Wang3 National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan Town, TAIWAN, 2Department of Oncology, National Taiwan University Hospital, Taipei, TAIWAN, 3Department of Public Health, College Of Medicine, National Cheng Kung University, Tainan, Taiwan, College of Medicine, National Cheng Kung University, Tainan, TAIWAN 1 Objectives: Malignant mesothelioma (MM) is a rare cancer with limited information on survival. We investigated clinical factors associated with survival and estimated life years lost based on a patient series in Taiwan. Methods: We retrospectively reviewed medical records of patients diagnosed with MM at the National Taiwan University Hospital from 1977 to August 2015, with follow-up of vital status through 31 October 2015. Assuming a constant excess hazard, we extrapolated lifetime survival function by a semi-parametric method. For each MM patient, we simulated age- and gender-matched referents based on the vital statistics of Taiwan to estimate expected years of life lost (EYLL) as an indicator of health gap. For recognizing prognostic factors associated with pleural MM, we performed univariate analyses using Kaplan–Meier survival functions with log-rank tests. Then multivariate Cox regression models were performed to identify significant risk predictors. Results: A total of 105 cases of MM were included. The mean age at diagnosis was 56.7±14.0 years. The EYLL due to MM was 20.2 years. There were 82 pleural MM, 17 peritoneal MM, 4 diffuse MM, and 2 testicular MM. The overall median survival for pleural MM was 14.8 months. Cox regression models revealed that age less than 65 years, clinical stages I~II, ECOG (Eastern Cooperative Oncology Group) performance status 0-1, and surgical operation were associated with longer survival. Conclusion: Substantial life years lost resulted from MM was found. Age less than 65, early stages, good performance status, and surgical operation were independent prognostic factors of pleural MM. Keywords: prognostic factor, Malignant mesothelioma, expected years of life lost Keywords: Fluoro-edenite, mortality/hospitalization, early exposure, pleural mesothelioma iMig2016.ORG 100 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.50: INVESTIGATING PALYGORSKITE’S ROLE IN THE DEVELOPMENT OF MESOTHELIOMA IN SOUTHERN NEVADA David Larson1, Amy Powers1, Jean-Paul Ambrosi2, Mika Tanji1, Andrea Napolitano1, Erin Flores1, Francine Baumann1, Laura Pellegrini1, Cormac Jennings1, Brenda Buck3 , Brett Mclaurin4 , Doug Merkler5, Cleo Robinson6 , Paul Morris1, Meral Dogan7, A. Umran Dogan7, Harvey I. Pass8 , Sandra Pastorino1, Michele Carbone1, Haining Yang1 University of Hawaii Cancer Center, Honolulu, HI, UNITED STATES OF AMERICA, 2Aix-Marseille Université, Provence, FRANCE, 3University of Nevada Las Vegas, Las Vegas, NV, UNITED STATES OF AMERICA, 4Bloomsburg University of Pennsylvania, Bloomsburg, AL, UNITED STATES OF AMERICA, 5USDA, Natural Resources Conservation Service, Las Vegas, NV, UNITED STATES OF AMERICA, 6University of Western Australia, Harry Perkins Institute for Medical Research, Nedlands, Perth, ACT, AUSTRALIA, 7University of Iowa, Iowa City, IA, UNITED STATES OF AMERICA, 8New York Langone Medical Center, New York, NY, UNITED STATES OF AMERICA 1 Objectives: Similar to asbestos fibers, non-regulated mineral fibers can cause malignant mesothelioma (MM). Recently, increased proportions of women and young individuals with MM were identified in southern Nevada, suggesting that environmental exposure to carcinogenic fibers was causing the development of MM. Palygorskite, a fibrous silicate mineral with a history of possible carcinogenicity, is abundant in southern Nevada. In this study, our aim was to determine whether palygorskite was contributing to the development of MM in southern Nevada. PP01.51: MESOTHELIOMA MORTALITY IN POLAND BETWEEN 1999 AND 2013 Gabriela Oledzka1, Ewa Wilk2, Agnieszka Skubiszewska1, Anna Minkiewicz1, Małgorzata Krowczynska2 Department of Medical Biology, Medical University of Warsaw, Warsaw, POLAND, 2Department of Geoinformatics And Remote Sensing, University of Warsaw, Warsaw, POLAND 1 Objectives: Many Western countries are currently suffering from a malignant pleural mesothelioma (MM) the increasing number of cases. Poland belongs to countries with low incidence rates or insufficient data of morbidity and mortality. In Poland, after asbestos was banned in 1997, the problems caused by asbestos focused on monitoring the health of workers with prior exposure to this substance and those currently involved in the demolition of asbestos-containing buildings and in asbestos removal tasks. In Poland as in various countries of Central-Eastern Europe, the crude incidence of mesothelioma appeared to be lower than in Western countries. The aim of this study was to evaluate the variations of pleural MM incidence in Poland. Methods: This article is based on a selective review of the literature, along with data from the central database of the National Cancer Registry. The evolution of pleural mesothelioma between 1999 and 2013 was investigated using data collected in 16 voivodship. Results: Methods: We studied and compared the toxicity and carcinogenesis of palygorskite fibers vs. crocidolite asbestos using our established in vitro and in vivo systems. Results: While palygorskite, in vitro, displayed some cytotoxicity towards HM cells and reduced their viability, the effects were roughly half of those observed when using similar amounts of crocidolite asbestos. No Balb/c (0/19) or MexTAg (0/18) mice injected with palygorskite developed MM, while 3/16 Balb/c and 13/14 MexTAg mice injected with crocidolite did. Lack of MM development was associated with a decreased acute inflammatory response, as injection of palygorskite resulted in lower percentages of macrophages (p=0.03) and neutrophils (p=0.02) in the peritoneal cavity 3 days after exposure. Additionally, compared to mice injected with crocidolite, palygorskite-injected mice had lower percentages of M2 (tumor-promoting) macrophages (p=0.008) in their peritoneal cavities when exposed to fiber for several weeks. The evolution of the MM incidence rates in men and women between 1999 and 2013 in Poland are described in Fig 1. The incidence rate for 100.000 person-year in men was 0.18 in 1999 and was estimated to be 0.65 in 2013. The incidence rate for 100.000 person-year in women increased between 0.06 in 1999 and 0.23 in 2013. Conclusion: Our study indicates that palygorskite found in the environment in southern Nevada does not cause MM in mice, seemingly because palygorskite, in vivo, fails to elicit inflammation that is associated with MM development. Therefore, palygorskite is not a likely contributor to the MM cases observed in southern Nevada. Keywords: Palygorskite, environment, mesothelioma, Nevada Figure 2 presents age-adjusted incidence of pleural mesotheiMig2016.ORG 101 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP lioma for men and women in 2013. Very few MMs occurred before the age of 45 years, and, in both genders, MM steadily increased at each subsequent age, up to age 60. Conclusion: The incidence of mesothelioma has increased off since 2012. Our results suggest that in Poland the national incidence of mesothelioma is not expected to drop in the next few years. Acknowledgements: This study was supported by the Ministry of Economy, Programme for Asbestos Abatement in Poland 2009–2032. Keywords: asbestos; malignant pleural mesothelioma, incidence PP01.52: RELATIONSHIP BETWEEN HISTOLOGICAL TYPE AND PLEURAL EFFUSION IN MALIGNANT PLEURAL MESOTHELIOMA Taiichiro Otsuki, Koji Mikami, Takayuki Terada, Kozo Kuribayashi, Takashi Nakano Internal Medicine, Hyogo College of Medicine, Nishinomiya, JAPAN Objectives: Pleural effusion is important for the diagnosis and treatment of malignant pleural mesothelioma (MPM), but an analysis of the clinical pathology is not always performed. The cytology positive rate for pleural effusion in MPM is lower than that in lung cancer (approximately 25–30%). This study analyzed the relationship between histological type and pleural effusion for elucidating the clinical findings of the latter in MPM. Methods: This study is a retrospective analysis of 143 patients (115 males and 28 females) who received a pathological diagnosis of MPM in our hospital from 2011 to 2014. Parameters analyzed include the existence of pleural effusion upon the patient’s initial visit, histological type , and clinical staging. Results: Histological type was epithelioid in 106 cases, biphasic in 15, and sarcomatoid in 22. There were 14 cases with no pleural effusion (epithelioid in four cases, biphasic in two, and sarcomatoid in eight). These cases were trending to the progression stage (IMIG stageⅠ/Ⅱ/Ⅲ/Ⅳ =1/1/2/9). The cytology positive rate for effusion in the epithelioid-type MPM was higher than in the other types of MPM (epithelioid/biphasic/sarcomatoid=34%/8.0%/7.1%). Conclusion: It has been theorized that many mesothelioma cells in pleural effusion are cells peeling from the epithelioid type and the epithelioid type component in the biphasic type. Therefore, it is suggested that the cytology positive rate for effusion in epithelioid-type MPM is higher than in the other types. One of the reasons for having fewer cases with pleural effusion in sarcomatoid-type MPM may be the progression of staging at the first visit in the sarcomatoid-type. PP01.53: PATTERN OF MALIGNANT PLEURAL MESOTHELIOMA IN EGYPTIAN PATIENTS Fatma M.A. Aou El-Kasem1, Abdel-Rahman M. Abdel-Rahman2, Amr Demery2, Mohamed Rahoma3 , Rabab M. Gaafar1, Hala Aziz Shokralla1, Maha Yehia1, Hisham Wahba4 Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2Surgical Oncology, National Cancer Institute, Cairo, EGYPT, 3Surgical Oncology, National Cancer Institute, Cairo, EGYPT, 4Radiology, National Cancer Institute, Cairo, EGYPT 1 Objectives: A cancer registry was analyzed to determine the clinico-pathologic characteristics affecting 194 malignant pleural mesothelioma (MPM) patients referred to National Cancer Institute, Cairo University , Egypt from 2012 – 2015. Methods: Retrospective review of patients with MPM presented to National Cancer Institute, Cairo University, Egypt;diagnosed between 2012 till 2015. Data regarding demographics, histology, tumor staging and CT finding were obtained from all patients. Pearson’s chi(2) and Fisher’s Exact tests were used for statistical analysis. Results: There were 194 cases of MPM referred to our Institute during this period 2012 and 2015. We found that chest wall invasion and pericardial infilteration ( p= 0.005), Transdiaphragmatic.extension (p= 0.016), presence of metastasis (p= 0.011) and invasion of mediastinal structures (p=0.05) are significantly correlated. Also, sex difference was statistically correlated with pericardial infilteration ( p=0.026) and Transdiaphragmatic extension (p= 0.021). Our patients’ age ranged from 15 to 76 years. Median age was 53 years. Ninity-five (49%)cases were males. One hundred and nineteen (61.3%)cases were right sided. Pleural thickening was nodular in 131 (69.7%)cases, diffuse in 46 (23.7%) cases and mass in 11 (5.7%) cases. Inter-lobar fissure was thickened in 57 ( 29.4%) cases. Mediastinal Pleura was affected in 72 (37.1%%) cases. Eighty-seven (44.8%) cases had effusion. Ossification & calcification was detected in 8 ( 4.1%) cases. Contraction of hemithorax was identified in 77 (39.7%) cases. Chest wall invasion was in 18 ( 9.3%) cases. Pulmonary nodules were detected in 37 ( 19.1%). Metastases were detected in 9 ( 4.6%) cases. Conclusion: There is statistical significant correlation between Chest wall invasion and pericardial infilteration ( p= 0.005), Transdiaphragmatic.extension (p= 0.016), presence of metastasis (p= 0.011)and invasion of mediastinal structures (p=0.05). Also, sex difference was statistically correlated with pericardial infilteration ( p=0.026) and Transdiaphragmatic extension (p= 0.021). Early diagnosis and aggressive treatment for MPM patients with chest wall invasion are recommended because of high incidence for metstasis. Keywords: positive rate, Pleural effusion, Malignant pleural mesothelioma, histological type iMig2016.ORG 102 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP The number of deaths from mesothelioma in the years 20002012 among men was three times lower than in Italy, twice less than in Germany and Sweden. PP01.54: ASBESTOS CONSUMPTION AND PLEURAL MESOTHELIOMA MORTALITY IN POLAND IN COMPARISON WITH OTHER EUROPEAN COUNTRIES Conclusion: Conclusion The estimated peak of mesothelioma cases appeared to be delayed in Poland in comparison with that observed in the United Kingdom, likely due to the peculiar Poland asbestos consumption curve. Acknowledgements: This study was supported by the Ministry of Economy, Programme for Asbestos Abatement in Poland 2009–2032. Małgorzata Krowczynska1, Ewa Wilk1, Agnieszka Skubiszewska2, Anna Minkiewicz2, Gabriela Oledzka2 Department of Geoinformatics And Remote Sensing, University of Warsaw, Warsaw, POLAND, 2Department of Medical Biology, Medical University of Warsaw, Warsaw, POLAND 1 Keywords: asbestos consumption, malignant pleural mesothelioma, Objectives: Malignant pleural mesothelioma (MM) is an disease which is almost exclusively due to inhalation of asbestos fibers. The protracted latent period of MM means that its incidence has continued to rise across Europe after the introduction of restrictions on asbestos use. Generally, the mortality curve for asbestos-related cancers follows the asbestos consumption curve with a lag of about 50 years. The incidence of mesothelioma has increased off since 2012 and steadily increasing in Poland. Like in most other industrial countries asbestos consumption increased in the twentieth century in Poland. There are no asbestos deposits suitable for industrial exploitation in Poland therefore manufacture of asbestos products in the years 1960 to 1997 was based on raw asbestos imported mainly from the Russia and Africa. The decade 1970s was the period of peak production of asbestos products, with an annual consumption of about 100 thousand tons of raw asbestos. We expecting at in Poland, the mortality peak of will be reached only around 2020. The objectives of the present study were: (i) compare of asbestos consumption in selected European countries (ii) compare of the incidence of malignant pleural mesothelioma (MM) in selected countries among men and women in the years 2000 to 2012. PP01.56: BLOOD DNA METHYLATION CHANGES IN MALIGNANT PLEURAL MESOTHELIOMA Elisabetta Casalone1, Simonetta Guarrera1, Marta Betti2, Daniela Ferrante3 , Cornelia Di Gaetano1, Clara Viberti1, Alessandra Biasi2, Sara Tunesi3 , Caterina Casadio4 , Francesco Ardissone5, Enrico Ruffini6 , Roberta Libener7, Roberto Guaschino8 , Ezio Piccolini9, Dario Mirabelli10, Corrado Magnani11, Irma Dianzani12, Giuseppe Matullo1 Department of Medical Sciences, Human Genetics Foundation and University of Turin, Torino, ITALY, 2Department of Health Sciences, University of Piemonte Orientale, Novara, ITALY, 3Department Translational Medicine, CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Novara, ITALY, 4Thoracic Surgery Unit, Azienda Ospedaliero-Universitaria‘‘Maggiore della Carità’’,University of Piemonte Orientale, Novara, ITALY, 5Department of Clinical And Biological Sciences, Chest Surgery, University of Turin, Orbassano, ITALY, 6Department of Oncology, University of Turin, Torino, ITALY, 7Pathology Unit, SS.Antonio e Biagio General Hospital, Alessandria, ITALY, 8Transfusion Centre, Azienda Ospedaliera Nazionale SS, Antonio e Biagio e Cesare Arrigo, Alessandria, ITALY, 9Santo Spirito, Hospital, Casale Monferrato, ITALY, 10Unit of Cancer Epidemiology, CPO-Piemonte and University of Turin and Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Torino, ITALY, 11Department Translational Medicine, CPO-Piemonte and Unit of Medical Statistics and Epidemiology and Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Novara, Torino, ITALY, 12Department of Health Sciences, University of Piemonte Orientale; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Novara, ITALY 1 Methods: This article is based on a selective review of the literature, along with data from the central database of the WHO - Cancer Mortality Database. Results: Objectives: The DNA-methylation status of various tissues has been shown to be modulated by environmental exposures and lifestyle. Epigenetic alterations have been also reported in target MPM tissues suggesting an important role in the carcinogenic process. Evaluating whole blood DNA methylation as a risk/diagnostic marker for cancer is of particular interest because whole blood DNA analysis is a noninvasive test and could both reflects some common epigenetic changes in relation to specific exposure and/or underlying specific immunological response. We aimed to assess whether epigenome-wide DNA methylation measured in white cells from whole blood samples was associated with increased risk of MPM. iMig2016.ORG 103 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Methods: We used the Illumina Human Methylation450 array to measure methylation status in whole blood from a population-based case-control study sampled in four Northern Italian towns: Casale Monferrato, Torino, Alessandria and Novara. The analysis was performed on 183 cases and 194 controls for which the level of asbestos exposure was assessed. Results: The sample population was randomly split into two groups: training and test set. In the training set three differentially methylated regions (DMRs) between cases and controls were found (FDR adjusted p< 0.01), adjusting for gender, age, asbestos exposure, and white blood cells percentage. We also detected a global hypomethylation in cases respect to controls (p = 0.007). We validated the DMRs prediction performance in the test set using a Recursively Partionated Mixture Model (RPMM) which clustered the samples in four classes on the basis of the methylation profile of the three DMRs in the training data. We assessed the increase in the performance of the methylation classifier by comparing receiver operating characteristic (ROC) curves and the area under the curve (AUC) of two nested models. The first included age, sex, centre and exposure as predictors; the second included also global and RPMM methylation classes. The AUC was 0.75 (95% CI: 0.69-0.83) for the first model and 0.78 (95% CI: 0.71-0.85) for the second, suggesting a slight increase in the prediction performance given by the use of DNA-methylation profiles. Conclusion: Further statistical analyses are ongoing in order to identify MPM methylation patterns taking into account possible interaction between loci and asbestos exposure. We suggest that epigenome-wide hypomethylation, and specific genomic region methylation profiles of DNA detected in whole blood MPM samples may be useful to further improve MPM risk estimation, in addition to traditional assessment of asbestos exposure. Keywords: asbestos, methylation changes, exposure PP01.57: MALIGNANT PLEURAL MESOTHELIOMA IN AFRICA tonnages. South Africa mined all three types of commercially viable asbestos, viz. chrysotile, amosite and crocidolite, while the other two countries mined only chrysotile. South Africa was the global leader in the production of crocidolite asbestos, the fibre most strongly linked with the development of mesothelioma - it was in this country that the link was first established and reported in 1960. South Africa was also the only commercial producer of amosite, the fibre closely implicated in the current British mesothelioma epidemic. Asbestos has been used in Africa for at least the past 5000 years (the ancient Egyptians used it in mummification) but, before the 20th century, its use was small scale. The 1920s onwards showed massive increases in its use, especially in North Africa, Nigeria and Southern Africa, but virtually every country south of the equator used asbestos in measurable tonnages. The largest consumers were (in decreasing order) Nigeria, Algeria, Egypt, Morocco, Zambia, Ghana and Tunisia, apart from the producer-countries. African consumption of asbestos exceeded 20,000 metric tonnes annually between 1960 and 2000. Asbestos is currently banned in Algeria, Egypt, Gabon, Mozambique and South Africa. Apart from South Africa, there are few quality epidemiological studies on mesothelioma in Africa. A common theme is under-ascertainment, especially among blacks. Mesothelioma rates have been increasing, but may be levelling. A recent analysis of mesothelioma deaths from the WHO mortality database (1994 – 2008) showed that, out of the 83 countries with data, Africans died the youngest, and South Africa was in the top 10 for cumulative mesothelioma deaths. It has been reported that South Africa has the highest rate of mesothelioma in those <50 years. For environmental mesotheliomas, both Egypt and South Africa have higher rates in women and children. Conclusion: On the African continent, population-based mesothelioma rates are available for only South Africa. These rates, despite being amongst the highest in the world, are likely to be underestimates of the true burden of disease. Explanations for this include under-reporting of cases, missed and misdiagnosis of mesothelioma, competing causes of death, and reduced longevity related partly to the HIV/AIDS epidemic. The longevity of South Africans is lower than that in other mesothelioma-reporting countries, so a smaller percentage of those exposed survive to ages where mesothelioma might develop. Scientific efforts in other African countries need to be encouraged. Keywords: South Africa, Egypt, asbestos, epidemiology Gill Nelson1, Jim Tewaternaude2 School of Public Health, University of Witwaterrand, Johannesburg, SOUTH AFRICA, 2School of Public Health, University of Cape Town, Cape Town, SOUTH AFRICA 1 Objectives: Many African countries have used asbestos after the 1920s and hence, millions of people have been exposed to it. We set out to describe the epidemiology of malignant mesothelioma in Africa. PP01.59: MALIGNANT PLEURAL MESOTHELIOMA LONG TERM SURVIVORS: A POPULATION BASED STUDY (LUME STUDY) Methods: We searched the published and grey medical literature, and consulted experts. Laura Botta1, Annalisa Trama1, Diego Signorelli2, Claudia Proto2, Marina Chiara Garassino2, Roberto Foschi1, Riccardo Capocaccia2, Sandra Mallone3 , Roberta De Angelis3 , Valerio Gennaro4 , Lucia Benfatto4 , Cecilia Francesca Lando4 , Barbara Dallari5, Dario Consonni5, Carolina Mensi5, Enzo Merler6 , Vittoria Bressan6 , Manuela Gangemi7, Carol Brentisci7, Dario Mirabelli7, Antonella Stura7, Antonio Romanelli8 , Cinzia Storchi8 , Elisabetta Chellini9, Francesca Battistini9, Adele Caldarella10, Results: Although nine countries were listed as producers, the only producers of significant amounts were South Africa, Zimbabwe and Swaziland who, together, accounted for 99.8% of asbestos production on the continent. The three countries mined, respectively, 47%, 43% and 9% of the continent’s iMig2016.ORG 104 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Cristiana Pascucci11, Mario Cocchioni11, Fabrizio Stracci12, Maria Saba Petrucci12, Valeria Ascoli13 , Italo Angelillo14 , Daniela Feola14 , Rosario Tumino15, Graziella Frasca16 , Maria Concetta Giurdanella16 , Giovanna Tagliabue17, Paolo Contiero2, Gemma Gola18 , Mariangela Corti18 , Francesca Bella19, Anna Clara Fanetti20, Salvatore Sciacca19, Antonio Ziino19, Rosanna Cusimano21, Rosalba Amodio22, Roberto Piro23 , Pina Candela24 , Tiziana Scuderi24 , Claudia Cirilli25, Lucia Mangone25, Massimo Vicentini25, Marcello Tiseo26 , Maria Michiara27, Anita Rimanti27, Anna Maria De Giorgi26 , Paolo Sgargi27, Fabio Falcini28 , Orietta Giuliani28 , Rosa Vattiato28 , Francesco Forastiere29, Elisa Romeo29, Mario Fusco30, Maria Francesca Vitale30, Silvano Piffer31, Roberto Vito Rizzello31, Gemma Gatta1 Preventive And Predictive Medicine, Evaluative Epidemiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY, 2Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY, 3Istituto Superiore di Sanità, Rome, ITALY, 4IRCCS, San Martino, IST-Cancer Inst., Genoa, Italy; Registro Mesoteliomi, Liguria, Genoa, ITALY, 5Registro Mesoteliomi della Lombardia, Milan, ITALY, 6Registro Regionale Veneto dei casi di mesotelioma, Padua, ITALY, 7Registro dei Mesoteliomi del Piemonte, Turin, ITALY, 8Registro Mesoteliomi dell’Emilia Romagna, Reggio Emilia, ITALY,9Centro Operativo Regionale Mesoteliomi della Toscana, Florence, ITALY, 10Registro Tumori della regione Toscana, Florence, ITALY, 11Registro Mesoteliomi delle Marche, Camerino, ITALY, 12Registro Mesoteliomi dell’Umbria, Perugia, ITALY, 13Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, ITALY, 14Registro Mesoteliomi della Campania, Naples, ITALY, 15Centro Operativo Regionale della Sicilia, Ragusa, ITALY, 16Registro Tumori, ASP, Ragusa, ITALY, 17Fondazione IRCCS Istituto Nazionale dei Tumori, Registro Tumori di Varese, Milan, ITALY, 18Cancer registry, Province of Como, Como, ITALY, 19Integrated Cancer Registry of Catania-Messina-Siracusa-Enna, Catania, ITALY, 20 Cancer registry, Province of Sondrio, Sondrio, ITALY, 21Cancer Registry of Palermo and province; Azienda Provinciale di Palermo, Palermo, ITALY, 22Cancer Registry of Palermo and province, Palermo, ITALY, 23U.O. Pneumology ASMN IRCCS, Reggio Emilia, ITALY, 24Cancer Registry, Province of Trapani, Trapani, ITALY, 25Epidemiology Unit, Azienda Unità Sanitaria Locale, Reggio Emilia; Arcispedale Santa Maria Nuova- IRCCS, Reggio Emilia, ITALY, 26Oncologia Medica, Azienda Ospedaliero- Universitaria di Parma, Parma, ITALY, 27Cancer Registry of Parma, Parma, ITALY, 28Cancer Registry of Romagna, Meldola, ITALY, 29Department of Epidemiology, Lazio Regional Health Service, Rome, ITALY, 30Cancer Registry, Campania, c/o ASL Napoli 3 Sud, Naples, ITALY, 31Cancer Registry of Trento, Trento, ITALY 1 Objectives: Malignant pleural mesothelioma (MPM) is a rare tumour with very poor prognosis, 50% of them dying within 9 months from diagnosis and survival time trends did not show improvements over the last decades. However, the RARECARE project observed long term survivors (LS=patients alive >3 years after diagnosis) suggesting the presence of milder phenotypes with a different prognosis and inspiring a dedicated population-based observational study: long-term survivors in pleural mesothelioma (LUME). Methods: We collected from 26 Italian cancer registries all the MPM newly diagnosed cases in the period 2003-2008 with cito-histological confirmation and with complete follow-up. In order to reproduce a correct representation of the Italian situation we selected all the LS of the 26 registries and randomly sampled short survivors in each registry. The selected population data included 2,475 MPM cases retrospectively collected. To compare the differences detected in each variables distribution between LS and short survival patients we use a χ2 test. The Cox model assessed the prognostic value of selected variables. Based on the results of each univariate model we selected the variables included in the multivariate model. Results: In our population the proportion of LS was 11%. The χ2 test defined that the LS had an higher proportion of young, female and epithelioid cases compare to short survivors. 55% of the LS had localized stage vs 44% of the short survivors, even if the proportion of missing stage is similar. Furthermore, bimodal/multimodal treatment was more frequent among LS (27% vs 11%). Interesting, 17% of LS (mean age 72) did not received any treatment, suggesting the identification of an indolent subgroup of cases. The Cox model showed age, sex, histotype, cTNM, treatment as significant prognostic variables (see the table below). Multivariate model Variables HR p-value Gender Male 1 Female 0.86 0.001 0-54 0.74 <0.001 55-64 0.93 0.173 65-74 1 75+ 1.29 <0.001 Mesothelioma NOS 1.09 <0.001 Sarcomatoid mesothelioma 1.35 <0.001 Epithelioid mesothelioma 1 Biphasic mesothelioma 1.78 Age class MPM histotype <0.001 Clinical TNM T1/T2, N0/N1 and M0 1 T3, N0/N1 and M0 or T1/T2, 1.18 N2 and M0 0.007 T4 or M1 or N3 1.53 <0.001 Missing 1.15 0.038 Bimodal/multimodal 0.70 <0.001 Chemotherapy only 1 Surgery only 0.89 0.215 None/best supportive care 1.49 <0.001 Missing 1.12 0.275 Treatment Diagnostic imaging Only RX 1 Imaging (PET, TAC or RMN) 0.98 0.838 Conclusion: Our large population study confirms the results of many clinical studies. Comparing with other population-based studies we collected more detailed clinical variables on stage, diagnostic procedures and treatment. Gender, age, histotype, iMig2016.ORG 105 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP type of treatment and stage were associated with prognosis. Further statistical analysis are ongoing, including hospital of diagnosis/treatment, immunohistochemistry and specific chemotherapy treatment. We also confirm the presence of MPM long-term survivors (11%). The identification of their biological features, which is one of the objectives of the LUME project, may help clinicians in the definition of treatment. in Southern Brazil are affected by inaccuracy and miscoding regarding cancer site and histology. Moreover, medical records are a poor source of information of industry and occupation. This preliminary information support the need of a mesothelioma registry in Southern Brazil, and probably also in other parts of the country. Keywords: Brazil, cancer registry, mesothelioma incidence Keywords: Population based study, Long term survivors, epidemiology, Prognostic factors PP01.60: EPIDEMIOLOGY OF MESOTHELIOMA IN SOUTHERN BRAZIL: A REALITY STILL TO BE STUDIED PP01.61: MALIGNANT PLEURAL MESOTHELIOMA IN YOUNG PEOPLE Ahmed El Bastawisy1, Maha Yahia1, M Rahouma2, Omnia Aboelazm3 , Jaylan Ahmed4 National Cancer Institute, Cairo University, Cairo, EGYPT, 2Cardiothoracic Surgery, Weill Cornell Medicine, New York, AL, UNITED STATES OF AMERICA, 3Medical Biostatistics, National Cancer Institute, Cairo University, Cairo, EGYPT, 4Clinical Pharmacy, Baheya Cancer Center, Giza, EGYPT 1 Francisco José Koller , Leila Maria Mansano Sarquis , Luciana Puchalski Kalinke1, Nen Nalú Alves Das Mercês1, Maria De Fátima Mantovani1, Dario Consonni2, Carolina Mensi2 1 1 Escola De Enfermagem, Universidade Federal do Paraná, Curitiba, BRAZIL, 2Department of Preventive Medicine, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, ITALY 1 Objectives: Brazil is currently one of the largest producer of chrysotile in the world. Mesothelioma occurrence in Brazil is apparently low. However, identification of cases of mesothelioma in Brazil is difficult because of miscoding of diagnosis and cause of death. For this reason, we are implementing a mesothelioma registry in Curitiba (Paranà). Our aim is to show preliminary data on mesothelioma occurrence in the Southern Brazil using existing sources. Southern Brazil includes the States of Paranà (PR, 10.4 million people), Santa Catarina (SC, 6.7 millions), and Rio Grande do Sul (RS, 11.2 millions). Methods: We extracted data from the website of the National Institute of Cancer in Brazil (INCA, https://irhc.inca.gov.br/ RHCNet/), containing data coming from hospital-based cancer registries (RHC). We selected records of cancer of the pleura (ICD-10: 38.4) or histology of mesothelioma regarding patients residing in any of the three States in the period 2001-2013. We describe clinical characteristics, demographics, and information on occupation. Results: We identified 199 potential cases. We excluded records unrelated to mesothelioma (26 adenocarcinomas, 22 lymphomas, 9 carcinomas, 7 sarcomas, and 6 with other morphology). We also excluded 70 records with a generic definition of “malignant neoplasia”, because of a somewhat unusual gender/age distribution (several women aged <50 years). Of the 57 remaining cases with histology of mesothelioma, 10 were epithelioid, 4 fibrous, 1 biphasic, and 42 not otherwise specified. Notably, 14 of them were incorrectly coded as lung cancer (ICD-10: C34). We found 17 cases (11 M, 6 F) from Paranà, 13 (6 M, 7 F) from SC, and 27 (22 M, 5 F) from RS. Regarding the occupational activities performed in the last three months, 30 (53%), had no information. The rest of subjects had been employed in various sector, including construction, metalmechanic, transport, and agriculture. Conclusion: Existing hospital data regarding mesothelioma Objectives: malignant pleural mesothelioma ( MPM) is characterized by long latency period between exposure to asbestos and development of the disease so we hypothesize that MPM in the young has different characteristics Methods: This is a retrospective study including all eligible patients with malignant pleural mesothelioma presenting to National Cancer Institute, Cairo University during the period from 2008 to 2013. Patients were divided into two groups: Group 1: patients aged ≤ 45 years. Group 2: Patients aged > 45 years. Both groups were assessed regarding different clinic-pathological features .Primary Objectives: comparison of different epidemiological features of both groups. Secondary Objectives: Assessment of clinical response (CR), progression free survival (PFS) and overall survival (OS) in both groups Results: 102 Patients were included with median follow up of 14.4 months. Group (1) included 35 patients with mean age 40± 3.65 years (31 to 45 years).Group (2) included 67 patients with mean age of 58.6± 8.5 years (46 to 87 years). 68% of group (1) came from endemic areas which is significantly higher than group (2): (35.8%), p = 0.02. History of Asbestos exposure was highly significantly different between the 2 groups, 77.1% in group (1) versus 38.8% in group (2), p < 0.001. Other factors showed no significant differences between the two groups. Overall clinical response (CR+PR) was 20% in group (1) versus 17.9 % in group (2). P=0.7. There was a trend towards longer median PFS in young patients, (19.8 ± 8.4 versus 6.9 ± 1.4 months). p = 0.09. The median OS of young patients is significantly longer (20.6± 6.3 months) than older patients (11.4 ± 3.6).p = 0.05. Conclusion: Mesothelioma in the young is more sensitive to asbestos exposure, has better OS and likely a different disease entity which needs further studies to understand its underlying biological features. Keywords: Malignant pleural mesothelioma, young iMig2016.ORG 106 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.62: MALIGNANT PLEURAL MESOTHELIOMA IN AUSTRIA: DATA FROM THE AUSTRIAN MESOTHELIOMA INTEREST GROUP DATABASE Mir A. Hoda1, Thomas Klikovits1, Yawen Dong2, Paul Stockhammer2, Madeleine Arns3 , Peter Schenk3 , Wolfgang Pohl4 , Christian Geltner5, Michael Studnicka6 , Peter Cerkl7, Martin Flicker8 , Josef Eckmayr9, Horst Olschweski10, Gertrude Blazek4 , Klaus Kirchbacher11, Peter Errhalt12, Bernhard Baumgartner13 , Helmut Popper10, Josef Bolitschek14 , Barbara Machan15, Walter Klepetko1 Division of Thoracic Surgery, Medical University of Vienna, Vienna, AUSTRIA, 2Thoracic Surgery, Medical University of Vienna, Vienna, AUSTRIA, 3LKH Hochegg, Hochegg, AUSTRIA, 4KH Hietzing, Vienna, AUSTRIA, 5Pneumology, Klinikum Klagenfurt, Klagenfurt, AUSTRIA, 6Pneumology, Paracelsus University Salzburg, Wels, AUSTRIA, 7Pneumology, LKH Hohenems, Hohenems, AUSTRIA, 8LKH Leoben, Leoben, AUSTRIA, 9LKH Wels, Wels, AUSTRIA, 10Medical University Graz, Graz, AUSTRIA, 11Hospital Wilhelminen, Vienna, AUSTRIA, 12LKH Krems, Krems, AUSTRIA,13LKH Vöcklabruck, Vöcklabruck, AUSTRIA, 14LKH Elisabethinnen Linz, Linz, AUSTRIA, 15AUVA RZ Tobelbad, Tobelbad, AUSTRIA 1 Objectives: Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor originating from the pleural cavity with strong association to previous asbestos exposure. Despite tremendous efforts in early diagnostics and therapeutic approaches, outcome for MPM patients remains dismal. In order to determine demographics, diagnostics, therapeutic strategies and prognosis of MPM patients in Austria, the Austrian Mesothelioma Interest Group (AMIG) was initiated in 2011. We intend to report on the current data from the AMIG MPM database Methods: A prospective cohort study starting from January 2011 was conducted. Follow up was completed until July 2015 Results: 203 patients with histologically confirmed MPM were included. There were 162 male and 41 female patients with a mean age of 67.1 (SD ± 11.4) years at the time of diagnosis. Asbestos exposure was confirmed in 103 (50.1%) patients. 158 (77.8%) patients were diagnosed with pleural biopsy, 18 (8.9%) with pleural puncture and 27 (13.3%) with other approaches. 190 (93.6%) patients had a chest computed tomography (CT), 120 (59.1%) received additional positron emission tomography (PET)/ CT and 20 (9.9%) a PET. Histological subtype revealed epithelioid in 133 (65.5%), sarcomatoid in 15 (7.4%), biphasic in 28 (13.8%), desmoplastic in 4 (2.0%) and not otherwise specified in 23 (11.3%) patients. 34 (16.7%) patients received best supportive care only, 59 (29.1%) chemotherapy (CHT) alone, 3 (1.5%) radiotherapy (RT) alone, 19 (9.4%) CHT/RT, 1 (0.5%) surgery alone and 72 (35.5%) curative surgery within multimodality treatment. Median overall survival was 17.9 (95% CI, 14.6-21.3) months. 1-, 3- and 5-year overall survival was 66%, 26% and 19% and was significantly better in patients undergoing surgery within multimodality treatment (5-year survival 14% vs 35%, p=0.001). Conclusion: Diagnostic and therapeutic approaches according to international guidelines are homogenous among different centers in Austria. Patients undergoing multimodality treatment including surgery had a favorable outcome. PP01.63: HISTOPATHOLOGICAL REPORTING OF MESOTHELIOMA RESECTION SPECIMENS David A. Moore1, David Francis2, John Le Quesne1, Cathy Richards1 Histopathology, University Hopsitals Leicester NHS Trust, WW, UNITED KINGDOM, 2University of Leicester, RH, UNITED KINGDOM 1 Objectives: University Hospitals Leicester NHS Trust is a leading centre for mesothelioma surgery and as such the histopathology department has developed considerable experience in reporting resection specimens. The aim of this study was to collate data from this valuable archive of cases to test the quality of diagnostic reporting for these specimens and to describe their typical pathological profile in one of the few large cohorts of these cases held in a single centre. Methods: All mesothelioma resections from a single surgical centre over a 5 year period were reviewed and the data was collated. The immunoprofiles of the tumours were reviewed and demographic data was also collected. Results: 218 mesothelioma resections were received in the pathology department over a 5 year period and were included in the study. The male to female ratio was 181:37 and the median age was 67 years. Of the 218 cases received there were 179 extended pleurectomy-decortications, 15 extrapleural pneumonectomies and 23 local resections. 78% of resected tumours were of the epithelioid mesothelioma subtype. The majority of cases included pericardium, diaphragm, lung parenchyma and lymph nodes. On TNM staging over half of all cases were tumour stage T3 and over half were nodal stage N2. Eight of the samples (1 in 27) were sufficiently diagnostically challenging to require external expert pathology review. Conclusion: Pathology specimens from radical mesothelioma surgery are complex and challenging cases which require specialist reporting. The data presented represents the first description of the pathological characteristics from a series of this scale from a single surgical centre. Keywords: pathology, staging, resection PP01.64: INHERITED PREDISPOSITION TO MALIGNANT MESOTHELIOMA Marta Betti1, Barbara Pasini2, Elisabetta Casalone3 , Alessandra Biasi1, Anna Aspesi1, Renzo Boldorini4 , Caterina Casadio5, Enrico Colombo6 , Laura C. Gironi6 , Daniela Ferrante7, Federica Grosso8 , Simonetta Guarrera3 , Antonella Maffè9, Dario Mirabelli10, Paola Ogliara2, Luisella Righi11, Simonetta Rosato12, Daniela Turchetti13 , Sara Miccoli13 , Valeria Ascoli14 , Roberta Libener15, Caterina Dianzani16 , Mauro Papotti11, Corrado Magnani17, Giuseppe Matullo3 , Irma Dianzani18 Department of Health Sciences, University of Piemonte Orientale, Novara, ITALY, 2AOU Città della Salute e della Scienza di To1 Keywords: database, epidemiology iMig2016.ORG 107 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP rino, SC Medical genetics U and Department of Medical Sciences, Turin, ITALY, 3Department of Medical Sciences, University of Turin; Human Genetics Foundation,HuGeF, Turin, ITALY, 4Department of Health Sciences, Section of Pathological Anatomy, University of Piemonte Orientale, Novara, ITALY, 5Thoracic Surgery Unit, Azienda Ospedaliero-Universitaria‘‘Maggiore della Carità’’, Novara, ITALY, 6Dermatology Clinic, Department of Clinical and Experimental Medicine, University of Piemonte Orientale, Novara, ITALY, 7CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Piemonte Orientale, Novara, ITALY, 8Division of Medical Oncology, SS.Antonio e Biagio General Hospital, Alessandria, ITALY, 9Molecular Genetics and Biology, Santa Croce e Carle, Cuneo, ITALY, 10Unit of Cancer Epidemiology, CPO-Piemonte and University of Turin; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Turin, ITALY, 11Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Torino, ITALY, 12Department of Obstetric, Gynecologic and Paediatric, Section of Clinical Genetics, Arcispedale S.Maria Nuova, Reggio Emilia, ITALY, 13Medical Genetics, Policlinico Sant’Orsola-Malpighi, Bologna, ITALY, 14Department of Radiological, Oncological and Pathological Sciences, Sapienza University, Rome, ITALY, 15Pathology Unit, SS.Antonio e Biagio General Hospital, Alessandria, ITALY, 16Department of Dermatology, “Campus Biomedico”, University of Rome, Rome, ITALY,17CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Piemonte Orientale; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Novara, ITALY, 18Department of Health Sciences, University of Piemonte Orientale; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Novara, ITALY Objectives: BAP1 (BRCA1-Associated Protein 1) germline mutations predispose to a cancer-prone syndrome (MIM#614327) that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common stepwise carcinogenic pathway. Methods: To evaluate this hypothesis and to better characterize this syndrome, we collected 40 families classified into three groups: 6 families with both mesothelioma and melanoma, 23 families with melanoma (without mesothelioma) and features of inherited cancer predisposition and 11 families with mesothelioma (without melanoma) and features of inherited cancer predisposition. BAP1 gene was sequenced in all families and the same families were also studied for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4 , TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. susceptibility and these tumors share key steps that drive carcinogenesis. It also suggests that other genes may be involved in inherited predisposition to malignant mesothelioma. Exome analysis has been performed in two multiplex families that did not show mutations in any of the tested genes. Keywords: BAP1, CDKN2A, germline mutation PP01.65: CHARACTERIZATION OF INTERTUMOR HETEROGENEITY IN MALIGNANT MESOTHELIOMA Noushin Nabavi, Raunak Shrestha, Yuzhuo Wang, Colin Collins Urologic Sciences, Vancouver Prostate Centre, Vancouver, BC, CANADA Objectives: Malignant mesothelioma is a rare and aggressive cancer. Here, we analyze the genomic and transcriptomic landscape of 87 pleural mesothelioma tumors to identify clinically actionable driver genes and dysregulated signaling pathways. Our longerterm objective is to compare and contrast the molecular profile of pleural mesothelioma with that of peritoneal mesothelioma to advance the existing and relatively archaic chemotherapeutic standard of care approaches. Methods: We used publically available genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) project consisting of 87 pleural mesothelioma patients. We used our bioinformatics methods to identify driver genes for mesothelioma and to integrate genomic (single nucleotide variant and copy number alterations) and transcriptomic (RNAseq gene expression) data with clinically actionable relevance using established genedrug interaction databases. One of our developed bioinformatics models, HIT’nDRIVE, relates the alterations at the genomic level to downstream changes in the transcriptome level, where likely effects are propagated through gene interaction networks. It then prioritize driver genes that dysregulates large portion of the transcriptome. Next we utilized our bioinformatics method, OptDis, which uses the driver genes to search other neighbouring genes to the driver in the interaction network (collectively called as subnetworks) such that the transcriptomic profile of the subnetworks correlate with the sample phenotype. These subnetworks help elucidate the molecular mechanisms and pathways dysregulated in the mesothelioma patients. Results: In two out of six families with both mesothelioma and melanoma we identified a BAP1 germline nonsense mutation (c.1153 C>T, p.R385X) and a common pathogenic germline missense mutation (c.301G>T, p.G101W) in CDKN2A. In both cases BAP1 and CDKN2A proteins were not expressed in the tumor tissues, respectively, supporting loss of heterozygosity (LOH). Moreover, a patient with multiple cutaneous amelanotic melanomas carried a BAP1 germline missense mutation (c.1700A>C, p.D567A) that was predicted to be pathogenic and a duplication of 5bp (c.-594dupCCCGT) in the BAP1 promoter region. Microsatellite analysis supports LOH in the tumor tissue. Results: We found a heterogenous inter intratumor molecular landscape doemalignant mesothelioma. Our analysis identified 15 driver genes with varying alteration frequencies across 87 pleural mesothelioma patients. Somatic mutations in BAP1, LATS2 and TP53 are among the previously identified driver genes in pleural mesothelioma. The driver genes in 87 patients along with their clinical characteristics have been summarized in the figure below. The common pathways amenable to clinical targeting fall in antigen processing and presentation, innate immunity, and pathogen recognition as well as autophagy and JAKSTAT signaling. We will further confirm these in sequencing data obtained from peritoneal mesothelioma tumors. Conclusion: Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma Conclusion: Here, we present the inherent heterogeneity of pleural mesothelioma at both pathologic and genetic levels. iMig2016.ORG 108 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP We identified commonly altered genes in all mesothelioma subtypes from copynumber alterations to mutations to expression. We also present the canonical pathways we identified from these datasets in each pathologic subtype (epithelioid, sarcomatoid, biphasic, and diffuse malignant) based on our computational analyses. The common pathways amenable to clinical targeting fall in antigen processing and presentation, innate immunity, and pathogen recognition as well as autophagy and STATJAK signaling. These findings infer the need for a multimodal therapeutic intervention to account not only for the heterogeneity of individual patient’s pathologic and genetic profile but also the unique properties of solid tumors and their microenvironment. Treatment effectiveness does not only depend on identifying the distinct molecular profile of malignant pleural mesothelioma on an individual patient basis, but also validation of the biomarkers in cell culture and animal models. For these purposes, we further aim to obtain mesothelioma cell lines and establish patientderived xenograft mouse models for further biomarker identification and validation. Keywords: pleural mesothelioma, peritoneal mesothelioma, sequencing, patient-derived xenografts PP01.66: PATHOLOGY ANALYSIS FOR MESOTHELIOMA STUDY IN THE UNITED KINGDOM: CURRENT PRACTICE AND HISTORICAL DEVELOPMENT 97% were pleural mesothelioma, in line with estimates from the LSHTM authors that only four per cent of their cases were peritoneal. The most prominent subtype was epithelioid (64% of study cases but only 49% of ineligible cases). Biphasic and sarcomatoid subtypes constituted 10% vs. 16% and 7% vs. 19% of study and ineligible cases, respectively, reflecting earlier deaths in those ineligible. Of recorded immunohistochemical stains for mesothelial cell origin, Calretinin (95%) and CK 5/6 or CK5 alone (84%) were by far the most common. Calretinin and CK 5/6 or CK 5 alone were also most sensitive and positive in 92% of cases having surgical pathology report. 90% of cases had at least one immunohistochemical marker for possible lung carcinoma applied, with BER-Ep4 and TTF-1 the most common at 68% and CEA at 58%. TTF-1 and CEA were positive in one per cent or less of cases. Keratin markers performed largely as expected; MNF116 was used much more often than is the case in Canada and was positive in 136 of 139 (98%). CK7 was negative in 19% and CK20 positive in 4%. Microscopic description was recorded in 655 of the 748 cases (87.6%), but electron microscopy was never reported. In 13 cases pathology report specified a different diagnosis with no mention of mesothelioma. In another 18, more than one diagnosis was given with no clear diagnosis favored by the pathologist. Conclusion: Pathology practice showed only minor differences from those in North America and Australia. Inclusion of nonmesothelioma cases could in theory result in lower odds ratios for asbestos exposure. The differences between those “eligible” and “ineligible” were related to shorter survivals. Keywords: epidemiology, mesothelioma, immunohistochemistry, pathology Bruce W. Case Pathology, Epidemiology, School of Environment, McGill University, Montreal, QC, CANADA Objectives: 799 mesothelioma cases were reviewed to provide an overview of current pathology diagnostic practice in the United Kingdom. Results were also aimed at identifying factors which could affect epidemiological studies of the same cases. Methods: Investigators at the London School of Hygiene and Tropical Medicine (LSHTM) ascertained 1732 male and 670 female mesothelioma cases diagnosed between 2005 and 2013 in the process of ongoing study as of May of 2013. Cases were deemed ineligible for further epidemiological study if they had died or were too ill to allow direct questionnaire or interview. Pathology reports were obtained as part of the file for 953 male cases (55%) and 357 female cases (53%). Of these, a two-thirds sample was evaluated for the current study (860 cases). 61 (7%) of these had been included on the basis of cytology reports, many of which gave equivocal diagnoses (e.g., mesothelioma “possible” or “unlikely”); these were excluded. Of the remaining 799, with tissue diagnosis reported, 748 had pathology reports sufficiently detailed for evaluation. Reports were examined for basis of diagnosis, differences between study cases and ineligible cases, pathology characteristics, and immunohistochemical and other tests used. Results: Cases were born 1925-1977, with 527 (66%) between 1940 and 1949. 566 were male (70.8%) and 233 female. Males were significantly younger at diagnosis (63 years vs. 67 for women), and born later (1942 vs. 1947) (mean, P<.0001). PP01.67: VARIATIONS IN COPY NUMBER IN THE MALIGNANT PLEURAL MESOTHELIOMA GENOME Marieke Hylebos1, Ken Op De Beeck1, Guy Van Camp2, Jan P. Van Meerbeeck3 Center for Oncological Research, University of Antwerp, Edegem, BELGIUM, 2Center of Medical Genetics, University of Antwerp, Edegem, BELGIUM, 3Thoracic Oncology, Antwerp University Hospital, Edegem, BELGIUM 1 Objectives: Despite improvements in the outcome of malignant pleural mesothelioma (MPM) with the advent of chemotherapy, the median overall survival remains only 1 year. This poor prognosis leaves ample room for the application of novel treatment strategies. In several other solid tumors, the identification of actionable genomic alterations has resulted in a paradigm shift in treatment towards specific targets. In an effort to identify these actionable targets in MPM, studies already reported on its genomic background. In this respect, karyotype analyses and comparative genomic hybridization techniques demonstrated a complex set of chromosomal copy number variations (CNVs) in most MPMs. These techniques however have a limited resolution compared to highly sensitive next-generation sequencing platforms, which allow genome-wide detections in a high-throughput manner. iMig2016.ORG 109 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Methods: The genomes of a set of 21 MPMs and matched normal samples were analyzed using low-pass whole genome sequencing (LP-WGS). Following DNA-extraction, sequencing libraries were formed and paired-end sequencing (2 x 100 bp) was performed on the ‘HiSeq 1500’ (Illumina). To enable the detection of structural variants, we aimed at a mean genome-wide coverage of 1-2x. The presence of CNVs in the samples was analyzed using in-house developed analysis pipelines. Results: Preliminary analyses of the copy number profiles of the paired samples showed striking differences. Whereas no CNVs could be observed in the normal samples, copy number losses and gains were visible in the tumor samples. Moreover, it was readily detectable that copy number losses occur more frequently compared to copy number gains. Overall, copy number losses were most often observed in chromosomes 1p, 3p, 4q, 6q, 9p, 13q and 22q. Beside genes such as BAP1, CDKN2A and NF2, which are often found to be mutated in MPM, these regions include several other possibly interesting targets. Conclusion: Using LP-WGS, CNVs were detected in the MPM-genome. Although the overall pattern of CNVs is heterogeneous and no single CNV was present in all of the samples, the CNVs seem to cluster in certain regions. Further analysis of these regions is ongoing and will be presented at the meeting. Keywords: Copy number variations, Next-generation sequencing, Malignant pleural mesothelioma PP01.68: HOMOZYGOUS 9P21 (P16/CDKN2A) DELETION IN MESOTHELIOMA–5 YEAR RETROSPECTIVE SPECIALIST DIAGNOSTIC PLEURAL PATHOLOGY AUDIT Lauren Harries1, Jayne Holme2, Matthew Evison2, Richard Booton2, Philip Crosbie2, Rajesh Shah3 , Paul Taylor4 , Clare Hodgson5, Nick Telford5, Paul Bishop1, Anshuman Chaturvedi1 Histopathology Department, University Hospital of South Manchester, Manchester, UNITED KINGDOM, 2Manchester Thoracic Oncology Centre, University Hospital of South Manchester, Manchester, UNITED KINGDOM, 3Department of Surgery, University Hospital of South Manchester, Manchester, UNITED KINGDOM, 4Oncology Department, University Hospital of South Manchester, Manchester, UNITED KINGDOM, 5Oncology Cytogenetics, Christie Hospital, Manchester, UNITED KINGDOM 1 Objectives: Detection of homozygous deletion of the p16/CDKN2A gene on chromosome locus 9p21 using fluorescence in-situ hybridisation (FISH) in mesothelial cells has been reported to improve diagnostic certainty of malignant mesothelioma (MM) while assessing mesothelial proliferations in morphologically difficult pathology cases. Histopathology department at University Hospital of South Manchester (UHSM) together with cytogenetics department at Christie Hospital over the previous 24 months (since early 2013) validated and then introduced p16/ CDKN2A FISH analysis, as a supporting technique, into routine diagnostic practice. This five-year retrospective audit sought to examine the volume and range of thoracic/pleural specimens reported to have mesothelial proliferations, focussing on provision of history of asbestos exposure, utilisation of immunohistochemistry (IHC) (including EMA and Desmin) and p16/ CDKN2A FISH analysis and the degree of diagnostic certainty in reporting of these specimens. Methods: Electronic search of hospital pathology database identified all thoracic/pleural specimens (fluid and biopsy) coded as having a ‘mesothelial’related pathology, over a fiveyear period (2010 to 2015). Pathology reports were reviewed systematically to ascertain provision of the history of asbestos exposure, specimen type, IHC use, utilization and results of p16/ CDKN2A FISH and the diagnostic morphological end-point. Results: 516 (82%) of the 628 specimens identified were included in final analysis (117 pleural fluid, 381 pleural biopsy, 6 resection, 5 frozen sections, 2 other biopsy, 7 aspirate cytology). Specimens excluded were those reported to have non-mesothelial pathology. 38 coronial post-mortems were also excluded. History of asbestos exposure was not provided with 326 (63%) specimens, while it was available and positive in 166 (32%) and negative in 24.IHC was performed in 455 (88%) specimens (EMA and/or Desmin used in 81 (15%)). p16/CDKN2A FISH analysis was attempted on 79 (15%) specimens. Insufficient material in two instances precluded FISH study. There was test failure with one specimen. Homozygous 9p21 ( p16/CDKN2A) deletion was detected in 53 (67%) of all tests performed. Remaining 25 specimens tested were negative. Diagnostic bottom-line in the 516 specimens included - confirmed diagnosis of MM (n=287; 55%); highly suspicious for MM (n=64); suspicious but not diagnostic of MM (n=51);suggestive of MM (n=12);atypical mesothelial proliferation (n=52); benign mesothelial cells (n=4); non-diagnostic (n=1); atypia mesothelial versus epithelial (n=33); MM versus carcinoma not established (n=4); mesothelial benign versus malignant (n=1). Of the specimens reported as MM, the tumour sub-type was epithelioid (n=199); sarcomatoid (n=41); biphasic (n=27); other (n=3). No subtype was recorded in 111 specimens. Conclusion: Definitive morphological diagnosis of mesothelioma is challenging. There is no diagnostic IHC profile for mesotheliomas. Identifying tumour infiltration into adjoining chest wall fat/ organ is the morphological feature widely-accepted to conclusively establish the diagnosis. However, in the routine clinical scenario, not uncommonly, material available is either limited superficial biopsy tissue or an initial cytology sample. New diagnostic biomarkers are therefore needed. In our experience, detection of homozygous deletion of p16/CDKN2A gene by FISH increased diagnostic certainty, including for diagnostic cytology specimens. p16/CDKN2A FISH analysis should be considered in challenging cases of atypical mesothelial proliferations where fat infiltration cannot be identified and also in cytology cases where this is the only specimen available. Keywords: Mesothelial proliferation, FISH, Cellular pathology, Homozygous 9p21 ( p16/CDKN2A) deletion iMig2016.ORG 110 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP01.69: MUTATION STATUS AND EXPRESSION OF THE MICRORNA-PROCESSING RIBONUCLEASE-III DICER1 IN MALIGNANT PLEURAL MESOTHELIOMA Alina Jørnild1, Morten Andersen1, Jesper Ravn2, Jens B. Sørensen3 , Claus B. Andersen1, Morten Grauslund1, Eric Santoni-Rugiu1 Department of Pathology, Dept. of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DENMARK, 2Department of Thoracic Surgery, Dept. of Thoracic Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DENMARK, 3Department of Oncology, Dept. of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DENMARK 1 Objectives: We and others recently reported that deregulated expression of specific microRNAs (miRNAs) in malignant pleural mesothelioma (MPM) may aid in the difficult differential diagnosis between MPM and benign reactive mesothelial proliferations (RMP), has prognostic significance, and depends at least in part on epigenetic mechanisms [1-3]. The ribonuclease-III Dicer1 plays a fundamental role in the biogenesis of miRNAs. In other cancer-types, somatic hot-spot mutations affecting the DICER1-gene or up-/down-regulation of Dicer1-mRNA/protein resulting in abnormal Dicer1-function and aberrant miRNA-biosynthesis with prognostic impact, have been described. Thus, we investigated whether DICER1-mutations and/or deregulated -expression may represent alternative mechanisms underlying MPM’s deregulated miRNA-profiling. Methods: Formalin-fixed paraffin-embedded tissue specimens from a cohort of 78 surgically resected MPMs (pleurectomy/ decortication) receiving neoadjuvant cisplatin-pemetrexed (40 epithelioid/38 biphasic; stage II-IV; period 2011-2015), 23 available patient-matched non-neoplastic pleuras (NNP), 10 adjacent non-invasive atypical mesothelial proliferations (AMP), and 5 unrelated chemotherapy-naïve diagnostic MPM-biopsies (DB; epithelioid), as well as 12 independent pneumothorax-induced RMP, were investigated. Possible hot-spot mutations of DICER1-gene were analyzed on genomic DNA by nested PCR and dideoxynucleotide-sequencing of exon 24-25 encoding the catalytic RNase-IIIb domain. Dicer1-mRNA expression was measured on total RNA by RT-qPCR normalizing to the internal reference MRPL19 -gene. Dicer1-protein expression was assessed by IHC using light microscopy and a modified semi-quantitative H-score. Significant (P<0.05) differences in Dicer1-mRNA/-protein expression between independent or paired groups of samples were detected by non-parametric Mann-Whitney and Wilcoxon signed-rank tests, respectively, while non-parametric Kruskal-Wallis ANOVA was used for comparing expression in samples from different groups. Results: Two patient-matched NNP-MPM pairs displayed single-nucleotide-polymorphisms, but no somatic mutations were identified in exon 24-25 of DICER1-gene in any of the MPM, NNP-, AMP-, DB- or RMP-samples analyzed, suggesting that as opposed to other cancer-types these hot-spot mutations are uncommon/absent in MPM. No significant difference (P >0.05) of Dicer1-mRNA expression in MPM vs. NNP, AMP or RMP was found. In contrast, significant upregulation of Dicer1-protein (P<0.05) was detected in MPM as compared to NNP or RMP but not AMP or DB. Comparable Dicer1 expression in MPM- and DB-groups indicated no significant influence of chemotherapy. A numerical (non-significant) trend of up-regulated Dicer1-mR- NA and -protein was observed in epithelioid vs. biphasic MPM, possibly reflecting the association between lower Dicer1 expression and poorer prognosis reported in some other cancers. Moreover, numerically higher Dicer1 expression was observed in MPM stage IV vs. earlier stages. Conclusion: DICER1 catalytic domain’s hot-spot mutations and Dicer1-mRNA expression level do not appear to be causal mechanisms for aberrant miRNA-expression in MPM. However, Dicer1-protein overexpression suggests a role for this ribonuclease in the miRNA-deregulation and possibly pathogenesis of this cancer. Together with observations in other malignancies, these results imply that causes and effetcs of aberrant Dicer1-function may depend on cancer type. Further research on Dicer1 and other miRNA-processing pathway’s components is required to clarify the mechanisms of miRNA-deregulation in MPM. 1. Andersen M. et al., J Mol Diagn 16:418–30, 2014 2. Andersen M et al., Anticancer Res 35:6223–9, 2015 3. Santoni-Rugiu E, Andersen M, Grauslund M, Current Biomarker Findings 6:1-21, 2016 Keywords: mesothelioma, microRNA-regulation, Dicer1 PP01.70: A COMPARISON OF THE GENETIC CHARACTERISTICS OF MURINE AND HUMAN MALIGNANT MESOTHELIOMA Sophie Sneddon1, Ian M. Dick1, Nicola Waddell2, John Pearson2, Richard J. Allcock3 , Bruce Robinson1, Jenette Creaney1 School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, WA, AUSTRALIA, 2QIMR Berghofer Medical Research Institute, Brisbane, QLD, AUSTRALIA, 3University of Western Australia, School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA, AUSTRALIA 1 Objectives: Next generation sequencing approaches have the potential to result in new treatment strategies for cancer. A murine model of mesothelioma can be an ideal tool for analysing the genetic changes of mesothelioma in finer detail and to allow testing of targetable genetic lesions, provided it is similar to the human disease. With the aim of ultimately taking advantage of the established pipeline of testing new therapies in preclinical murine models of disease we have compared the exome sequence of mesothelioma in patients and in asbestos-induced tumours in mice. Methods: Whole exome sequencing (WES) was performed on primary mesothelioma cultures from 29 patient and 16 mouse effusions using the Ion Torrent Proton sequencer along with normal tissue as controls. Somatic single nucleotide variations (SNVs) were identified using VarScan2 and SomaticSniper software, pooled and annotated. Small regions of copy number variation (CNV) were identified using ExomeCNV and R. GISTIC2.0 and MutSigCV were used to identify significant SNVs and CNV across all samples. Mutational signatures were derived using SomaticSignatures in R. Results: There was an average of 6.6 SNVs per Mb across iMig2016.ORG 111 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP the human and 9.7 per Mb in the murine samples with a high number of C>T and G>A transitions. There was evidence for selection pressure of missense mutations, indicating the presence of possible driver mutations. Both species showed a higher proportion of copy number losses than gains. Evidence of a possible mutational signature was identified. The most frequent genetic change in both human and murine mesothelioma was p16 loss. Genetic alterations in BAP1 and NF2 occurred at lower frequency in mouse relative to human mesothelioma. Conclusion: MM is a complex tumour with a number of genetic characteristics. Not only is there similarity in phenotypic characteristics between asbestos-induced tumours in humans and mice, there are similarities at the genetic level. This study supports the use of the immune-competent murine model for future mesothelioma genetics and treatment studies. Keywords: bioinformatics, mutations, exome sequencing, murine model PP01.71: MUTATIONAL BURDEN AND CDKN2A STATUS AS A ROBUST OUTCOME PREDICTOR FOR RADICAL SURGERY IN MESOTHELIOMA Annabel J. Sharkey1, Robert Hastings2, David A. Moore3 , John Le Quesne3 , Morag Taylor4 , Phillip Quirke4 , Apostolos Nakas5, David Waller5, Sara Busacca1, Dean Fennell1 Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 2University of Leicester, Leicester, UNITED KINGDOM, 3Histopathology, University Hopsitals Leicester NHS Trust, Leicester, UNITED KINGDOM, 4Leeds Institute of Pathology and Tumour Biology, Leeds, UNITED KINGDOM, 5Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UNITED KINGDOM 1 Objectives: Mesothelioma is a heterogeneous cancer with respect to its natural history, with a subset of patients exhibiting relatively indolent cancer associated with long time to progression (TTP) and overall survival (OS) following surgical resection. The aim of this study was to interrogate the extent of genomic instability of this indolent phenotype through copy number analysis in order to identify predictive molecular features. Methods: 50 matched patients were identified from the Leicester Mesothelioma radical surgery tissue bank from 1999-2014. OS of these 436 patients was 15 months (range 0-167 months). Patients were categorized according to either long OS (>15 months) or short OS (<15 months). OS for long survivors (LS) was 45.8 months (17.3-66.2 months), and short survivors (SS), 6.2 months (1.0-14.5 months). Patients were matched based on all known clinic-pathological prognostic factors, and all were epithelioid histological subtype. No patients received neoadjuvant chemotherapy and four patients, 2 in each group, were treated with platinum/pemetrexed at progression. Somatic copy number alteration (SCNA) was determined from FFPE extracted DNA using an array based platform (Affymetrix Oncoscan v3). Putative SCNAs were identified using a circular binary segmentation algorithm, and significant recurrent SNCAs were identified by GISTIC algorithm. Total SCNA, or SCNA(N), was estimated as a surrogate for mutational burden using NEXUS Express v3.1. Test and validation cohorts comparing LS versus SS were segregated and the area-under-the-curve (AUC) of corresponding receiver-operator curves, defined. Results: Twenty-eight matched patients were subgrouped into a test cohort comprising 14 long survivors (LS) versus 14 short (SS). A validation cohort comprised 16 patients. SCNAs: LS losses 6q25.3 (79%), 3p22.1 (64%), 1p12 (50%), 9p21.3 (43%), 22q11.23 (36%), 17q25.3 (29%) 16p11.2 (24%), 8p11.22 (21%), 6p25.3 (7%), 1q21.2 (7%). LS gains 22q11.23 (57%) and 16p11.1 (36%). SS losses 9p21.3 (CDKN2A) (79%), 22q11.23 (50%) 1q21.2, (36%),8p11.22 (14%). SS gains 22q11.23 (64%), 8p11.22 (29%) and 16p11.2 (29%). Median SCNA(N) was 96 (range 8-398) and negatively correlated with both OS and TTP for all patients (OS; ρ -0.526, p=0.004, TTP; ρ -0.631 p=0.002). Median SCNA(N) for LS was 74.5 (8-159) and SS was 113.5 (58-398). The cut off of SCNA(N) ≥90 most accurately predicted long versus short OS and TTP (AUC(OS) =0.750 and AUC(TTP) = 0.818). 9p21.3 (CDKN2A locus) loss predicted OS and TTP; AUC(OS) = 0.719, AUC(TTP) = 0.657. Using either SCNA(N) ≥90 or the presence of CDKN2A loss (either homozygous or heterozygous), or both, improved the outcome prediction accuracy; AUC (OS) = 0.806 and AUC(TTP) = 0.798. Having SCNA(N) ≥90 plus CDKN2A loss gave an AUC(OS) = 0.833 and AUC(TTP) = 0.838. In the validation cohort (median OS 56.3 months, range 3.5-152.3 months, median TTP 17.9 months, range 2.1- 145.4 months), CDKN2A loss did not correlate with mutational burden or clinico-pathological features. However longer OS was associated with SCNA(N)≥90 plus CDKN2A loss (56.3 vs. 28.5 months p=0.518), as was TTP (18.4 vs. 6.2 months p=0.058). Conclusion: CDKN2A wild type mesothelioma tumours harbouring <90 SCNAs may exhibit long TTP and OS following radical surgery. Further validation of this potential prognostic tool is required. PP01.72: WHOLE-GENOME DNA METHYLATION AND TRANSCRIPTOME CHANGES IN ASBESTOS EXPOSED MET5A CELLS Elisabetta Casalone1, Alessandra Allione1, Simonetta Guarrera1, Clara Viberti1, Barbara Pardini1, Marta Betti2, Cornelia Di Gaetano1, Corrado Magnani3 , Irma Dianzani4 , Elisabetta Aldieri5, Giuseppe Matullo1 Department of Medical Sciences, Human Genetics Foundation and University of Turin, Torino, ITALY, 2Department of Health Sciences, University of Piemonte Orientale, Novara, ITALY, 3Department Translational Medicine, CPO-Piemonte and Unit of Medical Statistics and Epidemiology and Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Novara, Torino, ITALY, 4Department of Health Sciences, University of Piemonte Orientale; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Novara, ITALY, 5Department of Oncology, Interdepartmental Center for Studies on Asbestos and other Toxic Particulates “G. Scansetti”, University of Turin, Torino, ITALY 1 Objectives: Occupational and environmental asbestos expoiMig2016.ORG 112 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP sure is the main determinant of MPM development, which is characterized by a long latency period. Apart asbestos induced mesothelial inflammatory processes that are thought to be the basic mechanism underlying MPM development, there are several other possible mechanisms through which asbestos may induce MPM, that have not been already explored. Asbestos exposure may act to induce epigenetic errors leading to the deregulation of gene expression. We investigated whether a dose-response relationship exists between alterations of DNA methylation profiles and asbestos exposure in a well-controlled in-vitro experimental setting, to determine the impact of methylation changes on gene expression. Methods: We measured whole genome expression and DNA methylation levels on Met5A human mesothelial cell lines treated with increasing concentration of crocidolite and chrysotile asbestos for 72 hours (0.5 ÷ 5.0 µg/cm2). Spearman’s rank correlation was employed in order to examine the association between DNA methylation or gene expression levels and asbestos fibre doses. Results: The DNA methylation dose-response relationship in crocidolite and chrysotile treated cells showed changes in methylation levels of numerous CpG sites (rho = ±1, p<0.05). Among the genes overlapping the set of CpGs associated with asbestos dose, we identified several genes already described with altered methylation patterns in MPM such as tissuewingless-type MMTV integration site family member 10B (WNT1 0B),NOTCH4 , homeobox A5 (HOX5), MutS protein homolog 2 (MSH2) and others. Expression analyses on mRNA levels revealed a significant association with crocidolite and chrysotile dose for 950 and 575 transcripts, respectively (rho = ±1, p<0.05). We recognized a large number of previously known as well as new potential asbestos-related differentially expressed genes and biological processes, among which we identified genes that play a role in the regulation of cell fate, cell cycle, cell growth and DNA damage repair. Noteworthy, there was the statistically significant linear correlation between DNA methylation and mRNA expression observed for 14 genes in crocidolite treated cells, including CDK6 , FANCB, and five genes in chrysotile exposed cells, such as IGFBP5 and ITGB5 (rho = ±1, p<0.05). Conclusion: This study identified several interesting targets for further investigation in relation to asbestos exposure and represents an important step to understand if asbestos-induced carcinogenesis may be related to DNA methylation changes. Additional analyses are ongoing in order to replicate the signals that have already been identified in MPM tissue and with a relevant biological function and to evaluate the impact of these processes in MPM development. Keywords: cells treatment, espression changes, asbestos, methylation changes PP01.73: GENOMIC INTERROGATION OF A CLONAL RECURRENCE OF PLEURAL MESOTHELIOMA 12.5 YEARS AFTER RADICAL SURGERY Annabel J. Sharkey1, Robert Hastings2, David A. Moore3 , John Le Quesne3 , Morag Taylor4 , Phillip Quirke4 , David Waller5, Apostolos Nakas5, Sara Busacca1, Dean Fennell1 Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 2University of Leicester, Leicester, UNITED KINGDOM, 3Histopathology, University Hopsitals Leicester NHS Trust, Leicester, UNITED KINGDOM, 4Leeds Institute of Pathology and Tumour Biology, Leeds, UNITED KINGDOM, 5University Hospitals of Leicester, Leicester, UNITED KINGDOM 1 Objectives: Malignant pleural mesothelioma (MPM) remains an incurable cancer. Little is known about the genotype-phenotype relationship that determines the natural history of mesothelioma, particularly in the context of extremely indolent mesotheliomas associated with exceptionally long times to progression (TTP) following radical surgery. Molecular classification of such patients could facilitate rational stratification for surgery to optimize outcomes. Accordingly we have conducted paired genome-wide somatic copy number alteration analysis of a patient who exhibited extreme TTP post extra-pleural pneumonectomy (EPP). Methods: A 69 year old man underwent right EPP after 3 cycles of neoadjuvant chemotherapy for epithelioid MPM in 2002 stage pT3N0. No further oncological treatment was given post-operatively. In 2015, 12.5 years after his original resection, he developed chest wall recurrence and nodules in the remaining lung. A paired biopsy was taken to confirm a diagnosis of recurrent MPM, and to allow comparable genetic analysis pre-surgery and at disease progression. The array based platform Affymetrix Oncoscan v3 was used to determine genome-wide somatic copy number alteration (SCNA) using FFPE extracted DNA from both the initial resection specimen, and the recurrence biopsy. SCNA number was determined using NEXUS Express v3.1. In previous work (abstract #374) we identified SCNAs specific to either long or short survival groups following surgery for MPM using the GISTIC algorithm for segregation of significant SCNAs. Results: Total SNCA was 18 in the original tumour and 55 in the recurrence sample, with 39 new SCNAs present in the recurrent tumour. Sixteen (88.9%) SCNAs were common between the two tumours and are therefore likely to be clonal. Of those genes commonly lost in our previous cohort of long survivors, 9 were found to be lost in this patient’s original tumour; ADAM3A (homozygous loss), ZDHHC14 (heterozygous loss), TMEM242 (heterozygous loss), MIR3692 (heterozygous loss), CCK (heterozygous loss), LYZL4 (heterozygous loss), and TP53 TG3, TP53 TG3B and TP53 TG3C (loss of heterozygosity). Of the cosmic mutations commonly found to be altered in MPM (CDKN2A, BAP1 and NF2) neither tumour harboured loss of CDKN2A, and both harboured BAP1 heterozygous loss. A new heterozygous loss of NF2 was found in the recurrence sample. Conclusion: In summary, clonal progression of mesothelioma is still possible after a decade of disease control. The mechanisms underlying dormancy are unknown. Bap1 loss does not preclude exceptionally long time to progression in the context of low mutational burden, and progression may have resulted iMig2016.ORG 113 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP from emergence of the NF2 driven subclone, coincident with increased mutational burden as suggested from parallel genomic studies to be presented. PP01.74: CDKN2A DELETION: A CLONAL MUTATION IN MALIGNANT PLEURAL MESOTHELIOMA DEVELOPMENT? Luke Martinson1, Annabel J. Sharkey1, Barbara Ottolini1, David A. Moore2, John Le Quesne2, Apostolos Nakas3 , David Waller3 , Jacqui Shaw1, Dean Fennell1 Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 2Histopathology, University Hopsitals Leicester NHS Trust, Leicester, UNITED KINGDOM, 3Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UNITED KINGDOM 1 Objectives: Intratumour heterogeneity is likely to contribute to treatment failure in malignant pleural mesothelioma (MPM), with the targeting of subclonal rather than clonal (ubiquitous) drivers. The most common genetic alteration observed via a single tumour biopsy, is homozygous deletion ofCDKN2A (p16/ p14ARF), observed in approximately 70% of cases. Determination of CDKN2A deletion as a clonal driver event is vital for both future therapeutic intervention and predicting patient outcome following treatment. Ongoing work in our group has indicated that patients harbouringCDKN2A deletion may exhibit a poorer clinical outcome following radical surgery (see Abstract 374). Therefore, providing CDKN2A deletion is confirmed to be an early clonal event, the analysis of a single site pre-operative tissue biopsy (or potentially a liquid biopsy) could be of prognostic benefit to patients undergoing radical surgery. Here, we investigate the clonal origin of CDKN2A deletion in MPM using Droplet Digital PCR (ddPCR) on multiregional tumour tissue. Methods: Multiregional tumour tissue (5 spatially separated anatomical regions) was obtained from patients undergoing extended pleurectomy/decortication (EPD). Each patient additionally provided a blood sample to allow for the isolation of lymphocyte DNA, to be used as a healthy genomic control. All tumour regions were assessed for approximate tumour content by a specialist thoracic histopathologist. ddPCR (Bio-Rad) was conducted using 5ng template DNA. An in-house RPPH1 assay was multiplexed with the CDKN2A assay, to act as a copy number reference (≈1 copy/haploid genome). H460 cell line was used as a positive control for CDKN2A deletion (HD). 7 of these samples were cross-validated for CDKN2A status using the OncoScan® FFPE Assay platform (Affymetrix), using one of the five tumour regions. Results: 53% of patients (9/17) exhibited evidence of CDKN2A deletion (HD/Loss of heterozygosity (LOH)), which is relatively consistent with current literature. Due to unavoidable contamination from stromal (healthy) cells within each tumour region, the threshold for CDKN2A deletion was set at 0.8/1 copy of reference, with values below 0.8 indicating evidence of deletion. Oncoscan® analysis showed that the ddPCR results were reproducible in all 7 cases. Samples with detected HD of CDKN2A via Oncoscan®, possessed an average copy number of 0.38 by ddPCR, compared to 0.78 for those with LOH Conclusion: In all patients exhibiting evidence of CDKN2A deletion, this was observed across all 5 tumour regions, implicating CDKN2A deletion as a clonal event in MPM development. These findings indicate that CDKN2A profiling from a single tumour biopsy (or potentially a liquid biopsy) using ddPCR could be viable, cost-effective and efficient in the clinical setting. Additionally this data consolidates CDKN2A as not only an ideal therapeutic target in future MPM treatment, but also allows CDKN2A status to be used as a possible prognostic marker for patient outcome following surgery. PP01.75: UPDATE: RECENT STUDIES EXAMINING IMPACT OF BAP1 MUTATION ON MESOTHELIOMA RISK AND IMPLICATIONS FOR MESOTHELIOMA LITIGATION Steven Kazan Kazan McClain Satterley & Greenwood, A Professional Law Corporation, Oakland, UNITED STATES OF AMERICA Objectives: Background: At iMig 2014 we discussed the ethical issues surrounding BAP1 testing and its role in asbestos lawsuits. 1. The case referenced in our poster (#P1.061) started jury trial on January 5, 2016 and resolved on February 3, 2016, just before closing arguments. The author of the affidavit cited in our 2014 poster was withdrawn as an expert by the asbestos cement pipe manufacturer which had retained him. Testimony by one of his co-authors contradicted his claims of causality, and the published medical literature also increasingly supports the role of the gene/environment interaction in the oncogenesis of mesothelioma in BAP1 cancer syndrome. An initial article had hypothesized that BAP1 mutations alone might be sufficient to cause mesothelioma. 2. However, since 2014, the majority of the literature concludes that BAP1 mutations leave an individual increasingly vulnerable to carcinogens like asbestos. Methods: A PubMed literature review was conducted on all peer reviewed English language articles indexed between 2014 and 2016, with keyword searching for germline BAP1 and mesothelioma. Twenty-seven articles were found. We then categorized the conclusions and charted the trends over time. Results: Four articles were eliminated as irrelevant. Eleven articles discussed exposure to environmental factors as a cause of oncogenesis. Two articles discussed low exposure to environmental factors as a cause of oncogenesis. One article hypothesized that asbestos exposure might not be necessary for the development of mesothelioma.3 Conclusion: Current literature strongly supports the conclusion that individuals with a germline BAP1 mutation are more vulnerable to oncogenesis of certain tumors after exposure to carcinogens. In the case of mesothelioma, this carcinogen is asbestos. The utility of using an existing BAP1 mutation as a defense to liability for mesothelioma is increasingly questionable. 1. Kazan and Kin. Hippocrates and BAP1 Genetic Testing in Mesothelioma Litigation. Abstract P1.061, iMig 2014, p. 30. 2. Testa, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nature Genetics 43.10 (2011): 1022-1025. iMig2016.ORG 114 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP 3. Carbone, et al. Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s. PLoS Genet 11.12 (2015): e1005633. Keywords: litigation, BAP1, mutation PP01.76: BAP1 VALUE IN DIAGNOSIS Michele Carbone University of Hawaii Cancer Center, Honolulu, HI, UNITED STATES OF AMERICA Objectives: BAP1 germline mutations cause malignant mesothelioma and other cancers, and BAP1 somatic mutations are the most common genetic alteration in sporadic mesotheliomas. We investigated the potetnial value of BAP1 testing in differentiating mesothelioma from other malignancies. Methods: We used an array of different molecular techniques and classical immunohistochemistry. Results: By testing a large number of mesotheliomas and human specimens we found significant differences that indicate that ascertain the BAP1 status is useful in the differential diagnosis of mesothelioma. are not well documented. This means that individual research groups often repeat similar experiments, resulting in an excess use of animals. In addition, unlike the human situation, it results in a highly variable use of chemotherapy dosages across the literature, with different biological effects. We set out to define the maximum tolerated dose (MTD) for 10 classes of chemotherapeutics in mice using a comprehensive and systematic approach and we investigated the effect of supportive care on chemotherapy-induced toxicity. Methods: Chemotherapy was administered to BALB/c mice with doses escalated until the endpoints of weight loss >15% or a clinical score >2 were met. A parallel series of experiments tested MTDs in C57BL/6J mice and multiple dosing at MTD. To determine the effect of supportive care, dexamethasone, ondansetron and supplementary feed were used both as single agents and in combination. Results: For nine of the ten drugs tested, weight loss was the dose-limiting toxicity, while clinical score determined the MTD of gemcitabine. For some chemotherapeutics the MTD was substantially higher than we commonly found in the literature. There was a slight variability in MTD between mouse strains. The tolerability of repeated cycles was drug-dependant. The use of either nutritional supplement or ondansetron did not reduce toxic effects of cisplatin chemotherapy while experiments with dexamethasone are ongoing; the results will be reported at the meeting. Conclusion: BAP1 testing should always be conducted in mesothelioma patients for diagnostic and prognostic reasons Conclusion: These data are a resource for future studies using chemotherapy in mice and should reduce the number of mice required for dose optimization experiments. Our studies also suggest that supportive care can reduce toxic side effects and increase the MTD. Keywords: Malignant mesothelioma, BAP1, pathology, differential diagnosis Keywords: Supportive care, chemotherapy, maximum tolerated dose PP01.77: A SYSTEMATIC INVESTIGATION OF THE MAXIMUM TOLERATED DOSE OF CYTOTOXIC CHEMOTHERAPY WITH SUPPORTIVE CARE IN MICE PP01.78: CANCER CHEMO IMMUNOTHERAPY EXPLOITING THE IMMUNOGENIC POTENTIAL OF CYCLOPHOSPHAMIDE Wayne J. Aston1, Danika E. Hope1, Scott Fisher1, Anna Nowak2, Richard Lake1, Willem J. Lesterhuis1 School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases. The University of Western Australia, Perth, WA, AUSTRALIA, 2School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases. The University of Western Australia. Sir Charles Gardiner Hospital, Perth, WA, AUSTRALIA 1 Objectives: Cytotoxic chemotherapeutics form the cornerstone of treatment for thoracic cancer. Because these drugs typically demonstrate a clear dose-response relationship, patients are given the highest dose that does not cause unacceptable side effects. In contrast, in murine cancer studies chemotherapy dosages are often based on custom practice from the literature or on small pilot studies for individual drugs, which often Wayne J. Aston1, Catherine A. Rinaldi1, Scott Fisher1, Anna Nowak2, Richard Lake1, Willem J. Lesterhuis1 School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases. The University of Western Australia, Perth, WA, AUSTRALIA, 2School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases. The University of Western Australia. Sir Charles Gardiner Hospital, Perth, WA, AUSTRALIA 1 Objectives: Identify the dynamics of leucocyte infiltration in mesothelioma tumours during immunogenic chemotherapy. Methods: BALB/c mice were inoculated subcutaneously with 5x105 AB1 mesothelioma cells. On d12 the mice were given 250 mg/kg cyclophosphamide intraperitoneally. The tumours were harvested at various times after chemotherapy and were analysed using H&E histology and flow cytometry to characterise iMig2016.ORG 115 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP the immune cell infiltrates. Results: AB1 tumours treated with cyclophosphamide regressed, appeared to regrow then regressed completely over a period of 20 days. Based on this four time points were selected for histology and flow cytometry analysis: growth before treatment, growth after treatment, the regrowth phase and the final regression phase. The most notable finding was in the final regression phase in which the resected tumour section showed large leukocytic infiltrates. We noted gross changes to immune cell populations across all time points including a decrease in FoxP3+ Tregs and a significant increase in both CD4+ and CD8+ T lymphocytes. Functional studies showed that CD8+ T cells were necessary for the curative effect of cyclophosphamide. immune related genes. A central hub in both modules, which was upregulated in responding mice was inducible nitric oxide synthase (iNOS). Cotreatment with competitive iNOS inhibitor L-NNA inhibited the response to anti-CTLA4 while conversely the NO generator isosorbide dinitrate significantly enhanced the cure rate from 10 to 80% in AB1-HA mesothelioma-bearing mice. The drug repurposing approach identified all-trans retinoic acid as a candidate synergistic drug. Indeed, cotreatment with anti-CTLA4 increased the response rate from 10% to 60%. Conclusion: This approach allows the identification of therapeutic targets and drugs that act synergistically with checkpoint blockade in cancer. Keywords: biomarker, tumour immunology, checkpoint blockade, systems biology Conclusion: Cyclophosphamide treatment of mesothelioma in vivo results in leukocytic infiltrates that mediate regression, particularly CD8+ T cells. Further studies will aim to further investigate the immunogenic mechanisms behind this. Keywords: Cyclophosphamide, Immunogenic, chemotherapy PP01.79: IDENTIFICATION OF REPURPOSED DRUGS THAT INCREASE IMMUNE CHECKPOINT BLOCKADE EFFICACY IN MESOTHELIOMA USING NETWORK ANALYSIS OF RESPONDING TUMOURS Rachael M. Zemek1, Catherine A. Rinaldi1, Richard Lake2, Michael J. Millward1, Anna Nowak2, Willem J. Lesterhuis2 School of Medicine and Pharmacology, University of Western Australia, Perth, WA, AUSTRALIA, 2School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases. The University of Western Australia, Perth, WA, AUSTRALIA 1 Objectives: Immune checkpoint blockade, such as anti-CTLA4 and anti-PD1 has shown impressive results in several cancer types, with durable complete regression in a proportion of patients. Conversely, the majority of patients do not display tumour regression. It is unknown what molecular events determine this dichotomous response, nor which co-treatments are likely to combine effectively with checkpoint blockade. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective therapeutic interventions. Methods: To compare the molecular events in responders versus non-responders, we treated mice with bilateral AB1-HA mesothelioma tumours, which respond symmetrically to anti-CTLA4. We used a weighted gene correlated network analysis (WGCNA) of gene expression profiling data from responding versus non-responding tumours to identify modules associated with response. In addition, we used upstream regulator analysis and interrogated genome-wide drug-pertubation signatures in the connectivity map database to identify repurposed drugs that would phenocopy the response-associated network, and thus increase the response rate to anti-CTLA4. Results: We found two modules highly significantly differentially expressed; one enriched for cancer-associated genes, one for iMig2016.ORG 116 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02: POSTER MIXER AND POSTER DISCUSSION SESSION 2 TUESDAY, MAY 3, 2016 18:00 – 19:30 PP02.02: LOCALIZED SPLENIC REOCCURRENCE IN MALIGNANT PERITONEAL MESOTHELIOMA Rivka Thurm, Gleneara E. Bates, Yaakov Bressler, Robert N. Taub Medicine, Columbia University Medical Center, New York, NY, UNITED STATES OF AMERICA PP02.01: ART AND SCIENCE: RELATIONSHIP WITH HUMAN ANATOMY FROM AESTHETIC AND SCIENTIFIC PERSPECTIVES Guillermo A. Villamizar FundClas, Bogotá, COLOMBIA Objectives: Along art history, different artists were important to get close the nature of anatomy expressed in bones, muscles and vessels to their audiences through drawings which permitted to see them in both ways: as science in their subject and art in their aesthetical potential. To reveal what is unknown is part art and part science and the body now speaks itself from deep-seated physical structures of human anatomy, something the eye of the artist can’t see, neither the physician. Represent that body is not possible anymore but only using the new technologies. And this way, it becomes a challenge when the sensitive spirit wants to show what he can’t see by its own tools: the eyes. Representation of the human body was for artist a contribution to the knowledge of diseases, and when this is not possible anymore, what the artist do is to draw a kind of social body. Why? It is a representation that only can be done by mobilizing forces beyond the artist studio and the wisdom that the drawing can offer to him. This is the reason for artist working now with physicians, scientist, workers and union workers, lawyers, sociologists, anthropologists and social activists, all a social body which helps to visualize what the eye can’t see: that disease which affects not only a person but yes to a wide population turning out into a problem of public health, as it is the case of ARD, including mesothelioma. Methods: This investigation is done from the art field and its methodologies are not scientific and therefore its methodologies are empirical. This type of job has a symbolic and communicative dimension that is not possible to measure in science parameters. Results: During last two years I have been involved –as artistdoing art exhibitions where the main focus of it has been asbestos hazards and ARD too. Every exhibition includes distribution of flyers, presentation of conferences and production of images alerting to the public in Colombia about ARD. My activity includes visits to medicine schools, meetings with union workers and lawyers for discussing actions to prevent and alert about ARD and seeking ways for banning asbestos in Colombia. Since then, many people in Colombia are conscious about asbestos hazards and ARD and Colombian society is giving steps toward banning asbestos. Conclusion: The mixing of art and science shows the extraordinary possibility that this approach have as a vehicle for communicate the ARD. Objectives: Metastases to the spleen, while relatively common in hematologic cancers, are rare in solid tumors, occurring in only 0.3–7.3% of cases. The rarity of splenic metastasis in solid cancers is thought to be a result of the splenic vascular structure inhibiting entry of emboli of metastatic cancer cells. It has also been proposed that the long retention time (~10 minutes) of leukocytes within the spleen creates a hostile environment for tumor seeding and growth. Of splenic metastases, the majority are found as part of late-stage systemic disease or are discovered on autopsy. Methods: An IRB approved, retrospective chart review of mesothelioma patients treated at CUMC from 1995–2015. Results: A single patient was identified as having an isolated splenic reoccurrence, which was discovered and monitored by serial CT scans and confirmed on splenectomy. In 2007, the 68-year-old male presented with weight loss, diffuse mid to upper body abdominal discomfort, loss of appetite, and postprandial fullness. CT scans showed infiltration of the mesentery and thickening of the omentum, and he underwent laparoscopy in June 2007. Several 2 to 4 mm pearly nodules were found on the parietal peritoneum and gutters bilaterally and the anterior abdominal wall. Pathology showed poorly differentiated malignant cells consistent with epithelioid mesothelioma. In August 2007, the patient underwent exploratory laparotomy, cytoreduction, and HIPEC with Cisplatin. The surgical pathology report was consistent with MPM with widespread infiltration of intra-abdominal soft tissue. Histology showed malignant mesothelioma, biphasic subtype (60% epithelioid, 40% sarcomatoid). The patient then received four cycles of intraperitoneal (IP) chemotherapy (Doxorubicin/Oxaliplatin) combined with six cycles of systemic chemotherapy (Gemcitabine/Oxaliplatin), followed by four weekly doses of IP gamma interferon (2 million units). Follow-up surveillance by CT scan was performed at 3-6 month intervals for three years, then yearly. A routine CT scan in October 2012 showed a new 33.6 mm mass in the spleen which mandated a follow-up scan three months later at which time the mass had grown to 44.6 mm. This prompted surgical consultation and splenectomy in February 2013. Pathology showed extensively necrotic malignant mesothelioma, biphasic subtype (70% epithelioid, 30% sarcomatoid) infiltrating into the splenic parenchyma. The tumor was WT1 and CK5 positive and P16 negative, indicating an aggressive phenotype similar to the parent tumor. Since splenectomy, the patient has been progression-free. Conclusion: Quarterly CT scans allowed early detection and intervention in this case, preventing the disease from spreading to the peritoneal space. This report demonstrates that continual monitoring by serial CT scans can help early detection of novel MPM reoccurrences. Keywords: mesothelioma, Peritoneal, Spleen, Metastasis iMig2016.ORG 117 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP ponent of histology shows non-sarcomatous type. PP02.03: RADIOLOGICAL FEATURES OF PLEURAL MESOTHELIOMA COMPARED WITH CASES DIAGNOSED BEFORE AND AFTER 2008 IN JAPAN Keywords: sarcomatous mesothelioma, pleural rind, pleural effusion without any pleural chages, feature of pleural mesothelioma Takumi Kishimoto Reseach Center For Asbesstos-related Diseases, Okayama Rosai Hospital, Okayama, JAPAN Objectives: We already presented 7 types of radiological patterns of pleural mesothelioma(PM) and the pleural rind occupied 42% and pleural effusion without any pleural changes 12%. In this study, we divided these cases into the time diagnosed before and after 2008 and compared the percentage of these patterns. Methods: Seven hundred and eight cases of pleural mesothelioma who were pathologically confirmed were evaluated. Four hundred and eighty two cases(group 1) collected from all over Japan in 2003 to 2008, 90 cases diagnosed before 2008(group 2) and 90 cases after 2009 (group 3) obtained from Okayama Rosai Hospital. The pattern of chest CT at the time which mesothelioma was diagnosed were classified into 7 category such as 1)solitary-mass formation, 2)pleural rind, 3)slight thickening of pleura, 4)thickening of mediastinal pleura, 5)pleural effusion without any pleural changes, 6)multi-mass formation and 7) specific type. Furthermore, the radiological patterns of the histological differences were evaluated. Results: For histological classification, 364(57.2%) cases showed epithelioid histology, 112 cases(17.6%) biphasic type and 155 cases(24.4%) were sarcomatoid type and 5 cases(0.8%) were specific type. The radiological patterns in each 3 groups shows in Figure 1. The pattern of pleural effusion without any pleural changes occupied 25.4% in group 3. On the other hand, pleural rind showed only 32.4%. This number significantly increased than only 7.1 % of group1 and 10% of group 2. Almost all cases who showed pleural effusion without any pleural changes were diagnosed in the early stages using thoracoscopy guided pleural biopsy. But for sarcomatoid type, this pattern occupied only 9.1% of Group 3. Fig1 Conclusion: Nowadays, in Okayama Rosai Hospital, about 25% of PM are diagnosed at the early stage which shows only pleural effusion without any changes of pleural and main com- PP02.04: CT FINDINGS OF MALIGNANT PLEURAL MESOTHELIOMA AND CORRELATION WITH THE SURVIVAL PERIOD Katsuya Kato1, Kenichi Gemba2, Kazuto Ashizawa3 , Takumi Kishimoto4 , Nobukazu Fujimoto5, Keisuke Aoe6 , Yukio Takeshima7, Kouki Inai8 Diagnostic Radiology2, Kawasaki Medical School, Okayama, JAPAN, 2Chugoku-Chuo Hospital, Fukuyama, JAPAN, 3Nagasaki University School of Medicine, Nagasaki, JAPAN, 4Research Center Of Asbestos-related Diseases, Okayama Rosai Hospital, Okayama City, JAPAN, 5Okayama Rosai Hospital, Okayama, JAPAN, 6National Hospital Organization Yamaguchi-Ube Medical Center, Ube, JAPAN, 7Hiroshima University School of Medicine, Hiroshima, JAPAN, 8Diagnostic Pathology Center, Hiroshima, JAPAN 1 Objectives: The aim of this study was to demonstrate CT findings of malignant pleural mesothelioma (MPM) and to determine their correlation with survival time in patients with MPM. Methods: In total, 142 patients with MPM were continuously enrolled at Okayama Rosai Hospital from Oct 1955 to Oct 2015. All these patients had 1) pathologically proven MPM; 2) undergone CT at the time of diagnosis, and 3) follow-up clinical records. The CT findings at the time of diagnosis were retrospectively reviewed and the survival periods were analyzed. To assess the extent of MPM lesion, the thorax was divided into three zones according to the upper border of the aortic arch and the inflow portion of the inferior pulmonary vein to the heart. The number of MPM-involved zones was scored as 0–3. We defined this score as the “extensive score” to quantify the tumor volume. Results: We found 142 patients with MPM between 1995 and 2015. Of these, 130 were men and 12 were women. The mean age at the time of diagnosis was 69 years (range, 42–91 years). The pathological subtypes were as follows: epithelial type, 99 cases (70%); biphasic type, 16 cases (11%); sarcomatous type, 25 cases (17%); lymphoepithelial type, 2 cases (1%). The overall median survival time (MST) was 12.0 months (range, 0.7–103.2 months). Pleural plaques were detected in 62 cases (44%) and calcification in 46 cases (32%). Asbestosis was present in only one (1%) case, and no case of diffuse pleural thickening was found. The MPM-related CT findings were as follows: circumferential pleural thickening, (“pleural rind”) 43 cases (30%); mediastinal pleural thickening, 104 cases (73%); interlobar fissural thickening, 78 cases (55%); pericardial invasion, 42 cases (30%); diaphragmatic invasion, 23 cases (16%); thoracic volume loss, 72 cases (51%); pleural effusion, 118 cases (83%); pneumothorax, 4 cases (3%); solitary mass formation, 12 cases (8%); and multiple mass formation, 42 cases (30%). The extensive scores were as follows: 0 points iMig2016.ORG 118 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP (no pleural thickening), 13 cases (9%); 1 point, 16 cases (11%); 2 points, 13 cases (9%); and 4 points, 100 cases (70%). The median thickness of the thickest part of the MPM lesions was 14 mm (range, 0–87 mm). Lesions with a thickness of 5 mm > (P = 0.001) and 10 mm > (P = 0.004) and extensive scores of 1–3 (P = 0.013) were significantly correlated with nonepithelial-type MPM. The other CT findings showed no significant correlation with the pathological subtypes. On a multivariate analysis, a low extensive score (0–2 points vs. 3 points) and the epithelial subtype were associated with longer MST (hazard ratio [HR], 1.95; 95% confidence interval (CI), 1.21–3.04; p = 0.006; and HR, 2.11; 95% CI, 1.42–3.13; p < 0.001). Conclusion: Epithelial mesothelioma was significantly associated with thin pleura and a low extensive score at the time of diagnosis. The other CT findings showed no significant correlation with the pathological subtypes. The epithelial histologic subtype and a lower extensive score on CT at the time of diagnosis were significantly related to a longer MST in patients with MPM. Keywords: CT, survival period, mesotheliom, pleura PP02.05: ASBESTOS BODY AND PLEURAL PLAQUE OF PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA WHO UNDERWENT EXTRAPLEURAL PNEUMONECTOMY Kazunori Okabe1, Hiroyuki Tao2, Toshiki Tanaka2, Tatsurou Hayashi2, Kouichi Yoshiyama2, Masashi Furukawa2, Kumiko Yoshida2, Katsuya Katou3 Division of Thoracic Surgery, Yamaguchi Ube Medical Center, Ube, JAPAN, 2Yamaguchi Ube Medical Center, Ube, JAPAN, 3 Kawasaki Hospital, Okayama, JAPAN 1 Objectives: Malignant pleural mesothelioma (MPM) has been recognized as related to asbestos inhalation. Pleural plaque is the main radiological finding of asbestos inhalation. The aim of this study is to analyze the asbestos body counts in the lungs and pleural plaques of patients with MPM who underwent extrapleural pneumonectomy (EPP). Methods: Forty consecutive MPM patients who underwent EPP from June 2006 to August 2014 were reviewed. Asbestos body quantification involved the digestion of 1-4 grams of lung tissue in bleach employing a modified Smith and Naylor method1). Pleural plaque in the contralateral chest was evaluated by CT, and graded as 0 (none), 1 (low), 2 (moderate), or 3 (high). [Reference] 1) Smith MJ, Naylor B. Am J Clin Pathol 1972; 58:250-254 Results: The median age was 61 years old (42 - 74). 32 males and 8 females were operated. The median asbestos body count was 6,540/g dry lung (range: lower than the detection limit 443,571). The asbestos body counts of eight patients (20%) were less than 1,000/g dry lung. The pleural plaques of 20 patients were graded as 0 (none), 16 patients were graded as 1 (low), 3 patients were graded as 2 (moderate), and 1 patient was graded as 3 (high). As shown on the table below, the asbestos body count was proportional to the pleural plaque. Table: Asbestos body count in the lung and pleural plaque grade The asbestos body counts were listed in numerical order. asbestos body /g, dry lung 7,169 7,209 7,706 7,862 7,882 8,125 9,029 9,313 9,471 10,087 16,556 18,756 19,916 24,036 51,073 153,110 159,579 186,649 319,989 443,571 pleural plaque grade 0 1 0 0 0 0 1 1 1 1 2 0 1 1 2 0 1 3 1 2 asbestos body /g, dry lung < lower limit < lower limit 65 196 265 524 711 878 1,600 1,772 2,030 2,279 2,319 2,340 2,532 2,994 3,412 4,027 5,127 5,911 pleural plaque grade 0 0 0 0 0 1 0 0 1 1 0 1 0 0 1 1 1 0 0 0 Conclusion: One half of the MPM patients who underwent EPP had no finding of pleural plaque on CT. The asbestos body counts in the lungs were less than 1,000/g dry lung in 20% of the MPM patients who underwent EPP. The asbestos body count in the lung was proportional to the pleural plaque. Keywords: pleural plaque, asbestos body, extrapleural pneumonectomy, Malignant pleural mesothelioma iMig2016.ORG 119 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.06: THE IMAGING JOURNEY OF A PATIENT WITH MALIGNANT MESOTHELIOMA Vincent Lam, Jan Brozik, Daniel T. Barnes 2015 demonstrated a large right pleural effusion and cytology demonstrated epitheloid mesothelioma. He was commenced on chemotherapy. After 2 cycles, a follow up CT demonstrated florid peritoneal and pleural disease and he is receiving further chemotherapy. Radiology Department, Glenfield Hospital, University Hospitals of Leicester, Leicester, UNITED KINGDOM Objectives: We will describe and demonstrate, with appropriate examples, the imaging of patients with malignant pleural mesothelioma (MPM) in a tertiary thoracic centre. We will highlight salient CT findings relating to: Diagnosis including appearances post-surgical intervention/ talc pleurodesis. Pre-operative imaging including contraindications for radical surgery. Post-operative appearances, particularly relating to radical versus non-radical surgery, as well as highlighting the difference between “normal post-operative appearances” and progressive disease. Methods: Cases were retrospectively analysed and selected from the dedicated, regional University Hospitals of Leicester Mesothelioma Multi-Disciplinary Team (MDT) meeting according to the above criteria, from June 2013 to December 2015. This MDT evaluated 445 patients (367 male) in this period. Results: It is important to recognise the normal post-operative appearances of MPM to correctly guide patient care. Appropriate images exemplifying different aspects of a patient’s imaging pathway are included. Fig 1. CT Chest Abdomen and Pelvis, coronal section of a 77 year old male referred for an extended pleurectomy and decortication with diaphragmatic patch repair. Post-operative imaging revealed an atypical loculated chylous collection (denoted by the asterix) with a right basal fluid collection either side of diaphragmatic patch (white arrows). Conclusion: Imaging is integral to the patient’s journey, beginning from the diagnosis of MPM through to staging, post-surgical follow-up and palliative care. The role of a radiologist is vital to delivering an optimum patient-centred service. Keywords: Post-operative appearances PP02.07: PATTERNS OF DETECTABLE TUMOR PROGRESSION IN PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA WITH AN FDG-PETNEGATIVE T1A TUMOR Kozo Kuribayashi1, Takayuki Terada1, Taiichiro Otsuki1, Eisuke Shibata1, Koji Mikami1, Tohru Tsujimura2, Seiki Hasegawa3 , Takashi Nakano1 Hyogo College of Medicine, Department of Respiratory Medicine, Nishinomiya, Hyogo, JAPAN, 2Hyogo College of Medicine, Department of Pathology, Nishinomiya, Hyogo, JAPAN, 3Hyogo College of Medicine, Department of Thoracic Surgery, Nishinomiya, Hyogo, JAPAN 1 Fig 2. CT Chest, Abdomen and Pelvis, coronal section. A 78 year old male presented with increased shortness of breath and previous asbestos exposure. An initial CXR in August Objectives: T1a refers to a very early tumor that involves only the parietal pleura of one hemithorax without any mediastinal or diaphragmatic involvement, and that spares the visceral pleura. T1 tumors are usually associated with free pleural space and large effusion. Early in its clinical course, malignant pleural mesothelioma (MPM) tends to remain localized to the ipsilateral hemithorax for a long period and radiological tests do not show any obvious nodules on the parietal pleura. Usually, FDG-PET/ CT cannot detect small malignant pleural nodules. We evaluatiMig2016.ORG 120 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP ed the patterns of detectable tumor progression in patients with MPM with an FDG-PET-negative T1a tumor. Methods: Seven MPM patients (5 males, 2 females) with an FDG-PET-negative T1a tumor were followed-up with FDG-PET at our institution. Results: The median interval between the first negative PET scan and the positive follow-up scan to identify ipsilateral malignant pleural nodule was 32 months (5-46 months). In two patients with epithelioid mesothelioma, the median interval, between the first negative PET scan and positive follow-up scan to identify malignant nodules at the sites of thoracoscopy, was shorter at 5 and 8 months, respectively. In 4 patients, PET detected localized pleural nodules that were 5.1–8.2 mm in diameter on the CT scan. One patient showed diffuse pleural thickening with an FDG-PET-positive tumor with a thickness of 6.5 mm. Conclusion: FDG-PET is a valuable modality for detecting the progression of T1a tumors >5 mm in diameter. The median interval between the first negative PET scan and the positive follow-up scan was long (32 months), and subcutaneous implantation at the site of thoracoscopy is an early manifestation of MPM. PP02.08: LYMPHANGITIC CARCINOMATOSIS: A COMMON FORM OF PROGRESSION IN MALIGNANT PLEURAL MESOTHELIOMA FOLLOWING RADICAL PLEURECTOMY Ian B. Berger1, Charles B. Simone1, Andrew Haas1, Evan Alley1, Keith A. Cengel1, Joseph Friedberg2, Urooj Khalid1, Akash Patel1, Sharyn Katz1 Perelman School of Medicine, Philadelphia, PA, UNITED STATES OF AMERICA, 2University of Maryland School of Medicine, Baltimore, MD, UNITED STATES OF AMERICA 1 Objectives: Lymphangitic carcinomatosis is a pattern of metastatic progression that is generally associated with a poor prognosis, but has not been well-described in the setting of malignant pleural mesothelioma. Here, we examine the incidence of development of lymphangitic carcinomatosis as a pattern of failure in the setting of radical pleurectomy. Methods: All patients with a diagnosis of malignant pleural mesothelioma undergoing radical pleurectomy at our institution between 2008 and 2012 were included in this retrospective study. Patients without available post-surgical follow-up CT imaging for review were excluded. CT images were reviewed by an experienced, board-certified thoracic radiologist for the presence of lymphangitic carcinomatosis characterized by progressive interlobular septal thickening often accompanied by axial peribronchial thickening. Cases felt to be positive or potentially positive for lymphangitic carcinomatosis were then reviewed by consensus by the PENN Mesothelioma and Pleural Program Multi-disciplinary Team. Results: Of the patients who underwent radial pleurectomy in the specified time frame, a total of 46 patients had serial follow-up imaging available at our institution. A total of 16 of the 46 patients (34%) developed lymphangitic carcinomatosis during the post-surgical period. The median time to lymphangitic carcinomatosis was 12 months following surgery, and the median post-surgical CT follow up period was 19 months. Conclusion: Lymphangitic carcinomatosis is a common and likely underreported manifestation of disease progression in patients with malignant pleural mesothelioma undergoing radical pleurectomy. Additionally investigation is needed to determine how lymphangitic carcinomatosis impacts survival in patients undergoing radical pleurectomy and if surgery alters failure patterns compared with systemic therapy alone in patients with malignant pleural mesothelioma. Keywords: pleurectomy, lymphangitic carcinomatosis, CT, mesothelioma PP02.09: MALIGNANT PLEURAL MESOTHELIOMA, DEMOGRAPHIC DATA AND CLINICAL STAGING OF 193 CONSECUTIVE PATIENTS Amr M. Eldemery1, Abdelrahman M. Abdelrahman2, Fatma M.A. Aou El-Kasem3 , Rabab M. Gaafar4 , Hisham Wahba5, Maha Yahia6 , Eman Loay7 Surgery, National Cancer Institute, Cairo, EGYPT, 2Surgery, National Cancer Institute, Cairo, EGYPT, 3Medical Oncology, National Cancer institute, Cairo, EGYPT, 4Medical Oncology, National Cancer Institute, Cairo, EGYPT, 5Radiology, National Cancer Institute, Cairo, EGYPT, 6Medical Oncology, National Cancer Institute, Cairo, EGYPT, 7Pathology, National Cancer Institute, Cairo, EGYPT 1 Objectives: Malignant pleural mesothelioma is a rising health problem in some countries allover the world including ours. In spite of rarity of this disease , we have rising incidence every year and the curve of referral to our institution is going up. The aim of this study is to outline the demographic data of our patients, analyze the clinical staging based on radiology and its relation to pathologic subtype of the disease. Methods: This is a retrospective study included 193 patient with pathology proven pleural mesothelioma referred to our hospital during the period from May 2014 to August 2015 . Computed tomography scan of the chest and abdomen is the primary diagnostic and staging modality in all patients. Full history Taking including residence near by or working in asbestos related industry. All radiologic data were revised with the same radiologist . Results: Of the 193 patients studied, we have 96 males with male to female ratio 1:1, the mean age was 43years. Right sided disease was present in 63.7% , bilateral disease was found in only 3 patients at the time of diagnosis. Pleural effusion was the only radiologic finding in 45.6% ,diffuse pleural thickening was found in 24.4%, 15.5% had nodular thickening , 9.8% had combined thickening and effusion and only 4.7% presented with solitary pleural based mass. Evident contacted hemithoiMig2016.ORG 121 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP rax by CT was found in 37.8%, mediastinal fat invasion was found in 36.8%, chest wall invasion in 9.3%, 4% had suspected pericardial invasion 2 of them with pericardial effusion. Adjacent organ invasion was found in 10 patients (5.1%). Lung invasion was found in 37 patients and there were 6 patients with metastatic disease at presentation ( 2 liver, 2 bone , 1 brain and one suprarenal) . Enlarged mediastinal lymph nodes by CT was found in72 patients (37.3%). By Computed tomography, 45% of our patients were stag 1, 33.3% stage III, 12.4% were stage IV and only 9.3 were stage II. Some patient were referred after pathologic diagnosis, for the rest of undiagnosed patients , biopsy either CT guided , open or thoracoscopic biopsy was done. There were 172 with epithelial histology, 11 with biphasic, 6 with sarcomatoid histoogy and we have 4 patients with pathology proven adenocarcinoma without any evidence of other primary. Two patients with biphasic histology had mediastinal nodal enlargement by CT, 2 with pulmonary nodules, one with both nodal enlargement and chest wall invasion and one with pericardial effusion. Of the 6 patients with sarcomatoid histology , one had metastatic disease and 2 had T2 ( pulmonary nodules) disease. Conclusion: Malignant pleural mesothelioma is arising health problem. Pleura effusion is a good clinical sign that lead to early symptomatology and diagnosis at early stage. Patients should be evaluated and treated in highly specialized centers. Patients with biphasic and sarcomatoid histology usually present with late stage. Keywords: Mesothelioma, clinical, staging PP02.10: INTO THE DEEP: CLOSER LOOK AT IMMUNE CELLS AND IMMUNE CHECKPOINT EXPRESSION IN HUMAN MALIGNANT PLEURAL MESOTHELIOMA Elly Marcq1, Vasiliki Siozopoulou2, Jorrit De Waele1, Jonas Van Audenaerde1, Karen Zwaenepoel2, Christophe Hermans1, Niel Hens3 , Patrick Pauwels2, Jan Van Meerbeeck4 , Evelien Smits1 Center for Oncological Research, University of Antwerp, Antwerp, BELGIUM, 2Department of Pathology, Antwerp University Hospital, Antwerp, BELGIUM, 3Interuniversity Institute for Biostatistics and statistical Bioinformatics, Hasselt University, Diepenbeek, BELGIUM, 4Thoracic Oncology/MOCA, Antwerp University Hospital, Antwerp, BELGIUM 1 immune cells in the tumor microenvironment. Methods: Immunohistochemistry was used to examine the expression of several immune cell markers, as well as the expression of PD-1 and PD-L1, in formalin fixed paraffin embedded (FFPE) tissue of 54 MPM patients (42 at diagnosis, 12 treated with chemotherapy). Identification of different subsets of cells present in MPM fluids (ascites and pleura) was done using multicolor flow cytometry and an enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of soluble PD-L1 in 10 MPM serum samples. To examine whether correlations exist between the expression data and several clinicopathological parameters of the MPM patients statistical analysis is being performed. Results: Immunohistochemistry showed PD-1 expression on lymphocytes in 67% of the treated and untreated samples, while the expression on tumor cells was only found in few samples. PD-L1 expression on its turn was seen on lymphocytes and on tumor cells, for the latter only in untreated tissues. All samples showed CD45RO positive lymphocytes. CD4+ and CD8+ lymphocytes were found in the stroma and in hotspots of the lymphoid aggregates in all samples. In more than half of the untreated samples, a subset of the CD4+ cells was also FoxP3+. The same holds true for the treated samples. Compared to the untreated, more CD4+FoxP3+ cells were found in lymphoid aggregates of the treated samples (36% vs 50%). Stromal CD68+ histiocytes and macrophages were found in all tissue samples. TIM-3 expression was found on tumor cells and lymphocytes in untreated, as well as in treated samples. Flow cytometry showed PD-1 expression on CD3+CD4+ T cells and CD3-CD56+ natural killer cells. PD-L1 was expressed on the CD11c+CD303+ dendritic cells. Correlations between expression data and clinicopathological parameters are currently being analyzed and will be presented. Soluble PD-L1 was found in all serum samples, with a concentration ranging from 0.71 ng/ml till 2.33 ng/ml. Conclusion: Immunohistochemistry and flow cytometry revealed the diversity of immune cells present in MPM. Since some of those cells express PD-1 or PD-L1, it would be worth further investigating the effect of immune checkpoint blockade in MPM. Reactivating immune responses that are silenced by immune checkpoint receptor-ligand interaction might offer new opportunities for the improvement of therapeutic strategies for mesothelioma. Surprisingly, all patient serum samples were positive for soluble PD-L1, requiring further investigation to determine its value as biomarker. Keywords: immune checkpoints, tumor microenvironment, Immunotherapy Objectives: Immune checkpoints, such as programmed death-1 (PD-1), are responsible for controlling and inactivating the immune system in order to avoid autoimmunity and prevent tissue damage. Blocking the ligand-immune checkpoint interaction already showed promising results in several cancer types. Data derived from a small number of mesothelioma patients suggest that blocking immune checkpoints could offer new opportunities for treatment of this very aggressive tumor. Gaining more insight in the immunological aspect of the tumor microenvironment in human malignant pleural mesothelioma (MPM) would be of great interest to develop an efficient immunotherapy. Therefore, we investigated the expression of PD-1 and its ligand PD-L1 in human MPM and identified different subsets of iMig2016.ORG 122 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.11: DEVELOPMENT OF NOVEL THERAPEUTICS TARGETING MALIGNANT PLEURAL MESOTHELIOMA PP02.12: INHIBITION OF METHYLTRANSFERASE EZH2 IMPROVES TUMORICIDAL ACTIVITY OF MACROPHAGES AGAINST MESOTHELIOMA CELLS Perry Devo Malik Hamaidia, Luc Willems Pharmaceutical, Environmental And Chemical Sciences, University of Greenwich, London, UNITED KINGDOMObjec- Molecular And Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège, Liège, BELGIUM tives: · To synthesise and investigate the anticancer potential of novel and newly discovered natural products against malignant pleural mesothelioma (MPM). · To synthesise and evaluate a number of analogues both to investigate the mode of action of these compounds and to improve on their anticancer potency. Methods: Natural products JBIR23, -24, -31, -88, -101 and -102 have all been isolated from various species of Streptomyces. Each compound has been shown to have anti-cancer properties against the ACC-MESO-1 cell line. Fragments building up to the natural product were also tested against MPM cell lines to evaluate their structure activity relationship and analogues were created depending on their anticancer activity. Results: Various attempts towards the synthesis of JBIR-23 and JBIR-101 will be reported. Using an optimised synthetic route, a number of chemical analogues have also been synthesised. These synthetic analogues were assessed for their anticancer activity and further analogues were synthesised to improve on their potency. The biological activity against the ACC-MESO-1 cell line will be presented. Conclusion: MPM is an aggressive neoplasm and current therapeutics are ineffective in the treatment of this malignancy. Therefore the investigation and development of potential novel chemotherapeutics is essential going forward. Our research to date has shown that natural products are a valuable source for the identification of novel compounds in the future treatment of MPM. Keywords: medicinal chemistry, Preclinical, chemotherapy, natural products Objectives: Clinical evidence indicates that tumor infiltration by tumor associated macrophages (TAMs) correlates with poor prognosis in malignant mesothelioma (MM). By attenuating the immune response, TAMs indeed promote survival of MM cells. TAMs share properties with alternative macrophages (M2) and are activated by anti-inflammatory (e.g. IL-10) or Th2-associated (i.e. IL-4, IL-13) cytokines. In contrast, classical (M1) macrophages are stimulated by interferon (IFN)-γ and microbial components (e.g. LPS). We hypothesized that macrophage activation is mediated by a transcriptional program tightly regulated by epigenetic modifications. We focused on the Polycomb Repressive Complex 2 (PRC-2) EZH2 lysine methyltransferase responsible for trimethylation of histone H3 at lysine 27 (H3K27me3). We investigated the effect of a selective EZH2 inhibitor (EPZ005687) on tumoricidal activity of Raw 264.7 and primary human monocytes-derived macrophages. Methods: Raw 264.7 macrophages were cultivated in presence of EPZ005687 for 24h and then LPS for 24h. Human macrophages were treated with EPZ005687 for 24h before polarisation into M1 (in presence of LPS and IFN-γ) or M2 (with IL-4). The phagocytic activity was evaluated by using dextran-FITC. ROS production was determined with the DCFH-DA probe. Expression of CD206 and HLA-DR was analysed by flow cytometry. Cytotoxic activity was performed by incubating AB-1 and M14K mesothelioma cells in media supplemented with 25% or 50% of macrophage supernatant. Viability of mesothelioma cells was assessed by performing MTS assay and Annexin-V labeling. NADPH oxidase was inhibited with apocynin. Results: Our data show that inhibition of EZH2 increases phagocytosis in response to LPS stimulation, reduces CD206 expression by human M2 macrophages and enhances cytotoxic activity against mesothelioma cells. We further demonstrate that EZH2 inhibition stimulates macrophage killing activity via reactive oxigen species produced by NADPH oxidase. Conclusion: The inhibition of EZH2 enhances the tumoricidal potential of macrophages. This strategy could improve immunotherapy of MM patients. Keywords: Immunotherapy, epigenetic inhibitors, Malignant mesothelioma, Tumor associated macrophages iMig2016.ORG 123 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.13: THE DL 922-947 ONCOLYTIC VIRUS AS A NEW POSSIBLE THERAPEUTIC TOOL AGAINST MESOTHELIOMA Carmelina A. Iannuzzi1, Carmela Passaro2, Iris M. Forte3 , Paola Indovina4 , Giuseppe Portella5, Antonio Giordano6 , Francesca Pentimalli3 Department of Medicine, Surgery And Neuroscience, University of Siena, Siena, ITALY, 2Dipartimento Di Scienze Mediche Traslazionali, University of Naples, Naples, ITALY, 3Oncology Research Center Mercogliano (crom), National Cancer Institute of Naples Pascale Foundation, Avellino, ITALY, 4Sbarro Institute for Cancer Research and Molecular Medicine, Philadelphia, PA, UNITED STATES OF AMERICA, 5University of Naples, Naples, ITALY, 6University of Siena, Siena, ITALY 1 Objectives: Malignant mesothelioma (MM) is a highly aggressive cancer for which, at present, no curative modalities exist. MM in fact is poorly responsive to the current therapeutic strategies, resulting in a dismal prognosis. New alternative therapeutic approaches are therefore urgently needed. Here we aimed at investigating at the preclinical level whether oncolytic viruses could represent a feasible strategy. Oncolytic viruses have different advantages as anticancer agents: they replicate selectively in tumor cells with amplification of the input dose; they are able to stimulate the antitumoral immune response; they can be used in combination with other cytotoxic agents; the pleural cavity in which pleural MM arises is easily accessible for such therapeutic approach. We focused on the dl 922-947 adenovirus having a 24 bp deletion in the E1A-conserved region 2, which binds and inactivates the retinoblastoma protein, resulting in a virus that cannot trigger S phase entry in normal cells, but can still replicate in cells with an aberrant G1-S checkpoint, a defect observed in over 90% human cancers, including MM. Methods: We studied on NCI-H28, NCI-H2452, MSTO-211H and NCI-H2052 (a panel of mesothelioma cell lines representative of the main different histotypes) the effects of dl 922-947 treatment used both as a single agent or in combination with other strategies (cisplatin and MK-1775). We analyzed the effects of these treatments on cell viability through sulforhodamine B (SRB) assay and FACS analyses. We analyzed the synergy among various treatment combinations through the Calcusyn Software and by Western blot we evaluated the underlying molecular mechanisms. Results: At first, dl 922-947 cytotoxicity was evaluated through SRB, which showed that all MM cell lines were susceptible to viral treatment, except NCI-H2052 cells, in which viral entry was not efficient, as shown through infection with a reporter adenovirus transducing GFP. Interestingly and consistently with the cytotoxic effect observed, FACS analysis showed that dl 922-947 treatment induced an increase of the subG1 cell fraction (suggestive of apoptosis induction) and of the hyperdiploid (4N) population (suggestive of mitotic defects). We also investigated by SRB the possible cytotoxic effects of dl922-947 in combination with other therapeutic strategies. In particular, we analyzed the effect of dl922-947 in combination with cisplatin, which is the first-line treatment against MM, and found that, by comparing different schedules of treatment, cisplatin increased the cytotoxic effect of the oncolytic virus. We also tested dl922947 efficacy in combination with MK-1775, an efficient inhibitor of the WEE1 kinase, which is currently being tested in clinical trials. We found that MK-1775, at doses equal to or above its IC50 value, is able to increase the cytotoxic effect of the oncolytic virus treatment. Conclusion: In conclusion our data indicate that treatment with the dl922-947 oncolytic virus might be a promising new approach against mesothelioma and warrants further investigation both as single agent and in combination strategies. Keywords: Oncolytic viruses, WEE1 kinase inhibitor, combination therapy, mesothelioma PP02.14: CHARACTERISING CTL RESPONSES AGAINST MESOTHELIOMA NEO-ANTIGENS Jonathan Chee, Shaokang Ma, Jenette Creaney, Bruce Robinson School of Medicine and Pharmacology, National Centre of Asbestos Related Diseases, University of Western Australia, Nedlands, WA, AUSTRALIA Objectives: A feature of carcinogen-induced cancers is the accumulation of mutations in the cancer cell. High throughput sequencing such as RNA and exome sequencing has allowed us to interrogate mutations from different cancers. Application of algorithms on sequencing data allows us to predict mutated proteins in a cancer that can be potentially recognised by host immune cells such as cytotoxic CD8 T cells (CTLs). CTLs respond against mutated proteins (neo-antigens), and in some experimental models, boosting CTL responses specifically against neo-antigens can cause tumour regression. We have sequenced mouse mesothelioma (AB1/AB1-HA), and described the first mesothelioma neo-antigens. Furthermore, we have demonstrated immune responses against one of the predicted neo-antigens: mutated Uqcrc2 (Uq2) in mesothelioma bearing animals. The objective of this study was to characterize further characterize T cell responses against neo-antigens in tumour bearing animals after different treatments that cause tumour regression in AB1 model. We hypothesize that treatments will increase the strength of responses to ‘existing’ neo-antigens such as Uq2, and could also lead to the detection of responses against other neo-antigens that would otherwise be undetectable without treatment. Methods: Mice were inoculated subcutaneously with mesothelioma cell lines (AB1-HA). AB1-HA bearing animals were treated either with anti-CTLA4 antibody (checkpoint blockade immunotherapy), anti-GITR antibody(Treg modulation), gemcitabine (chemotherapy) or depleted of Tregs (removal of immunosuppression). We tested T cell responses at the draining lymph nodes and tumours against predicted neo-antigens using different immunoassays such as IFNg ELISPOT, pMHC tetramers and flow cytometry. Results: The frequency of T cells specific for a single neo-antigen (Uq2) is low (<0.1%). ELISPOT was the only immunoassay tested that could detect responses against neo-antigens. Conventional pMHC staining and flow cytometry was not sensitive iMig2016.ORG 124 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP enough to detect a positive signal for low frequency T cells. Using the ELISPOT assay, we demonstrate the frequency of T cell responses to neo-antigen Uq2 was highly variable between mice after treatment, and showed a general trend of increase after checkpoint blockade immunotherapy, chemotherapy or Treg removal (compared to non-treated mice). Treatments did not increase T cell responses to 30 other predicted neo-antigens. Conclusion: As the frequencies of neo-antigen specific T cells are low, we were only able to consistently detect neo-antigen responses with one immunoassay. Assays with increased sensitivities, or an additional T cell expansion step must be used to detect and phenotype neo-antigen specific T cells. Even though we detected an increase in neo-antigen T cell responses after treatment, further work needs to be done to validate if Uq2 or other neo-antigen responses are essential for an anti-tumour immune response. Keywords: Neo-antigens, Next generation sequencing, Immunotherapy PP02.15: GENE PROFILE OF MESOTHELIOMA TUMORIGENESIS AND INITIATION AFTER CHEMORADIATION TREATMENT IN VITRO AND IN VIVO MODELS to observe tumorigenesis. Results: Prime-PCR results indicated that some genes (Bcl2, Birc5, Bub1, Ccnb1, Gjb6, Foxa1, Muc1, Ndc80, Nkx2-1, Sox2) are upregulated more than 10 times in the peritoneum of mice after RN5 tumor challenge compared with naïve mice. Treatment with chemo- or radiation therapy resulted in increased expression of identified genes of interest in both RN5 and AB12 cell lines. Despite the presence of a lower number of cells (105 and 104) among the chemoradiation-treated surviving cells, their implantation resulted in similar tumor incidence and 10 times higher tumor growth than the use of a higher number of number of parental cells (106 and 105), suggesting that surviving tumor cells after chemoradiation share the property of stemness. RT-PCR results demonstrated that some of the genes associated with stemness (CD44, Sox2, Sca-1, Birc5) had already been demonstrated in mesothelioma and other types of cancer. However, other genes (Batf, Foxa1, Ndc80, Wwc1, Nkx2-1, etc) had not been reported in mesothelioma stem cells. The potential importance of these newly detected genes was confirmed by confirming their presence in highly enriched mesothelioma stem cells as positive controls. Further functional characterization of these genes and their potential role to target stem cells with immunotherapy needs to be studied. Conclusion: Molecular identification of mesothelioma cells and stem cells may provide a novel venue for immunotherapy against mesothelioma cells as well as cancer stem cells. Keywords: Murine mesothelioma, cancer stem cell, primePCR, Immunotherapy Licun Wu1, Zhihong Yun1, Walter Blum2, Beat Schwaller2, Emanuela Felley-Bosco3 , Marc De Perrot1 Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Center, Toronto, ON, CANADA, 2Department of Medicine and Anatomy, Department of Medicine and Anatomy, University of Fribourg, Fribourg, SWITZERLAND, 3Department of Molecular Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 Objectives: Immunotherapy has shown promising results for cancer treatment including mesothelioma, however, the major issue is a lack of specific antigens for monitoring the immune response and to target tumor stem cell specifically. To overcome this hurdle we attempt to look for potential candidate genes determining tumor cell initiation and proliferation in mesothelioma. Based on this finding, it would then potentially be possible to design specific immunotherapy to target mesothelioma stem cells. Methods: We employed the newly developed Prime-PCR assay specifically designed for mouse mesothelioma to screen the genes of interest. The expression of the selected genes was confirmed by real time-PCR, flow cytometry and immune fluorescent staining. Murine mesothelioma cells RN5 and AB12 were both developed by intraperitoneal (ip) injection of asbestos fibre. RN5 cells were injected ip into mice and the peritoneum tissues were collected at different time points to determine gene expression. Both cell lines were treated with cisplatin-based chemotherapy or Cs37 γ-ray radiation in vitro to evaluate the expression of these selected genes using real-time PCR and flow cytometry. Serial numbers of surviving tumor cells after chemo- or radiation therapy were injected into mice PP02.16: THE ELEVATED LEVELS OF G-MDSC IN MESOTHELIOMA PATIENTS INHIBIT T CELL PROLIFERATION AND FUNCTION BY ROS GENERATION Swati Khanna1, Francis Mussai2, Anish Thomas1, Gary Middleton2, Constance Yuan3 , Betsy Morrow1, Jingli Zhang1, Ira Pastan4 , Maryalice Stetler-Stevenson3 , Raffit Hassan1 Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA, 2Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UNITED KINGDOM, 3Laboratory of Pathology, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA, 4Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA 1 Objectives: The role of myeloid derived suppressor cells (MDSCs) in mediating tumor immunosuppression in patients with malignant mesothelioma has not been well characterized. The goal of our study was to analyze for the presence of both monocytic and granulocytic myeloid cells in peripheral blood of mesothelioma patients, evaluate their immunosuppressive capability and characterize their mechanism of suppression of T cell responses. Methods: We evaluated the peripheral blood of patients with mesothelioma (n=25) and healthy donors (n=20) for the presiMig2016.ORG 125 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP ence of granulocytic myeloid cells (CD11b+CD15+CD14-HLADR-) and monocytic myeloid cells (CD11b+CD14+HLADR-) by a flow cytometry panel. Due to higher frequency of granulocytic myeloid cells, the T cell suppression assays were setup using sorted autologous T cells and granulocytic myeloid cells. T cell proliferation and function was evaluated by CFSE dilution and IFN-γ released by T cells in the supernatants, respectively. To determine the mechanism by which Gr-MDSC inhibit T cells, we tested the levels of reactive oxygen species (ROS), and nitrite oxide species and arginase activity in Gr-MDSC (with or without inhibitors) sorted from peripheral blood using flow cytometric and colorimetric assays. Arginase inhibitor nor-NOHA and iNOS (inducible nitric oxide synthase) inhibitor L-NMMA were used at a concentration of 500 μM. TBHP was used as a positive control for ROS assay while D-NMMA was used as a negative control for nitrite assay. Results: The granulocytic myeloid cells were significantly elevated in peripheral blood of mesothelioma patients as compared to healthy donors (61.2% vs. 47.8%; p=0.009). The levels of monocytic myeloid cells in patients and healthy donors were 0.2% and 0.1%, respectively (p=0.04) and were much lower than the granulocytic subset. Granulocytic subset was investigated further due to the their elevated levels and higher frequency in mesothelioma patients. Granulocytic myeloid cells from mesothelioma patients were found to inhibit the proliferation of both autologous CD4 and CD8 T cells (mean inhibition of proliferation of 61.9% for CD4 and 75.5% for CD8 at 1:2 T: G-myeloid ratio), which was accompanied with ~ 10 fold decrease in IFN-γ levels in co-culture supernatants. Thus, this granulocytic subset is in fact granulocytic myeloid derived suppressor cell (G-MDSC). The arginase levels in G-MDSC (0.3±0.3 vs. 0.2±0.3 μM) and nitrite levels in G-MDSC culture supernatants (1.8±2.5 vs. 0 μM) were below detection limit in both patients and normal donors and were marginally affected by the addition of their respective inhibitors (nor-NOHA and L-NMMA). The addition of these inhibitors also did not reverse the suppressive effect of G-MDSC on T cells proliferation. However, the average levels of ROS in G-MDSC derived from mesothelioma patients were 3 folds higher than that from healthy donors (average MFI ~15000 vs. ~5000; p=0.03). PP02.17: NOVEL MEDICINAL CHEMISTRY APPROACHES IN MESOTHELIOMA: THE ROLE OF NATURAL PRODUCTS Adrian Dobbs Pharmaceutical, Chemical and Environmental Sciences, University of Greenwich, Chatham Maritime, Kent, UNITED KINGDOM Objectives: Human malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm that originates in the pleura and is highly invasive. It is generally associated with exposure to asbestos fibres. One of the greatest challenges is that it is resistant to most conventional therapies, including chemotherapy, radiotherapy and surgery and the prognosis for patients is poor. This makes the development of new therapeutic agents all the more crucial. Historically, the majority of drugs on the market – for any symptom – have their origins in a natural product (something isolated from nature). Unfortunately there are no novel drugs in development specifically targeting MPM: principally because until very recently, there were no reported natural products to serve as the lead compound. This changed in 2009, with the report of JBIR-23 and -24, two microbial metabolites isolated fromStreptomyces sp. AK-AB27 : the first natural products specifically to demonstrate cytotoxicity against MPM cell lines, with modest IC50 values. More importantly, JBIR-23 inhibited the proliferation of MPM cells that were otherwise resistant to clinical anticancer drugs and without evident side effects in mice. Since the report of JBIR-23, a further 6 compounds have been reported, also demonstrating activity against ACC-MESO-1 cells with similar IC50 values. (See next page.) Conclusion: In summary our results show that G-MDSC are a major immunosuppressive cell population in mesothelioma patients and they suppress T cell proliferation and function mainly through generation of reactive oxygen species. Keywords: mesothelioma, Myeloid derived suppressor cells, ROS, Arginase iMig2016.ORG 126 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP However, no synthetic or medicinal chemistry studies towards the preparation of these compounds, or any structure-activity studies based around them as lead compounds has been conducted. Thus the aim of work is to investigate the synthesis and mode of action of these compounds. Methods: We have employed the tools of synthetic chemistry in developing syntheses of these natural products. These have been designed to be highly modular and flexible, to permit rapid preparation of analogues of the natural products. We shall report the synthetic methodologies developed and the various libraries of compounds that have been prepared. Biological data will be reported against ACC-MESO-1 cell lines. Results: We shall report our studies on the synthesis and medicinal chemistry of these lead compounds: our successful attempts at their preparation and also the construction of related analogues; we shall also report initial biological data relating to these libraries of compounds Conclusion: There is an urgent and unmet need for new approaches and novel agents to treat MPM. Exploiting natural products via synthesis, analogue preparation and structure-activity studies is one such approach. The results reported herein have shown that this traditional medicinal chemistry approach towards drug discovery has considerable potential in finding potential new therapies for MPM. Keywords: medicinal chemistry, organic chemistry, natural products PP02.18: HMGB-1 RELEASE AND THE CD8+ T CELL RESPONSE ELICITED BY RADIATION TREATMENT IN MALIGNANT PLEURAL MESOTHELIOMA Matthew Wu1, Luis D.L. Maza1, Licun Wu1, Holly Guo1, Hana Yun1, Marc De Perrot2 Thoracic Surgery, University Health Network, Toronto, ON, CANADA, 2Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Center, Toronto, CANADA 1 Objectives: Surgery for Mesothelioma After Radiation Therapy (SMART) has demonstrated substantial benefits in patient survival compared to other treatment modalities. The benefits exhibited by SMART treatment may rely on immune activating effects of radiation before surgery through the release of pro-inflammatory molecules, such as Danger Associated Molecular Pattern (DAMP) molecules associated with cancer cell death. We studied the role of HMGB-1 released from dying tumor cells as an immune system potentiator after radiation treatment for Malignant Pleural Mesothelioma (MPM). Methods: Human and mouse epithelioid MPM cell lines were irradiated in a single fraction of 25Gy radiation. Cell death was measured by Annexin V and eFluor450 viability dye staining. Immunohistochemical staining of HMGB-1 was compared between paraffin embedded MPM samples from patients who received no treatment (biopsy or extrapleural pneumonectomy (EPP) ) or Surgery for Mesothelioma After Radiation Therapy (SMART) treatment. Mice were inoculated with the mouse epithelioid MPM cell line AE-17-OVA and were split into 1) untreated 2) radiation treated and 3) radiation treatment + HMGB-1 blockade groups. Radiation treatment was delivered in three 5Gy fractions of radiation (15Gy total dose) on days 8, 9, and 10 after cell injection. Serum HMGB-1 was measured by ELISA and tissue staining was performed by immunofluorescence. Results: In vitro radiated epithelioid MPM cell lines demonstrated increased HMGB-1 release that correlated with increased viability dye staining. We did not find any significant difference in staining intensity of HMGB-1 stained MPM paraffin embedded patient samples. Radiation treated mice showed slower tumor growth, increased serum HMGB-1, and increased tumor infiltrating CD8+ T Cells. Blocking of HMGB-1 during radiation led to increased tumor growth compared to radiation treatment alone. iMig2016.ORG 127 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP LRT in combination with HMGB-1 demonstrates greater tumor growth compared with LRT alone. AE-17-OVA mice either received no treatment (N=5), local radiation therapy (N=4), or local radiation therapy in combination with anti-HMGB-1 antibody (N=5, 100µg per day on days 8-12 after tumor inoculation). Untreated mice (NoRx) demonstrate the greatest tumor growth compared to LRT + anti-HMGB-1 and LRT groups. Mice receiving LRT + anti-HMGB-1 exhibit greater tumor volume than mice treated with LRT alone. Conclusion: This work supports the beneficial pro-inflammatory role of HMGB-1 in MPM treatment. Thus future studies of HMGB-1 as a therapeutic strategy would be valuable. Keywords: HMGB-1, Immunotherapy immune suppressive molecule PD-L1, costimulation molecules B7-1/2, MHC class II, macrophage markers, cancer stem cell markers and so on, which are potentially applied to design specific immunotherapy against mesothelioma. Tumor-specific immunity against RN5 mesothelioma was evaluated by in vitro cell killing assay. Splenocytes derived from RN5-bearing or naïve mice, and RN5 cells were used as effectors and targets, respectively. After overnight co-culture of effector T cells (E) and RN5 cells as targets (T) with pulsation of whole cell lysate, both effectors and targets were harvested to determine T cell activation and RN5 cell proliferation. Results: RN5 cells express a wide variety of immune associated phenotypes PD-L1, B7-1/2, Gr-1, MHC II and D11c, and mesothelial precursor markers (mesothelin/CD34/CD90), and also express cancer stem cell markers (CD44, Sox2, Oct4, Sca-1) at different levels. Interestingly, they share some macrophage phenotypes MHC II, CD11b, F4/80, CD68, CD206 and Arg-1. Our results indicated that splenocytes derived from RN5-bearing mice were able to be activated by pulsation of whole tumor cell lysate, thus resulting in cytotoxic lysis of target cells. RN5 cell proliferation was significantly suppressed by activated T cells in an E:T ratio dependent manner. CD8 T cell activation and proliferation was 2-3 times higher after pulsation with tumor cell lysate than that in the non-pulsed group. On the contrary, tumor cell proliferation rate was 30.6±4.4% and 17.6±3.0% at E:T10 and E:T50, respectively, significantly lower compared with target cells alone (87.5±0.5%). Conclusion: Tumor-specific immunity can be generated by pulsation with whole cell lysate. We need to explore the potential antigens that are involved in this immune response. Keywords: tumor cell lysate, Immunotherapy, Murine mesothelioma RN5, phenotype PP02.19: IMMUNOPHENOTYPE OF A NOVEL MURINE MESOTHELIOMA CELL LINE RN5 AND SPECIFIC IMMUNITY GENERATED BY PULSATION WITH CELL LYSATE Licun Wu1, Zhihong Yun1, Walter Blum2, Beat Schwaller2, Emanuela Felley-Bosco3 , Marc De Perrot1 Thoracic Surgery, Toronto General Hospital and Princess Margaret Cancer Center, Toronto, ON, CANADA, 2Department of Medicine and Anatomy, Department of Medicine and Anatomy, University of Fribourg, Fribourg, SWITZERLAND, 3Department of Molecular Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 Objectives: This newly generated murine mesothelioma model was reported recently by Blum et al from our team. RN5 cell line was established from neurofibromatosis 2 (merlin) heterozygous (Nf2+/-) mice, as evidence has indicated that approximately half of the malignant pleural mesothelioma patients have Nf2 mutation. Characterization of the novel mesothelioma cell phenotypes needs to be investigated in order to develop personalized immunotherapy. Methods: Cultured RN5 cells were used to determine the phenotypes that are associated with immune response, such as PP02.21: FOCAL ADHESION KINASE INHIBITION TARGETS MACROPHAGES IN VITRO AND IN VIVO IN A MESOTHELIOMA MOUSE MODEL Lysanne Lievense1, Floris Dammeijer1, Menno Van Nimwegen1, Koen Bezemer1, Yan Wang2, Jonathan Pachter2, Joost Hegmans1, Joachim Aerts1 Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, NETHERLANDS, 2Verastem Inc., Boston, MA, UNITED STATES OF AMERICA 1 Objectives: Recent evidence suggests that FAK inhibition could have a beneficial effect on the anti-tumor immune response via depletion of regulatory T cells and increase in cytotoxic T cells in addition to targeting cancer stem cells. This leads to new immunotherapeutic possibilities for FAK inhibitors despite the recent negative results of the COMMAND trial in advanced mesothelioma patients which used a FAK inhibitor, VS-6063, as single agent maintenance after chemotherapy doublet treatment. Tumor-associated macrophages (TAMs) of the M2 phenotype are prominent immunosuppressive cells in the mesothelioma microenvironment and a promising therapeutic target, especially in combination with checkpoint inhibitors iMig2016.ORG 128 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP and cellular immunotherapies. Since FAK is known to regulate diverse macrophage functions, FAK inhibition could be a strategy to target TAMs. The aim of this study is to investigate the influence of FAK/PYK2 inhibition on macrophage phenotype in vitro and macrophage tumor infiltration in vivo. Methods: Bone marrow cells from healthy wildtype Balb/c mice were differentiated into macrophages and subsequently polarized to the M1 or M2 phenotype in the presence of different FAK inhibitor concentrations (VS-4718, small molecule FAK/PYK2 inhibitor). The expression of signature M1 and M2 markers was measured after culture using flow cytometry. In addition, SCID mice bearing mesothelioma xenografts were treated with VS-4718 (50 mg/kg, po) twice daily. Mice were sacrificed after 10 days, tumors were harvested, and macrophage abundance was assessed by immunofluorescence staining of the F4/80 marker. Results: Addition of VS-4718 to the standard M1 macrophage culture resulted in a more prominent M1 polarized phenotype, demonstrated by a higher expression of MHCII and PD-L1 compared to the M1 macrophage control. Furthermore, expression of the M2 markers CD206 and CD115 was downregulated on macrophages in the presence of VS-4718 compared to the M2 macrophage control. In vivo, there was a significant downregulation of macrophages in the tumors of mice treated with VS-4718. Growth of the MM87 xenograft tumors was also significantly inhibited by VS-4718 treatment. Conclusion: The effect of FAK inhibition on macrophages was investigated both in vitro and in vivo in mesothelioma mouse models. We demonstrate that by inhibiting FAK signaling, the macrophage phenotype can be skewed towards a more M1like pro-inflammatory phenotype in vitro. Furthermore, in a mesothelioma mouse model, total TAM numbers were diminished after treatment with the FAK inhibitor. Further studies are needed to confirm these preliminary results and to investigate how FAK inhibitors can be optimally used to target TAMs in the mesothelioma microenvironment. The current study illustrates the potential to use FAK inhibitors in novel ways in the clinic to enhance anti-tumor immunity, for example, in combination with checkpoint inhibitors. however local immunosuppressive mechanisms could hamper their efficacy. Macrophages are abundantly present within the mesothelioma microenvironment. This study investigates the influence of the macrophage phenotype and their capacity to inhibit local immune responses and the decisive role of pleural effusion (PE) in this regard. Methods: Healthy monocytes derived from a buffy coat were used to culture macrophages in the presence of PEs (n=6) to create a mesothelioma environment. Macrophage phenotype was investigated using RT-PCR. Macrophages and healthy T cells were co-cultured in the presence of PEs and accompanying mesothelioma cell line supernatants (n=6). T cell proliferation after co-culture was calculated as output measure using flow cytometry. The levels of 11 pro- and anti-inflammatory cytokines and the prostanoid prostaglandin E2 (PGE2) were measured in PEs (n=6) and accompanying tumor cell line supernatants (n=6) using a magnetic-bead based multiplex assay and ELISA. The presence and phenotype of macrophages and T cell subsets was measured in the PE of mesothelioma patients (n=30) using flow cytometry. Results: PE induced a tumor promoting M2 phenotype in macrophages. Macrophages cultured in the presence of PEs firmly suppressed T cell proliferation during co-culture (p<0.05, compared to co-culture in the presence of normal human serum). The mesothelioma cell line supernatants did not exert this effect. The level of PGE2 present in PEs correlated with the induction of the suppressive capacity of macrophages, this correlation could not be found with any of the measured cytokines. Macrophages isolated from PEs of mesothelioma patients displayed an M2 phenotype and were negatively correlated with T cells in vivo (rho -0.90, p<0.001). Conclusion: The current study demonstrates that macrophages in pleural effusion can play a pivotal role in directly hampering the anti-tumor T cell immune response. This emphasizes the potential of macrophages as a therapeutic target in mesothelioma and indicates that the presence and phenotype of macrophages in pleural effusion should be taken into consideration in the application of (intrapleural) immunotherapies, besides being also a potential prognostic measure. Keywords: tumor-associated macrophages, focal adhesion kinase, mesothelioma mouse model Keywords: tumor-associated macrophages, tumor microenvironment, Pleural effusion PP02.22: PLEURAL EFFUSION OF PATIENTS WITH MALIGNANT MESOTHELIOMA INDUCES MACROPHAGE-MEDIATED T CELL SUPPRESSION PP02.23: THE ABSCOPAL EFFECT OF RADIOTHERAPY IN THE CONTEXT OF CHECKPOINT BLOCKADE IN A MOUSE MESOTHELIOMA MODEL Lysanne Lievense, Koen Bezemer, Robin Cornelissen, Margaretha Kaijen-Lambers, Joachim Aerts, Joost Hegmans Alistair M. Cook1, Jason Waithman2, Willem J. Lesterhuis1, Martin Ebert3 , Roslyn Francis1, Scott Fisher1, Alison Mcdonnell1, Sean Bydder4 , Sally M. Lansley5, Bruce Robinson1, Richard Lake1, Anna Nowak1 Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, NETHERLANDS School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, AUSTRALIA, 2Telethon Kids Institute, Subiaco, WA, AUSTRALIA, 3School of Physics, The University of Western Australia, Crawley, WA, AUSTRALIA, 4School of Surgery, The University of Western Australia, Crawley, WA, AUSTRA1 Objectives: Clinical studies have demonstrated beneficial effects of immunotherapy in malignant pleural mesothelioma. The pleural cavity, close to the target tumor, seems an attractive compartment to administer these type of therapies, iMig2016.ORG 129 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP LIA, 5Pleural Medicine Unit, Institute for Respiratory Health, Perth, WA, AUSTRALIA Objectives: In people with advanced cancer, including mesothelioma, local radiotherapy is often used to alleviate discomfort from specific tumour sites. Very rarely, radiotherapy to one site can induce shrinkage of tumours elsewhere in the body. Termed the ‘abscopal’ effect, this has been attributed to the way that radiotherapy modifies the tumour microenvironment, and in particular the manner in which it kills cancer cells. This ‘immunogenic’ cell death can release damage-associate molecular patterns (DAMPs) that can activate dendritic cells and in turn tumour-specific cytotoxic T cells, thereby generating an immune response by turning a tumour into its own ‘vaccine’. However, the fact that the abscopal effect is so rare is likely due to localised or systemic immune suppression. Crucially, the abscopal effect is more frequently observed in patients receiving immunotherapy, particularly during recent trials of immunological checkpoint antibodies e.g. CTLA-4 or PD-1 pathway blockade, and there is emerging evidence that local radiotherapy can enhance the efficacy of immunotherapy. However, immunological synergy between radiotherapy and checkpoint blockade remains poorly studied, particularly in thoracic cancers. Here, we present a strategy to study the abscopal effect by combining radiotherapy and immune checkpoint blockade in a mouse model of mesothelioma. Results: Preliminary data will be presented. Conclusion: We will develop a relevant, tractable preclinical model of mesothelioma in which to study the interaction of radiotherapy and the immune system. The intrapleural/flank tumour model in particular is highly relevant to the clinical setting. Keywords: radiotherapy, intrapleural, Preclinical, Immunotherapy Methods: This project uses CT-targeted precision irradiation, as the best available pre-clinical equivalent to clinical radiotherapy, to irradiate single tumours in mice bearing dual mesothelioma tumours on opposite flanks (Figure 1). We will use flow cytometry to characterise both local and systemic immunological changes occurring in response to radiotherapy, including the expression of the checkpoint molecules CTLA4, PD-1/ PD-L1, OX40 and TIM3. This will be followed by an evaluation of which checkpoint antibodies are most effective when combined with targeted radiotherapy, initially as individual treatments and proceeding to double combinations in addition to radiotherapy. The most effective combinations will be tested by irradiating single flank tumours in mice bearing intrapleural tumours, mimicking pleural disease with irradiated chest wall metastasis. PET/CT and MRI will be used to assess tumour growth in mice with intrapleural mesothelioma. iMig2016.ORG 130 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.26: TARGETED DEPLETION OF REGULATORY T CELLS IN MESOTHELIOMA Scott Fisher, Jessica Solin, Wayne J. Aston, Amanda Cleaver, Willem J. Lesterhuis, Andrea Khong, Bruce Robinson, Richard Lake School of Medicine and Pharmacology, National Centre for Asbestos Related Diseases. The University of Western Australia, Perth, WA, AUSTRALIA Objectives: Recent advances in the use of checkpoint blockade immunotherapies such as CTLA-4 and PD-1 that act to block different aspects of negative T cell regulation are beginning to be explored in mesothelioma. Regulatory T cells (Treg) play an important role in suppressing anti-tumour immunity and their depletion has been linked to improved outcomes. We used the BALB/c FoxP3.dtr transgenic mice to specifically target and deplete Treg via Diphtheria toxin (DTX) to better understand the role of Treg in limiting the efficacy of different mesothelioma treatment protocols. Methods: Mice bearing AB1 mesotheliomas were subject to different treatment protocols, with or without DTX Treg depletion and tumour growth and survival monitored. Polychromatic flow cytometry analysis was used to confirm Treg depletion, phenotype immune cell populations and assess immune correlates with the outcome of each treatment protocol Results: DTX specifically depletes Treg in FoxP3.dtr mice bearing mesothelioma tumours. Treg depletion lasts around three days and occurs in a dose dependent manner with maximum depletion observed one day after treatment. Treg depletion did not alter the proportion of non-Treg CD4 or CD8 effector T cells, but Treg recovery was associated with a significant increase in effector T cell activation and proliferation. Systemic administration of DTX caused depletion of Treg in all tissues, although the kinetics of Treg recovery in the tumour was slower than other organs and the level of CD8 T cell activation was less pronounced. PP02.27: LEGAL CLAIMS FOR ASBESTOSIS IN THE NETHERLANDS POSSIBLE SINCE 2014: HOW IT WORKS Wanda Hagmolen Of Ten Have1, Jos Rooijackers2, Wieneke Buikhuisen3 , Jan Grutters4 , Sjaak Burgers3 Pulmonology, Radboudumc, Nijmegen, NETHERLANDS, 2Institute For Risk Assessment Sciences, UMCU, Utrecht, NETHERLANDS, 3Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 4Pulmonology, St. Antonius hospital, Nieuwegein, NETHERLANDS 1 Objectives: Patients with mesothelioma can claim financial compensation via the Dutch institute for asbestos victims. In March 2014 the Dutch Minister of Social Affairs and Employment announced that the same should be possible for patients with asbestosis. The diagnosis of asbestosis can only made definitive with histological (biopsy) material. However, in contrary to patients with mesothelioma histological material is almost never available. The risks of invasive biopsies do not weigh against the benefits because there is no specific treatment available to fight asbestosis. The so-called ‘Mesothelioma Clinical Expert Panel of the Dutch Thoracic Society’ was asked to assess the available clinical data of the victims to assess whether the victim has (putative) asbestosis or not. Methods: A flow diagram of the diagnostic work-up was constructed for patients that applied to the Dutch institute for asbestos victims (see figure). (See next page.) Conclusion: This pre‑clinical study suggests that mesothelioma is likely to respond to Treg depletion and therefore targeted removal of Treg could be an effective therapeutic strategy. A major problem in translating this into clinical reality is identifying markers that specifically target Treg without affecting effector T cells. In our related studies (abstract 198), we have shown that tumour resident Treg express high levels of the immune checkpoint molecules CTLA-4, GITR and OX40, while tumour infiltrating lymphocytes express PD-1 and TIM-3. Taken together, these data suggest that specific combinations of checkpoint blockade immunotherapies could be designed to specifically target Treg and simultaneously enhance effector T cell function to generate effective therapy for mesothelioma. Keywords: Immunotherapy, Treg, mesothelioma iMig2016.ORG 131 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Results: Over 180 claims have been received since April 1th 2014. Until now about 40 victims might have asbestosis and received € 19.417 in 2015. The majority of asbestos victims who applied for the financial compensation had pleural plaques and no fibrosis. Conclusion: In 2014 the Dutch government extended existing regulation for financial compensation for asbestos victims to patients with asbestosis. Until now about 40 victims succeeded in their claim. Updated data will be presented at the iMig 2016. PP02.28: EVALUATION OF CURCUMIN I.P. FOR THE TREATMENT OF SARCOMATOID MESOTHELIOMA, EXPERIMENTAL STUDY ON A RAT MODEL Daniel L. Pouliquen1, Béatrice Nawrocki-Raby2, Joëlle Nader1, Myriam Robard3 , Philippe Birembaut2, Marc Grégoire1 UMR 892 INSERM / 6299 CNRS, Nantes, FRANCE, 2UMRS-903 INSERM, Reims, FRANCE, 3Plateforme MicroPICell, SFR F. Bonamy, Nantes, FRANCE 1 Objectives: Both the literature and clinical trials have confirmed the potential of curcumin against various types of cancers. Additionally, the epigenetic modulation of target genes by this molecule has been recently highlighted, pointing out the interest of drugs relevant to polypharmacology. In this study, a rat model of sarcomatoid mesothelioma, mimicking some of the worse clinical conditions faced in clinics, was used to evaluate the therapeutic potential of curcumin administered intraperitoneally. Methods: The M5-T1 cell line, selected from a collection established from F344 rats induced with crocidolite given i.p. over a period of 136 to 415 days, was inoculated intraperitoneally in syngeneic rats, producing in three weeks macroscopic tumors growing on the omentum together with metastases in several normal tissues including the liver, diaphragm, pancreas and spleen. The potential of i.p. administration of curcumin to kill tumor cells in vivo and induce infiltration with immune cells, was evaluated in comparison with a reference epigenetic drug, SAHA, in tumor-bearing rats. iMig2016.ORG 132 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Results: Both agents administered at days 21 and 26 after tumor challenge produced necrosis within the solid tumors at day 28. Quantification of the surfaces covered by necrotic cells demonstrated that the extent of necrosis within the invaded omentum was significantly higher after treatment with curcumin compared with treatment with SAHA. Quantification of residual tumor cells within these necrotic areas also revealed their number was very significantly lower after treatment with curcumin relative to SAHA. After treatment with curcumin, the tumor tissue at the periphery of necrotic areas was characterized by the presence of numerous mononuclear phagocytic cells. In contrast, treatment with SAHA was characterized by the presence of foci of resistant cells within the tumor tissue and infiltration by numerous isolated CD8+ cells. The treatment of tumor bearing rats one week after tumor challenge with four successive injections of 1.5 mg/kg curcumin on days 7, 9, 11 and 14 dramatically reduced the total tumor mass at day 16. Clusters of CD8+ lymphocytes were also observed at the periphery of small tumor masses remaining in the peritoneal cavity where the number of mitosis per field was significantly reduced compared with tumors in untreated rats. Conclusion: These data open up interesting new prospects for the therapy of malignant mesothelioma with curcumin or its many derivatives administered intracavitary. Keywords: Peritoneal mesothelioma, Sarcomatoid, Curcumin, Rat tumor model PP02.29: BIPHASIC PLEURAL MESOTHELIOMA: UNUSUAL CLINICAL BEHAVIOR Abdulhadi Almutairi, Ahsan Cheema, Ikram Chaudhry Surgery, King Fahad Specialist Hospital, Dammam, SAUDI ARABIA Objectives: Biphasic pleural mesothelioma is a fatal disease, which shows aggressive clinical behavior with low survival potential. We report two cases treated only with external beam radiation and both patients survived for 4 and 5 years, respectively. Methods: Retrospective chart review of two cases that presented with symptomatic unilateral pleural effusion and pleural nodularity. Both patient underwent uniportal VATs pleural biopsy and both biopsies confirmed the diagnosis of biphasic pleural mesothelioma. Both patients were offered surgical resection but refused and opted for external beam radiation Therapy (EBRT). In both patients, no asbestos fibers were identified on pathology slides review. Results: Case 1: A 65-year-old heavy smoker male with no asbestos exposure risk presented in 2010 with shortness of breath and a right-sided pleural effusion (Fig 1a). Patient was treated with EBRT with a total dose of 24 Gy over 2 weeks. The patient remained asymptomatic for four years. Periodic imaging, both chest x-ray and CT scan, confirmed no effusion recurrence (Fig 1b). Patient presented in 2015 with brain metastasis and passed away few days after presentation. Case 2: A 48-year-old non- smoker female patient with no exposure risk, presented in 2011 with chest discomfort and a left sided pleural effusion (Fig 2a). She was offered surgical resection but refused and treated with EBRT in similar manner. Patient still alive and symptom-free till the time of this abstract (Fig 2b). Conclusion: Radiation therapy may have a significant role that prolongs survival in subset of patient with biphasic pleural mesothelioma. Further studies are needed to explore prognostic risk factors and stratify different spectrum of biphasic pleural mesothelioma. Keywords: mesothelioma, Survival, biphasic, radaition PP02.30: MARS 2: A FEASIBILITY STUDY COMPARING (EXTENDED) PLEURECTOMY DECORTICATION VERSUS NO PLEURECTOMY DECORTICATION Eric Lim Royal Brompton Hospital, London, UNITED KINGDOM Objectives: The aim of the MARS 2 study is to determine if it is feasible to recruit patients with malignant pleural mesothelioma with disease amenable to surgical resection into a randomised trial of (extended) pleurectomy decortication (lung sparing surgery) versus no surgery. The feasibility component will also assess if there is any evidence of harm associated with (extended) pleurectomy decortication. Methods: Patients with a histological confirmation of mesothelioma with disease confined to one hemi-thorax are eligible for enrolment. Patients are ineligible if they are unable to give informed consent or are unwilling to be randomised or if they have disease that is not deemed to be surgically resectable, an ECOG status 2 or more, a predicted pre-operative FEV1 or TLco less than 20%, severe heart failure, end stage kidney failure, liver failure or are already participating in another interventional clinical trial. All patients will receive the usual standard of care chemotherapy. After 2 cycles, participants will be re-assessed by CT to screen for progressive disease. Patients with no evidence of disease progression beyond the limits of surgical resection will be randomised to either: A). (Extended) pleurectomy decortication or B). No surgery. All patients will then receive the remaining 4 cycles of chemotherapy. Results: Two lead surgical centres in the UK, Leicester and Sheffield, are performing the surgery for this feasibility phase. 10 other medical centres in the UK are also currently recruiting patients with another 10 medical centres in set-up. To date, 19 patients have been enrolled and 7 patients randomised. Conclusion: The results from the MARS 2 feasibility study will determine if it is possible to recruit patients with malignant pleural mesothelioma with disease amenable to surgical resection into a randomised trial of (extended) pleurectomy decortication (lung sparing surgery) versus no surgery. The feasibility study will also assess if there is any evidence of harm. If feasibility and safety are demonstrated, the MARS 2 feasibility iMig2016.ORG 133 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP study will be extended to a larger study powered to assess survival and quality of life. Keywords: Extended Pleurectomy Decortication, Lung sparing surgery PP02.31: MESOTRAP: A FEASIBILITY STUDY OF INDWELLING PLEURAL CATHETER VERSUS VAT PLEURECTOMY FOR TRAPPED LUNG IN MESOTHELIOMA Robert C. Rintoul1, Angela Tod2, Pasupathy Sivasothy3 , Graham Sherlock-Brown4 , David Waller5, Aman Coonar1, John Edwards6 , Nick Maskell7, Naj Rahman8 , Julia Fox-Rushy9, Linda Sharples10 Thoracic Oncology, Papworth Hospital NHS Foundation Trust, Cambridge, UNITED KINGDOM, 2University of Manchester, Manchester, UNITED KINGDOM, 3Cambridge University Hospitals, Cambridge, UNITED KINGDOM, 4Patient Public, Glenfield Hospital, Leicester, UNITED KINGDOM,5Glenfield Hospital, Leicester, UNITED KINGDOM, 6Northern General Hospital, Sheffield, UNITED KINGDOM, 7University of Bristol, Bristol, UNITED KINGDOM, 8University of Oxford, Oxford, UNITED KINGDOM, 9Brunel University, London, UNITED KINGDOM, 10University of Leeds, Leeds, UNITED KINGDOM 1 Objectives: Pleural effusion in malignant pleural mesothelioma (MPM) is often managed by promoting a talc pleurodesis between the visceral and parietal pleura. However if the pleura are unable to appose, an effective pleurodesis is unlikely. In MPM tumour is commonly present over the visceral surface of the lung which prevents the lung from re-inflating - so called ‘trapped lung’ (TL). In this situation pleural fluid usually recurs and patients go through repeated cycles of fluid drainage and re-accumulation. TL is a challenging management issue causing significant morbidity and in case series of TL, 13-37% have been due to MPM. Some authorities recommend placement of an indwelling pleural catheter (IPC) under local anaesthesia to facilitate repeated drainage in the community. Others have advocated general anaesthesia video-assisted thoracoscopic partial pleurectomy/decortication (VAT-PD) to remove as much tumour from the visceral pleural surface as possible to allow the lung to re-expand to permit a pleurodesis. Recognising that management of dyspnoea due to TL lung in MPM is a significant unmet need, our ultimate aim is to undertake a randomised controlled trial comparing VAT-PD with IPC. However, prior to undertaking a full phase III study we need to address several uncertainties: i) How prevalent is TL in MPM? ii) Will patients accept randomisation to IPC or VAT-PD? iii) What is the standard deviation of Visual Analogue Scale scores for dyspnoea and chestpain in each treatment group? (This will be used to estimate parameters that will be included in the sample size estimates for a full trial). Therefore initially we will undertake a feasibility study, the primary objective of which will be to determine the ability to randomise patients into a trial of VATPD versus IPC in patients with TL and pleural effusion due to MPM. To help inform the design of a phase III trial secondary objectives will be: i) The prevalence of TL in patients with MPM ii) Visual Analogue Scale scores for dyspnoea and chest pain and the patterns of change over time in each treatment group iii) Quality of Life data at baseline, 1, 3, 6 and 12 months post randomisation iv) Collection and documentation of Adverse Events v) Health economic analysis Methods: Six UK thoracic surgical centres with expertise in performing both IPC and VAT-PD along with linked non-surgical referring hospitals, all of whom are previous/existing mesothelioma study collaborators, will randomise 36 patients (1:1) in 18 months. Inclusion criteria: confirmed MPM; TL (>20% of one hemithorax without lung markings on chest x-ray) following fluid drainage; deemed suitable for VAT-PD by a thoracic surgeon. Following ethics approval, a trial management group, trial steering and data monitoring committees will provide governance. The study will be registered with an International Standard Randomised Controlled Trial Number (ISRCTN) and ClinicalTrials.gov. Results: Section not applicable Conclusion: The feasibility study will provide information as to a) whether a full randomised controlled trial is achievable in a reasonable time frame, b) the number of patients required. A full trial will determine best management of trapped lung in MPM. Keywords: Malignant pleural mesothelioma, Indwelling Pleural Catheter, Trapped Lung, Video Assisted Thoracoscopic Pleurectomy PP02.32: LUME-MESO: A PLACEBO-CONTROLLED PHASE II/III STUDY OF NINTEDANIB + PEMETREXED/CISPLATIN FOLLOWED BY MAINTENANCE NINTEDANIB Giorgio V. Scagliotti1, Rabab M. Gaafar2, Anna Nowak3 , Martin Reck4 , Jan Van Meerbeeck5, Arsene-Bienvenu Loembe6 , Ute Von Wangenheim7, Derek Velema8 , Sanjay Popat9 Department of Oncology, University of Turin, Torino, ITALY, 2National Cancer Institute, Cairo University, Cairo, EGYPT, 3School of Medicine and Pharmacology Qeii, Medical Centre Unit, University of Western Australia, Crawley, WA, AUSTRALIA, 4Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Member of the German Center for Lung Research (DZL), Grosshansdorf, GERMANY, 5Department of Thoracic Oncology, University Hospital Antwerp, Edegem, BELGIUM, 6Boehringer Ingelheim B.V., Alkmaar, NETHERLANDS, 7Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GERMANY, 8Boehringer Ingelheim (Canada) Ltd./Ltée, Burlington, ON, CANADA, 9Royal Marsden Hospital NHS Foundation Trust, London and Surrey, UNITED KINGDOM 1 Objectives: Pemetrexed/cisplatin doublet is considered the front-line standard-of-care treatment for patients with unresectable malignant pleural mesothelioma (MPM) and yields a median overall survival time of roughly one year. Additional improvements in therapy are clearly needed. Nintedanib is an oral, twice-daily, angiokinase inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1–3, platelet-derived growth factor receptors α/β, and fibroblast growth factor receptors iMig2016.ORG 134 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP 1–3, as well as Src and Abl kinase signaling, which are involved in regulating tumour angiogenesis, growth, and metastasis of MPM. Inhibition of the VEGF pathway as a successful treatment approach for MPM has been previously demonstrated with bevacizumab in the Phase III IFCT-GFPC-0701 MAPS trial (J Clin Oncol 33, 2015: suppl; abstr 7500). Nintedanib has shown clinical benefit and a manageable safety profile in several tumour types, and can be co-administered with various anticancer drugs. Nintedanib (VARGATEF®) in combination with docetaxel is approved in the European Union and additional countries for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after first-line chemotherapy. Nintedanib (Ofev®) monotherapy is approved in the USA and EU for idiopathic pulmonary fibrosis. LUME-Meso is an international, double-blind, randomised, multicentre, placebo-controlled Phase II/III study to evaluate the efficacy and safety of nintedanib combined with pemetrexed/ cisplatin for the treatment of unresectable MPM. Following a data review by the Data Monitoring Committee (DMC) after all planned Phase II patients had been enrolled, the Phase II exploratory study was changed to a confirmatory Phase III trial. The trial is ongoing, remains blinded and the primary analysis has not been conducted. Methods: Chemo-naïve patients from 25 countries worldwide (≥18 years of age, ECOG PS 0–1, and histologically confirmed epithelioid or biphasic MPM; 87 patients in Phase II and 310 to 450 patients in Phase III) will be randomised in a 1:1 ratio to receive up to six cycles of pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on Day 1 administered along with nintedanib (200 mg bid) or placebo from Days 2–21. Patients without disease progression (PD) will continue to receive maintenance treatment with either nintedanib or placebo until PD. The primary endpoint is progression-free survival (PFS), with overall survival (OS) as the key secondary endpoint. The study will use an adaptive design strategy, with sample size reassessment by an external DMC during the trial based on an interim analysis, to ensure sufficient power for PFS and OS. Depending on the treatment effect, a maximum of 450 additional patients will be randomised. Additional secondary endpoints include objective tumour response and disease control according to modified RECIST. Other assessments include frequency and severity of adverse events and changes in laboratory parameters to measure safety, baseline change in forced vital capacity as a measure of pulmonary function, health-related quality of life and exploratory biomarker analyses that will focus on exploring predictive biomarkers in tumour and blood specimens. The study is currently enrolling patients into Phase III. Clinical trial identifier: NCT01907100. Keywords: Phase II/III clinical trial, Nintedanib, unresectable malignant pleural mesothelioma, angiogenesis PP02.33: AUTOLOGOUS DENDRITIC CELL IMMUNOTHERAPY LOADED WITH AN ALLOGENIC TUMOR CELL LYSATE IN PATIENTS WITH MESOTHELIOMA Joachim Aerts1, Paul Baas2, Rosanna Berardi3 , Dean Fennell4 , Jan Van Meerbeeck5, Arnaud Scherpereel6 , Joost Hegmans1 Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, NETHERLANDS, 2Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 3University hospital Ancona, Ancona, ITALY, 4Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 5Thoracic Oncology/MOCA, Antwerp University Hospital, Antwerp, BELGIUM, 6Pulmonary and Thoracic Oncology Department, Hospital of the University (CHU) of Lille, Lille cedex, FRANCE 1 Objectives: Immune therapy with checkpoint inhibition has shown clinical efficacy in a number of malignancies including mesothelioma. However despite impressive clinical responses, a substantial proportion of patients do not respond to this treatment. Althoug this number of responding patients may be increased by combining different checkpoint inhibitors it has now become clear that in a substantial proportion of patients cell based therapy is neccessary to yield an effective immune response. We have shown in former trials that dendritic cell immunotherapy is an effective cell therapy to induce an anti-tumor T-cell response in patients. We have now been granted by the Europian Union, a research proposal to investigate the effect of dendritic cell based immunotherapy compared to BSC. The co-primary objectives are to determine the effect on overal survival and the percentage of patients without progression at 12 months in patients with mesothelioma who were not progressing after platinum pemetrexed chemotherapy Methods: Patients, non progressing after 4-6 cycles platinum pemetrexed chemotherapy, can be included in the trial. Patients will be randomised 1:1 to either dendritc cell therapy or best supportive care (BSC). In case of active treatment, after the completion of chemotherapy, patients will undergo a leucopheresis, during which monocytes are isolated. From these monocytes immature dendritic celles are generated. These immature dendritic cells willl be loaded with an allogenic lysate generated from mesothelioma patients derived clinical grade cellines (Pheralys). We plan to include around 200 patients to achieve a hazard ratio below 0.7 for the overal survial comparing active treatment and BSC. Results: No results are present Conclusion: This study will invetigate the effect of dendritic cell therapy compared to BSC. The planned start of the study is in 2016 and accrual is planned untill 2018. Keywords: Immunotherapy, dendritic cell iMig2016.ORG 135 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.34: RANDOMISED PHASE II TRIAL OF VINORELBINE AS 2ND-LINE THERAPY FOR PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA – VIM TRIAL ed by the Wales Cancer Trials Unit, Cardiff, UK. This abstract is submitted on behalf of the VIM TMG. Keywords: Malignant pleural mesothelioma (MPM), Vinorelbine Lisette S. Nixon1, Georgina Gardner1, Angela Casbard1, Jason F. Lester2, Dean Fennell3 Wales Cancer Trials Unit, Centre For Trials Research, Cardiff University, Cardiff, UNITED KINGDOM, 2Velindre Cancer Centre, Velindre NHS Trust, Cardiff, UNITED KINGDOM, 3Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM 1 Objectives: Malignant pleural Mesothelioma (MPM) is increasing worldwide. However there is no approved therapy in the second-line setting. Vinorelbine exhibits promising activity in a proportion of patients, although there has been no randomised evaluation or validation of biomarkers to support patient stratification. We have reported that BRCA1 is an essential regulator of MPM sensitivity to vinorelbine, and its expression is lost in approximately 38%. The aim of the VIM clinical trial is to establish the anti-tumour activity of vinorelbine as measured by overall survival (OS), time from randomisation to death. Secondary outcome measures include progression-free survival and objective response rate using modified RECIST, safety, tolerability and feasibility. Tumour and blood samples will be collected for future translational research including investigation of BRCA1 expression as a putative predictor of vinorelbine sensitivity. Methods: A UK multicentre open-label randomised phase II trial. Eligible patients will have histological diagnosis of mesothelioma, received at least one line of platinum doublet based chemotherapy as standard, be 18 years or older, have measurable lesions by modified RECIST, radiological evidence of disease progression and given informed consent. Patients will be randomised to either control (ASC) or ASC plus vinorelbine using a 1:2 allocation ratio. ASC will be administered as per local practice, continuing follow-up for at least 18 months. Vinorelbine will be administered at a dose of 60mg/m2 po od on day 1 (equivalent to 25mg/m2 iv day 1) weekly for the first cycle (3 weeks), then subsequently increased to 80mg/m2 weekly (equivalent to 30mg/m2 iv), in the absence of haematological toxicity for subsequent cycles. Patients will continue chemotherapy until evidence of radiological progression, unacceptable toxicity, or patient withdrawal. The primary endpoint of the trial is overall survival, with secondary endpoints of tolerability, response rate, change in tumour volume and progression-free survival. A subgroup analysis will explore the effect of BRCA1 expression on overall survival. The median OS for patients in the control arm is expected to be 9.7 months. With 90% power and a one-sided α of 0.2, 104 events and 133 patients are required to detect a hazard ratio of 0.65, based on the logrank test. The sample size was inflated to allow sub-group analysis of BRCA1 expression at the end of the trial: 133 will be recruited to the vinorelbine arm and 67 to the control arm. Results: Not applicable. Conclusion: Not applicable. The UK National Cancer Research Institute Lung Clinical Studies Group have helped to develop the VIM clinical trial. The study is funded by a research grant from Cancer Research UK (CRUK/12/056) and vinorelbine is supplied and distributed free of charge from Pierre Fabre Ltd. The trial is sponsored by University of Leicester, and coordinat- PP02.35: A RANDOMIZED STUDY OF AMATUXIMAB WITH PEMETREXED AND CISPLATIN AS FRONTLINE THERAPY FOR SUBJECTS WITH PLEURAL MESOTHELIOMA Bruce A. Wallin1, Kimberly Hoffman1, Megan Mclaughlin1, Raffit Hassan2 Clinical Development, Morphotek, Inc, Exton, PA, UNITED STATES OF AMERICA, 2Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA 1 Objectives: Amatuximab is a chimeric monoclonal antibody that binds to mesothelin, which is highly expressed in malignant mesothelioma. Amatuximab was studied in a Phase 2 malignant pleural mesothelioma (MPM) trial which demonstrated that the safety profile of amatuximab in combination with P/C was consistent with that seen previously for the P/C regimen. Although PFS was not significantly different from historical results of P/C alone, the median OS was 14.8 months (as compared to 13.3 months for P/C). The post-hoc PK/PD analysis demonstrated that amatuximab trough concentrations were a significant predictor of both OS and PFS with higher amatuximab concentrations associated with longer OS (583 days; p=0.0202) and PFS (238 days; p<0.001). The primary objective of the study is to demonstrate whether weekly amatuximab, 5 mg/kg, in combination with pemetrexed and cisplatin, has superior OS compared with pemetrexed and cisplatin and placebo in subjects with unresectable MPM. Methods: This Phase 2, double-blind, placebo-controlled study (NCT02357147) is ongoing in 6 countries. Eligible patients (pts) have a confirmed diagnosis of unresectable, epithelioid MPM with measurable disease at screening, and an ECOG Performance Status 0 or 1. Prior chemotherapy, radiation, or surgery with curative intent is not allowed. 560 subjects will be randomized 1:1 to receive weekly amatuximab, 5 mg/kg or saline placebo IV in combination with pemetrexed, 500 mg/m2, and cisplatin, 75 mg/m2, on Day 1 of each 21-day cycle for 6 cycles. Pts with tumor response or stable disease continue amatuximab monotherapy or placebo weekly until disease progression or study termination. The primary endpoint will be a comparison of overall survival between amatuximab and placebo groups in the intent-to-treat population using the unstratified log-rank test. Secondary endpoints include progression-free survival, overall response rate, and duration of response. Safety data will include the usual metrics, including human anti-drug antibody measurements. An interim analysis for futility will be performed by an Independent Assessment Group after approximately 86 OS events are accrued. An IDMC will review the results of the interim analysis for futility and provide final recommendations. Six of the planned 560 pts are enrolled. iMig2016.ORG 136 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Keywords: mesothelioma, amatuximab PP02.36: SWITCH-MAINTENANCE WITH GEMCITABINE FOR PATIENTS WITH MALIGNANT MESOTHELIOMA: FEASIBILITY OF A RANDOMIZED PHASE II STUDY Josine Quispel-Janssen1, Paul Baas1, Wieneke Buikhuisen1, Vincent Vd Noort2, Joachim Aerts3 , Robin Cornelissen3 , Harry Groen4 , Bonne Biesma5, Robbert Van Heemst6 , Magdolen El Soud Youssef7, Jeske Staal-Vd Brekel8 , Sjaak Burgers1 Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 2Statistics, Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 3Dept. Of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, NETHERLANDS, 4Dept Of Pulmonary Medicine, University Medical Center Groningen, Groningen, NETHERLANDS, 5Dept Of Pulmonary Medicine, Jeroen Bosch Hospital, Den Bosch, NETHERLANDS, 6Dept. Of Pulmonary Medicine, Deventer Hospital, Deventer, NETHERLANDS, 7Dept Of Pulmonary Medicine, Maxima Medical Center, Veldhoven, NETHERLANDS, 8Dept. Of Pulmonary Medicine, Zorggroep Twente, Almelo, NETHERLANDS 1 Objectives: The prognosis of malignant mesothelioma (MM) remains poor in spite of an increasing use of second line treatment. No randomized clinical trial in second line has demonstrated improved survival yet. There is scarce data on maintenance chemotherapy in MM showing that maintenance with pemetrexed after 6 cycles combination therapy is feasible. However, studies from other solid tumors suggest that switch-maintenance with a non-cross resistant drug may be more effective. Gemcitabine has extensively been tested in MM in combination with cis- or carboplatin and has resulted in response rates ranging from 12% to 48%. Here, we describe the trial design and first toxicity results of a switch-maintenance trial with gemcitabine monotherapy. Methods: In this Dutch multi-center, randomized phase II study, patients without progression after first line chemotherapy, are randomized to receive either gemcitabine 1250mg/ m2 i.v. on day 1+8 every three weeks plus best supportive care (BSC), or BSC alone. Primary endpoint is progression free survival (PFS). Secondary objectives include response rate, overall survival, toxicity and identification of potential biomarkers for response. A total of 124 patients will be recruited to achieve a power of 90% with a false-positive error of 0.1. Results: Since the start of the study in March 2014 35 patients have been randomized. Seventeen received at least one cycle of gemcitabine. A total of 34 adverse events were seen in 11 patients; 6 receiving gemcitabine and 5 BSC. In the gemcitabine arm , two patients had an infection leading to hospitalization. One of these patients died due to sepsis. The other recovered without further symptoms. Besides this, toxicity so far is mild and manageable. Keywords: maintenance, randomized, gemcitabine, best supportive care PP02.37: MESOCLIN: A FRENCH NATIONAL NETWORK OF EXPERT CENTERS FOR THE MANAGEMENT OF MPM PATIENTS AND FOR RESEARCH PROMOTION Arnaud Scherpereel1, Myriam Locatelli2, Laurent Greillier3 , Jacques Margery4 , David Planchard5, Xavier Dhalluin1, Françoise Galateau-Sallé6 , Eric Wasielewski1, Françoise Le Pimpec-Barthes7 Hospital of the University (CHU) of Lille, Lille, FRANCE, 2Hospital of the University (CHU) of Lyon, Lyon, FRANCE, 3Assistance Publique Hôpitaux de Marseille, Marseille, FRANCE, 4Hôpital Percy, Paris, FRANCE, 5IGR, Villejuif, FRANCE, 6MESOBANK, Lyon, FRANCE, 7Inserm U.1162, INSERM U.1162, PARIS, FRANCE 1 Objectives: Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis, usually associated with previous asbestos exposure. Its management, from the diagnosis to a multimodal treatment, may be complex and tricky. In 2012, the national French institute against cancer (INCa) funded a network of expert centers to improve the management of this tumor with the help of patients’ associations and to stimulate the research in this field. Methods: 15 French centers were established according to the experience of their multimodal team and board in MPM (number of patients per center, publications in the field…). Starting 2016, every case of MPM in France (submitted online through dedicated software and website) should benefit from diagnostic and/or therapeutic advice by these experts teams. In close collaboration with partners such as Mesopath, Institut National de Veille Sanitaire (InVS), asbestos victims associations, French intergroup of thoracic oncology (IFCT)…, we also aim at stimulating all research studies and clinical trials in MPM, helping the recruitment of patients and the collection of data and samples in the MESOBANK project. Results: Between 2012 and 2014, 1736 (new or pretreated) MPM patients were managed by the teams of the MESOCLIN network. It represents about one third of the new patients in France during the same period of time; 271 out of these 1736 patients were recruited into clinical trials, most of them in academic trials. Full and updated data of the MESOCLIN network will be presented during the 2016 iMig meeting. Conclusion: The MESOCLIN network was not fully established and effective yet till 2016 but, in collaboration with all our partners, it aims at targeting an exhaustive and comprehensive management of MPM patients in France, with associated research studies and clinical trials. Keywords: network, management, mesothelioma, research Conclusion: Maintenance treatment with gemcitabine is feasible in patients with mesothelioma. iMig2016.ORG 137 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.39: DOES OPEN ACCESS EXPERT PHONE TRIAGE BASED ON 2012 IMIG GUIDELINES FOR VETERANS RECEIVING CARE WITHIN THE VA, ALTER THERAPY? Charles J. Siegert1, Pietro M. Fisichella2, Quin Huang3 , Jennifer Moseley2, Abraham Lebenthal4 Surgery, Brigham and Women’s / Boston VA, West Roxbury, UNITED STATES OF AMERICA, 2Surgery, VA Boston Healthcare System, West Roxbury, UNITED STATES OF AMERICA, 3Pathology, VA Boston Healthcare System, West Roxbury, UNITED STATES OF AMERICA, 4Surgery, Brigham and Women’s Hospital/ Boston VA, West Roxbury, UNITED STATES OF AMERICA 1 Objectives: INTRODUCTION. In the United States, Veterans are comprise less than 7% of the population yet account for approximately 1/33 of new Malignant Pleural Mesothelioma (MPM) patients annually. MPM is often recognized as a service connected disease. The overwhelming majority of Veterans within VHA are not offered maximal cytoreductive surgery. The VHA is the largest integrated healthcare system in the United States caring for 10 million Veterans. The Boston VA Healthcare System (VABHS) is a Harvard teaching hospital, providing: regional (New England), in network, high volume, complex tertiary general thoracic surgical care. Staff surgeons hold appointments at VABHS and Brigham and Women’s Hospital (BWH), and are members of International Mesothelioma Program (IMP). In attempt to improve access for Veterans, we decided to pilot: ‘open access expert phone triage’ nationally. Utilizing IMiG 2012 guidelines, we attempt to asses feasibility of phone triage and travel for consultation, impact on therapeutic recommendations and ultimate in network treatment Veterans received at VABHS. Methods: Following iMig 2012, the senior author, a general thoracic surgeon, specializing in MPM provided open access phone triage to Veterans eligible for VHA Patients were referred by multiple sources. After initial screening interview patients were instructed to setup electronic access to their medical records at VABHS, and send by overnight mail: disks containing imaging and pathology slides. We reviewed records in a multidisciplinary setting, independently evaluating source data (imaging, pathology, etc.). Veterans that appeared to be reasonable candidates for cytoreductive surgery were encouraged to fly to Boston for further assessment. Veterans that received appropriate care locally were reassured. Results: 91 patients attempted to utilize our phone triage, 60 were US Veterans, 16 were where out of state non-veterans that were excluded, and 14 where international patients seeking therapeutic guidance (this was offered pro-bono, 12/14 were non-veterans)). Not all of the 60 veterans interviewed over the phone had active VHA benefits, of those eligible, 38 patients from 25 states travelled an average 997 miles to VABHS for initial surgical consultation. 2 likely operative candidates chose non operative therapy locally. The majority of the remainder chose surgical consultation elsewhere. In 71% (27/38) of patients we examined at the VABHS initial therapeutic plans were alter based on IMiG guidelines. These patients were evaluated locally and deemed non surgical candidates, 18/27 were recommended definitive chemotherapy 7/27 were initially offered palliative care, 1/27 radiation and chemotherapy and 1/27 surgical resection. Ultimately, 21 out of the 27 patients (78%) had definitive resection (11 radical pleurectomy/ decortication P/D and 10 extrapleural pneumonectomy EPP). 2 patients were advised to start chemotherapy for extrathoracic disease rather than initiate a resection. 3 patients chose to not pursue surgery and chose to continue chemotherapy. One patient surgery was aborted due to unresectable disease following neoadjuvant therapy for N2 disease. Conclusion: Open access expert phone triage and travel based on 2012 IMiG guidelines for Veterans receiving care within the VHA is feasible for the majority of patients that were encouraged to come for surgical second opinion altering treatment recommendations and therapy. Keywords: Veterans, mesothelioma, IMiG guidelines, Veteran Healthcare System PP02.41: MINE PROJECT - MESOTHELIOMA INFORMATION NETWORK IN EUROPE Giorgio V. Scagliotti1, Egbert Smit2, Carlo Di Pietrantonj3 , Gerald Schmid-Bindert4 , Marianne Nicolson5, Corrado Magnani6 , David Planchard7, Luis Paz-Ares8 , Silvia Mattone9, Natalia Motas10 Department of Oncology, University of Turin, Torino, ITALY, 2Vu University Medical Center, Amsterdam, NETHERLANDS, 3ASL AL, Alessandria, ITALY, 4UMM, Mannheim, GERMANY, 5NHS Grampian, Aberdeen, UNITED KINGDOM, 6Dep. Translational Medicine, University Eastern Medicine, Novara, ITALY, 7IGR, Villejuif, FRANCE, 8FIBH12O, Madrid, SPAIN, 9Oncology Department, Università degli Studi di Torino, Orbassano, ITALY, 10IOB, Bucharest, ROMANIA 1 Objectives: MINE (Mesothelioma Information Network in Europe) is a European project funded by CHAFEA (Consumer, Health, Agriculture and Food Executive Agency). It includes a partnership of 9 institutions from Italy, France, Germany, Romania, Spain, The Netherlands and United Kingdom. The project, through the realization of a European network of MPM centres, aims to contribute to the advancement of current knowledge and to the harmonization of diagnostic and therapeutic processes for MPM and to increase awareness of risks in target populations. MINE will analyze the state of the art of the guidelines for MPM diagnosis and therapy and promote the development and harmonization of MM registries and tissue banks and foster the cooperation among clinical centres so to provide homogeneous statistics and specific guidelines. Methods: The advancement of those objectives will be pursued along three lines: a) update and dissemination of guidelines; b) information and facilitation of the participation in clinical trials, and c) availability of biological material for preclinical research on MM. The methods employed by the project are: surveys of diagnostic and therapeutic procedures in selected hospitals on clinical, radiological and pathological procedures for MPM. Evidence based guidelines on diagnosis and therapy of MPM are prepared following state of the art methodology. Analysis of existing MM registries and local database collections and their interaction with tissue banks will be reviewed. A systematic mapping of the existing biological tissue banks for MM is iMig2016.ORG 138 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP pursued with a survey of pathology units. MINE will generate user-friendly educational and informative materials to be made available at large and to be also disseminated through primary care physicians and advocacy groups to target groups subjects in selected areas of high relevance. Results: The expected results of the project will be to create and disseminate a report describing the current diagnostic treatment procedures for MPM in Europe with a focus on the major needs for development on clinical and epidemiological resources for MPM in Eastern Europe. We will work on improved tissue bank guidelines and on a proposal for harmonization in MPM registration. The work will also focus on asbestos related risks and the importance on health surveillance. Conclusion: So far, the project designed and disseminated the surveys and results are currently analyzed. This analysis will provide the bases on which the future steps will be built: gathering the differences among European centres in diagnosis, treatment, registration and collection of samples that will help the consortium in creating harmonized and updated guidelines on the topics covered by the project and it will help in providing the landscape of the MPM in European countries. Results: The review of attendance information suggests that four categories of people requiring support can be identified: 1. Patients who are newly diagnosed and want clinical information and support, 2. Patients in a stable condition, who want to live a ‘normal’ life, 3. Patients with symptomatic and progressive disease, and 4. The bereaved who struggle with grief and loss. There are barriers that impact on each category and potentially affect the uptake of our service. They include: 1. Travel time (up to 3 hours and distances of more than 100 kms.) 2. Appointments for treatment that need to be kept as well as changes in performance status that may affect travel capabilities. 3. Some patients prefer to avoid the confrontation with other patients and only welcome one-on-one conversation. Conclusion: While developing our MPM support service we have identified that patients and carers prefer a personalised approach to physical and emotional support. In the coming period we will continue to monitor the uptake of our service and at the same time explore the addition of interactive technologies to target typical physical symptoms of MPM and the informational needs of patients, carers and the bereaved and translate this in a personalised approach. 1. Mesothelioma in Australia 2012. 4th Annual Report. Australian Mesothelioma Registry, 2014 2. Van Zandwijk N, Clarke C, Henderson D, et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. Journal of Thoracic Disease. 2013;5(6):E254-E307. doi:10.3978/j.issn.2072-1439.2013.11.28. Keywords: support, personalised, patients’, mesothelioma, PP02.42: PERSONALISED SUPPORT FOR PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA (MPM) IN NEW SOUTH WALES, AUSTRALIA Jocelyn Mclean1, Nico Van Zandwijk2 1 Asbestos Diseases Research Institute, Sydney, AUSTRALIA, 2Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA Objectives: The Australian Mesothelioma Registry reported 641 new cases of MPM in 2014. Of those cases, 185 were from NSW. 1 The symptom burden of this incurable disease is very high as is the need for medical and emotional support.2 Data about the needs of these patients is currently being collected in an observational study of health related quality-of-life in people with MPM at the Asbestos Diseases Research Institute (ADRI). In the meantime, we have started to develop a support service that will reflect the personal needs of patients, carers and the bereaved across NSW. Three different groups of individuals with a request for support were identified: patients receiving standard (palliative) care, patients who have had radical (combined-modality) treatment, and the bereaved. Methods: The Australian Mesothelioma Registry reported 641 new cases of MPM in 2014. Of those cases, 185 were from NSW. 1 The symptom burden of this incurable disease is very high as is the need for medical and emotional support.2 Data about the needs of these patients is currently being collected in an observational study of health related quality-of-life in people with MPM at the Asbestos Diseases Research Institute (ADRI). In the meantime, we have started to develop a support service that will reflect the personal needs of patients, carers and the bereaved across NSW. Three different groups of individuals with a request for support were identified: patients receiving standard (palliative) care, patients who have had radical (combined-modality) treatment, and the bereaved. PP02.43: SURGICAL CYTOREDUCTION AND HYPERTHERMIC INTRATHORACIC CHEMOTHERAPY (HITHOC) FOR MALIGNANT PLEURAL MESOTHELIOMA Michael Ried1, Reiner Neu1, Christian Großer2, Tamas Szöke2, Hans-Stefan Hofmann1 Department of Thoracic Surgery, University Medical Center Regensburg, Regensburg, GERMANY, 2Department of Thoracic Surgery, Hospital Barmherzige Brüder Regensburg, Regensburg, GERMANY 1 Objectives: Combination of surgical cytoreduction and hyperthermic intrathoracic chemotherapy (HITHOC) perfusion is performed more often for therapy of malignant pleural mesothelioma (MPM) within a multimodality treatment concept. We describe our perioperative management and clinical experience. Methods: Between September 2008 and January 2015 a total of n= 23 patients with MPM were enrolled. Perioperative management, postoperative morbidity and mortality were analyzed. Next follow-up analysis is scheduled for April 2016. Results: Included were n= 18 male and n= 5 female patients with a mean age of 61.7 ± 8.2 years. All patients received multimodality therapy depending on tumor stage, histology and their overall condition. Histologic subtype of patients with MPM was epitheloid (n= 19; 83%) or biphasic (n= 4; 17%). Induction iMig2016.ORG 139 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP chemotherapy with cisplatin/pemetrexed was performed in n= 21 patients (91%). All patients underwent radical surgical cytoreduction with pleurectomy/decortication (P/D; n= 13; 57%), extended P/D (resection of pericardium and/or diaphragm; n= 7; 30%) or extrapleural pneumonectomy (EPP; n= 3; 13%) followed by HITHOC perfusion at 42°C for one hour. HITHOC was performed with an increasing concentration of cisplatin (100 mg/m2 BSA n= 7; 150 mg/m2 BSA n= 11; 175 mg/m2 BSA n= 1) or combination of cisplatin/doxorubicin (175 mg/m2 BSA / 65 mg n= 4). Macroscopic complete resection (R0/R1) was achieved in n= 22 patients (96%). Severe chemotherapy-related complications were not observed. Operative revision was necessary in n= 2 patients (9%) due to rupture of the diaphragmatic patch. Postoperative renal insufficiency was observed in n= 3 patients (13%) with no patient requiring temporary postoperative dialysis (0%). Prolonged bronchopleural fistula was documented in n= 2 patients (9%) after lungsparing P/D or eP/D. 30-day mortality was 4.4%, because n= 1 patient died after EPP. Adjuvant chemotherapy was accomplished in n= 14 patients (61%). Last follow-up analysis in July 2015 showed a mean recurrence free interval of 23 months and mean overall survival was 32 months. Taken together, at this time n= 12 patients (52%) were still alive. Conclusion: Surgical cytoreduction in combination with HITHOC can be performed with acceptable morbidity and mortality rates in selected patients. Patients should be evaluated interdisciplinary to determine their eligibility for this multimodality approach. Early clinical results may encourage the use of additional HITHOC to provide better local tumor control. Keywords: pleural mesothelioma, hyperthermic intrathoracic chemotherapy, pleurectomy/decortication, surgical cytoreduction MPM at clinically IMIG-stage II underwent RP via right-sided postero-lateral thoracotomy as part of multimodality treatment. RP was performed as a standardized surgical procedure at our institution. Additionally, partial resection of the diaphragm and thymus was performed. Soft tissue foci at the chest wall were resected. The diode-pumped Nd:YAG Laser LIMAX® 120 (wavelength: 1318 nm, Gebrüder Martin GmbH & Co KG, Tuttlingen, Germany) and a power output of 100 watts was utilized to scissor through lung tissue in case of lung infiltration aiming to accomplish MCR. Results: With a hand piece and under direct visual control, the diode-pumped Nd:YAG laser permitted intraparenchymal cut through lung tissue in the basilar segments. Simultaneously, the diode-pumped Nd:YAG laser caused tissue vaporization and coagulation of the resection surface, respectively. The appearance and functionality especially of the lower lobe could be preserved. The blood loss could be maintained low (approximately 450 mL). Lung-scarifying procedures could be avoided. MCR could be achieved at the end of the procedure. Operative time (4 hours 47 minutes) was acceptable despite the extent of surgery. No intraoperative side-effects of the laser application could be observed. Pathological IMIG-stage was found to be IV (pT4 pN0 (0/17)) due to completely resectable tumor extending into the soft tissue of the chest wall (two foci) in addition to the lung infiltration. The patient could be discharged from hospital at postoperative day 13 after removal of the pleural drainages. No postoperative complications occurred. He successfully underwent adjuvant radiation of the chest wall and chemotherapy without any delay. Conclusion: The diode-pumped Nd:YAG laser might be an important tool in the surgical armamentarium for parenchyma-sparing, macroscopic complete resections in the treatment of malignant pleural mesothelioma. However, further experimental investigations and clinical studies are warranted. Keywords: Malignant pleural mesothelioma, lung-sparing surgery, diode-pumped Nd:YAG laser PP02.44: DIODE-PUMPED ND:YAG LASER FOR LUNG-SPARING SURGICAL TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA - FIRST EXPERIENCE Servet Bölükbas , Michael Eberlein 1 2 Thoracic Surgery, Helios Klinikum Wuppertal, Wuppertal, GERMANY, 2Pulmonary, Critical Care And Occupational Medicine, University of Iowa Hospitals and Clinics, Iowa, IA, UNITED STATES OF AMERICA 1 Objectives: The goal of surgery is macroscopic complete resection (MCR) for multimodal treatment of malignant pleural mesothelioma (MPM). Deep infiltration of the basilar segments of the lung might obviate lung-sparing radical pleuractomy (RP). Commonly, lung-sacrifying procedures (extrapleural pneumonectomies or lobectomies) are performed in these situations. It has been demonstrated that high-output Nd:YAG laser precisely scissor, seal lung tissue and coagulate at the same time for the treatment of lung metastases. We report our first experience with diode-pumped Nd:YAG laser intending to avoid lung-sacrifying surgeries for MPM. Methods: A 53-year-old patient with biopsy-proven epitheloid PP02.45: PATHOLOGICAL EVALUATION OF THE VISCERAL PLEURA STAMP IN THE RADICAL PLEURECTOMY/DECORTICATION FOR MPM PATIENTS Masashi Kobayashi, Chihiro Takasaki, Sachiko Kumazawa, Hironori Ishibashi, Kenichi Okubo Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, JAPAN Objectives: In recent years, procedure of radical pleurectomy/ decortications (P/D) was increased in surgical treatment of resectable malignant pleural mesothelioma. And macroscopic complete resection (MCR) in resectable MPM is most important. However, there are no reports such as clinical results of evaluating providence with visceral pleura side pathologically in P/D cases. Visceral pleura is microscopically composed of mesothelial layer, submesothelial layer, external elastic layer, interstitial layer, and internal elastic layer. We investigated the iMig2016.ORG 140 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP dissection plane of decortication of the visceral pleura from the lung. Methods: Ten MPM patients who underwent radical pleurectomy/decortication at Tokyo Medical and Dental University Hospital between April 2010 between October 2015 were studied. Among these patients, there were 8 epithelioid tumors, 1 biphasic tumor, and 1 desmoplastic tumor, - 4 patients with stage I MPMs, 2 patients with stage II MPMs, 4 patients with stage III MPMs. We performed analysis to site of visceral pleural lesions in radical MPM patients, using the EV& HE staining to evaluate for ten cases and site of visceral pleural as: Right upper 5 lesions, middle 6 lesions, lower 7 lesion Left upper 5 lesions, lower 8 lesions, totally 31 lesions. Results: In all specimens, the growth of tumor cells in the visceral pleura surface was indicated in diffuse partially or nodules. Fourteen of 31 lesions with MPM cell invasion directly to the lung parenchyma epitomized, but all 14 lesions with any depth of invasion of them were excised from the lung parenchyma. On the other hand, although 17 lesion sites were excised at lung parenchyma, those lesions were remained intravascular pleura without invasion of lung parenchyma. Each visceral pleuron was dissected in lung parenchyma, no relation to depth of tumor invasion or pleural thickening on all lesions. Furthermore, regardless of extent of invasion, lung parenchyma was disconnected in the visceral pleura in the vicinity of the site in the pleural thickening; thin section was cut off in the deep part of the lung parenchyma. There was no residual tumor in lung parenchyma for 31 lesions. Conclusion: In respectable malignant pleural mesothelioma, visceral pleura dissection plane in the P/D was lung parenchyma. Keywords: radical pleurectomy/decortication PP02.46: CLINICAL AND IMMUNOLOGIC IMPACT OF SURGERY FOR MALIGNANT PLEURAL MESOTHELIOMA Vincenzo Ambrogi1, Franco Stella2, Tommaso Claudio Mineo1 Thoracic Surgery, Tor Vergata University, Rome, ITALY, 2Thoracic Surgery, University of Bologna, Bologna, ITALY 1 Objectives: The aim of the two intentionally-curative surgical procedures, extra-pleural pneumonectomy and radical pleurectomy/decortication, is mainly focused on the impact on survival. Unfortunately, this is not significantly improved whatever the operation. Conversely, the clinical impact of surgery is poorly investigated. The object of this study is to analyze the effects of these two operations on immunology, symptoms and quality of life. pathology undergoing a non-intentionally curative procedure (i.e. video-assisted thoracoscopy plus biopsy and possible pleurodesis). The effects on immunitary response were analyzed with total lymphocyte count, lymphocytes subpopulations and interleukin-6 and 10, measured pre and postoperatively (days 1, 7 and 14). Symptoms, function and quality of life were assessed before surgery and at 3, 6, 12 and 18 months during the follow-up. Quality of life was tested with Medical Outcomes Study SF-36 and the St. George’s Respiratory Questionnaire, administered to the patients at the same intervals. Results: There was no perioperative mortality in any group. One patient died 20 days after extrapleural pneumonectomy for pulmonary embolism. Thirty-day postoperative major morbidity was 45% (14/31) for extrapleural pneumonectomy, 23% (10/44) for pleurectomy/decortication and 14% (5/35) for the control group (p=0.04). Median survivals in the extrapleural pneumonectomy and pleurectomy/decortication groups were 20 and 15 months, respectively (p=0.09), whereas in the control group was 10 months. Total lymphocyte count and natural killer subtype significantly decreased in both intentionally-curative groups, but especially after extrapleural pneumonectomy. Interleukin-6 and -10 were significantly increased in all groups. However, intergroup comparison evidenced more elevated values in the extrapleural pneumonectomy group at postoperative day 7 for both interleukin-6 (p=0.01) and interleukin-10 (p=0.04). The control group showed a faster normalization of interleukin-10 values when compared to the other procedures. In the early postoperative period patients undergoing pleurectomy/decortication presented greater symptomatic and functional improvement. After 1 year patients treated with extrapleural pneumonectomy generally showed greater improvements. Nearly all SF-36 domains showed a significant amelioration at 3 months in the pleurectomy/decortication group. After extrapleural pneumonectomy we experienced a slower amelioration of all domains except the physical component. Thereafter all domains, physical component included, improved and persisted significantly better than the preoperative value up to one year. In the control group the improvements were insignificant. Similar scores were assessed with the George’s questionnaire. After one year we experienced a progressive worsening of all quality of life parameters. However more durable values were found in the extrapleural pneumonectomy group. Conclusion: Both surgical procedures performed with curative intent still have a scant impact on overall survival. Extrapleural pneumonectomy had a greater negative impact on immunological status thus producing a significantly greater risk of postoperative infection implying a higher morbidity rate. Both procedures were effective in ameliorating symptoms and quality of life with a more rapid effect for pleurectomy/decortication but longer for extrapleural pneumonectomy. Keywords: Surgery, Immunology, Malignant pleural mesothelioma, quality of life Methods: From 1995 to 2014 a total of 75 with malignant pleural mesothelioma underwent extrapleural pneumonectomy (n=31) or pleurectomy-decortication (n=44) with intentionally curative intent in our two centres. These two groups were also compared with a control group of 35 patients with the same iMig2016.ORG 141 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Table 1. Demographics and Perioperative Variables PP02.47: WHO BENEFITS FROM MACROSCOPIC COMPLETE RESECTION IN MALIGNANT PLEURAL MESOTHELIOMA? Hasan Batirel1, Muzaffer Metintas2, Hale B. Caglar3 , Guntulu Ak2, Fulden Yumuk4 , Rengin Ahiskali5, Zeynep Bilgi1, Tunc Lacin1, Bedrettin Yildizeli1, Mustafa Yuksel1 Thoracic Surgery, Marmara University Faculty of Medicine, Istanbul, TURKEY, 2Pulmonary Medicine, Eskisehir Osmangazi University, Eskisehir, TURKEY, 3Radiation Oncology, Medipol University Faculty of Medicine, Istanbul, TURKEY, 4Internal Medicine, Div Of Medical Oncology, Marmara University Faculty of Medicine, Istanbul, TURKEY, 5Pathology, Marmara University Faculty of Medicine, Istanbul, TURKEY 1 Objectives: Macroscopic complete resection (MCR) is the recommended surgical principle in malignant pleural mesothelioma (MPM). The objectives of this study are to analyze whether MCR contributes to survival in a specific subgroup of patients and to compare outcomes in patients who underwent PD with MCR and partial PD. Methods: Between September 2005 and August 2015, 80 patients underwent PD for MPM in our clinic. All surgeries were performed through a posterolateral thoracotomy with removal of 6th rib. Diaphragmatic and pericardial reconstruction were performed in 19 and 13 patients respectively. If grossly visible tumor was left behind, the resection was accepted as partial PD. Patient data were recorded in a prospective database. Demographic criteria (age, gender), histology, postoperative morbidity and mortality (90-day), length of hospital stay, pathologic stage, use of neoadjuvant/adjuvant treatment, follow-up, site of recurrence and survival were recorded. Whole cohort, patients who had PD with MCR (n=33) or partial PD (n=47) were evaluated separately. Student t-test, Kaplan-Meier survival and uni- and multivariate analyses were performed. Results: Average age was 56 ± 11 (36 females). 51 had epithelioid histology. Postoperative morbidity occurred in 20 (prolonged air leak in 11). Mortality was seen in 2 patients due to sepsis and ARDS. Median length of hospital stay was 7.5 ± 3.5 days. Upfront treatment was applied in 23. 70 underwent adjuvant treatment. Mean follow-up was 18 ± 15 months. Recurrence occurred in 61 patients (only locoregional [n=50], locoregional and distant [n=8], only abdomen [n=3]). Overall median survival was 17.4 months. 2 and 5-year survivals were 35 and 19% respectively. In uni- and multivariate analysis histology and postoperative N status were significant (0.05 and 0.026 respectively). Patients with epithelioid histology, N0 status and PD with MCR (n=16) had a 2-year survival of 71% and median survival was not reached. Comparison of patients who had PD with MCR to partial PD are shown in Table 1. Overall and 2-year survivals were similar between patients who had PD with MCR or partial PD. PD with MCR (n=33) Partial PD (n=47) p value Age (y), Gender (Male/Female) 55 ± 11, 14/19 56 ± 10, 30/17 0.5, 0.06 Histology (Epithelioid/Biphasic/Sarcomatoid) (n) 22/10/1 29/15/3 0.68 T1+2/T3+4 (n) 22/11 9/38 <0.001 N (0/1/2/X) (n) 25/1/ 5/2 17/0/3/27 <0.001 Upfront treatment (n) 7 16 0.22 Perioperative Morbidity/90-day Mortality (n) 13/2 7/0 0.013/ 0.09 Hospital Stay (d) 9 ± 4.5 6.5 ± 2.2 0.001 Median and 2-year Survival (months/%) 14.1/39 18.2/33 0.76 Conclusion: MCR does not translate to prolonged survival in all patients with MPM who undergo PD. Patients with epithelioid histology and N0 status benefit most from this surgical technique. Efforts should be focused on better preoperative mediastinal N staging and histologic diagnosis Keywords: pleurectomy/decortication, Macroscopic Complete Resection PP02.48: IS SURGERY FOR MESOTHELIOMA IN THE UK A DYING MODALITY IN THE MANAGEMENT OF MALIGNANT MESOTHELIOMA? UPDATE ON OUR EXPERIENCE Mohammed Khalil1, Syed Qadri2, Mubarak Chaudhry2, Alexander Cale2, Mahmoud Loubani2, Michael Cowen2 Cardiothoracic Surgery, Castle Hill Hospital, Cottingham, UNITED KINGDOM, 2Castle Hill Hospital, Cottingham, UNITED KINGDOM 1 Objectives: The Mesothelioma and Radical Surgery (MARS) trial adversely affected surgery for mesothelioma in the UK, especially extrapleural pneumonectomy (EPP) with significantly reduced referrals, although we had demonstrated good outcome of EPP in our department. Following iMIG 2012, we have changed our practice to pleurectomy/decortication (EPD) as a part of trimodality treatment if they were not fit for extrapleural pneumonectomy (EPP). We aim to present our result of limited experience. Methods: All patients who had any surgical procedure for malignant mesothelioma cytoreduction except EPP were iMig2016.ORG 142 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP included. Thirty-four patients underwent pleurectomy, extended pleurectomy/decortication or radical pleurectomy for malignant mesothelioma from September 2007 to April 2015. Results: Thirty-three patients underwent extended pleurectomy/decortication. Median age was 65 years with 82% being male with mean postoperative hospital stay of 11 days. There was no in-hospital or 30-days mortality. Overall median survival was 16.5±5 months (CI 6.7-26.2) with longer survival in epitheloid than biphasic mesothelioma. Conclusion: This update of our limited experience still reflects poor referral from respiratory physicians for surgery. We here continue to demonstrate that surgery for mesothelioma as a part of trimodality treatment is safe with no operative mortality, acceptable morbidity and better survival. Keywords: pleurodecortication, trimodailty PP02.49: THE ANALYSIS OF THE RECURRENCE OF THE PATIENTS WHO UNDERWENT SURGICAL RESECTION FOR MALIGNANT PLEURAL MESOTHELIOMA Nobuyuki Kondo1, Toru Nakamichi2, Ayumi Kuroda2, Masaki Hashimoto2, Teruhisa Takuwa2, Seiji Matsumoto2, Kozo Kuribayashi3 , Tohru Tsujimura4 , Noriaki Tsubota5, Takashi Nakano6 , Seiki Hasegawa1 Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, JAPAN, 2Department of Thoracic Surgery, Hyogo College of Medicine, Nisinomiya City, JAPAN, 3Respiratory Medicine, Hyogo College of Medicine, Nishinomiya Hyogo, JAPAN, 4Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, JAPAN, 5Department of Thoracic Oncology, Hyogo College of Medicine, Nishinomiya, JAPAN, 6Hyogo College of Medicine, Nishinomiya, JAPAN 1 Objectives: Currently combined treatment modalities are the most frequently used approach for malignant pleural mesothelioma (MPM) as a feasible therapeutic strategy. Because surgery for malignant pleural mesothelioma (MPM) is cytoreductive, not radical, a certain ratio of recurrence is inevitable after curative-intent operation. Here we analyzed the recurrence after surgery with induction chemotherapy for MPM patients (n=100). Methods: From 2004 to 2015, Hyogo College of Medicine MPM Surgery Program has given induction chemotherapy followed by surgery with or without radiation therapy to surgical candidates with histologically confirmed MPM, clinical stage T1-3N0-1M0 disease, performance status 0–1, and no major comorbidity. Surgery for MPM contains extrapleural pneumonectomy (EPP) and pleuractomy/decortication (P/D). Surgery for MPM contains extrapleural pneumonectomy (EPP) and pleuractomy/decortication (P/D). Results: 100 consecutive patients (81 male and 19 female) underwent surgical resewction. The median age was 61 years(range, 37-74years). The numbers of pathological stage I/ II/III/IV were 11/19/55/15, respectively. Histological types were diagnosed as epithelioid (n=89),biphasic (n=8), sarcomatoid (n=1), othrs (n=2). 93 patients underwent surgical resection : 58 EPP, 35 P/D, 7 exploratory thoracotomy, respectively. Macroscopic complete resection was achieved in 87 patients. Of 100 patients, 64 patients were confirmed the recurrence within the observation period. The site of recurrence is classified: new lesion in the ipsilateral thoracic cavity (chest wall, mediastinum and residual lung) were found in 39 (61.0%)/15 (23.4%) in the abdominal cavity/ 3 (4.7%) in subcutaneous or muscular tissue/ 9 (14.1%) lymph node metastasis/ 12 (19.1%) in contralateral thoracic cavity/ 3 (4.7%) distant metastasis. 9 cases were expired without confirmation of recurrence of MPM (14.1%) but revealed recurrence or metastasis after an autopsy. Recurrence-free survival time was 434 days. In EPP group, recurrence in ipsilateral thorax was (57.1%), whereas recurrence and metastasis at other distant site were relatively frequent: the abdominal cavity (4.7%), lymph node metastasis (14.1%), contralateral thoracic cavity (19.1%), and distant metastasis (7.1%). In contrast, most of recurrence were found in the ipsilateral thorax in P/D group. Conclusion: We examined the recurrence in 100 of MPM patients who underwent surgical resection in combination with chemotherapy. Keywords: pleuractomy/decortication, recurrence, extrapleural pneumonectomy PP02.50: IPSILATERAL PNEUMONECTOMY AFTER PLEURECTOMY/DECORTICATION IN A PATIENT WITH MALIGNANT PLEURAL MESOTHELIOMA Toru Nakamichi, Seiki Hasegawa, Nobuyuki Kondo, Masaki Hashimoto, Teruhisa Takuwa, Ayumi Kuroda Department of Thoracic Surgery, Hyogo College of Medicine, Nisinomiya City, JAPAN Objectives: Background: One of the purposes of pleurectomy/ decortication (P/D) in patients with malignant pleural mesothelioma (MPM) is to induce ipsilateral lung re-expansion by resecting thickened visceral pleura. However, in patients with highly restrictive lungs, re-expansion failure of decorticated lungs may directly cause persistent air leakage and intrathoracic infection. Selection of surgical technique and intraoperative decision whether or not to discard such lungs is highly difficult. Methods: Case report Results: A 72-year-old male underwent resection of right ycT2N0M0 epithelioid MPM after three cycles of preoperative chemotherapy. Selection of surgical technique was debatable because the right lung was highly collapsed before and after video-assisted thoracoscopic pleural biopsy performed three months before. Trapped lung was speculated as the cause of restriction rather than tumor invasion to the pulmonary parenchyma. Although P/D was successfully performed, re-expansion of decorticated right lung was insufficient and air leakage was massive. Discarding right lung was considered during operation, but was not adopted in expectation of postoperative gradiMig2016.ORG 143 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP ual improvement. On day 3, severe respiratory failure due to persistent air leakage and massive suppurative secretion from collapsed right lung developed and the patient was intubated. On day 10, life-saving right pneumonectomy was required due to progressive infiltration in the left lung.The patient successfully recovered. Conclusion: P/D is contraindicated when the diseased lung is presumably non-reexpandable. Selection between P/D and extrapleural pneumonectomy is sometimes difficult in case where reexpansion potential is unclear. Intraoperative decision to discard poorly-expandable lungs after completion of decortication is also very hard. However, it should be noted that such lungs are not only non-functional but also life-threatening. In the present case, discard of the right lung should have been decided just after completion of decortication. Results: Of 129 registered patients, 11 were excluded from this analysis: 2 referred after induction chemotherapy, 6 refused surgery after registration, and 3 did not undergo induction chemotherapy. Response to the induction chemotherapy in the remaining 118 patients were partial response (20 patients, 16.9%), stable disease (87 patients, 73.7%), and progressive disease (11 patients, 9.3%). A total of 11 patients (9.3% of 118) could not undergo surgery due to progressive disease (n=10, 8.4% of 118) or serious adverse event of chemotherapy (n=1, 0.8%). 107 underwent surgery (EPP 56, P/D 44, exploratory thoracotomy 7). Median survival time and 5-year survival for operated (n=107) and non-operated patients (n=11) were 38.6 and 11.0 months, and 30.3% and 0%, respectively. Surgical mortality rates at 30 and 90 days were 1.9% (2/107) and 3.7 (4/107), and surgical morbidity was 34.6% (37/107). Keywords: Ipsilateral pneumonectomy, pleurectomy/decortication PP02.51: INDUCTION CHEMOTHERAPY FOLLOWED BY SURGERY FOR MALIGNANT PLEURAL MESOTHELIOMA Nobuyuki Kondo1, Toru Nakamichi1, Ayumi Kuroda1, Masaki Hashimoto1, Teruhisa Takuwa1, Seiji Matsumoto1, Yoshitomo Okumura2, Taiichiro Otsuki3 , Kozo Kuribayashi3 , Fumihiro Tanaka4 , Noriaki Tsubota5, Tohru Tsujimura6 , Norihiko Kamikonya7, Takashi Nakano3 , Seiki Hasegawa1 Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, JAPAN, 2Thoracic Surgery, Itami City Hospital, Itami, JAPAN, 3Respiratory Medicine, Hyogo College of Medicine, Nishinomiya Hyogo, JAPAN, 4Surgery Ii, University of Occupational and Environmental Health, Kitakyusyu, JAPAN, 5Department of Thoracic Oncology, Hyogo College of Medicine, Nishinomiya, JAPAN, 6Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, JAPAN, 7Department of Radiation Oncology, Hyogo College of Medicine, Nishinomiya, JAPAN 1 Objectives: Since any surgery for malignant pleural mesothelioma (MPM) is cytoreductive, not radical, effective chemotherapy is a prerequisite of curative-intent operation. However, it remains unclear whether chemotherapy should be administered before or after surgery. Here we report our 11-year experience with induction chemotherapy followed by surgery. Methods: Hyogo College of Medicine MPM Surgery Program has given induction chemotherapy followed by surgery with or without radiation therapy to all surgical candidates with histologically confirmed MPM, clinical stage T1-3N0-1M0 disease, performance status 0–1, and no major comorbidity. From March 2004 to December 2015, 129 patients were intended to undergo surgical treatment after chemotherapy. Trimodality treatment with induction chemotherapy followed by extrapleural pneumonectomy (EPP) and hemithoracic 54Gy radiation therapy has been intended to all patients during 2004 and 2012. After 2012, most patients underwent bimodality treatment with induction chemotherapy followed by pleuractomy/ decortication (P/D) and postoperative chemotherapy. Conclusion: Approximately 90% of the patients with surgical intent successfully underwent either of EPP or P/D after induction chemotherapy with acceptable surgical mortality and morbidity. Keywords: Surgery, induction chemotherapy iMig2016.ORG 144 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.52: ANTI-TUMOR EFFECTS OF METFORMIN AND NUTLIN-3A IN MALIGNANT PLEURAL MESOTHELIOMA Yuji Tada1, Takao Morinaga2, Toshio Suzuki3 , Hideaki Shimada4 , Koichiro Tatsumi5, Kenzo Hiroshima6 , Masatoshi Tagawa2 Respirology, School of Medicine Chiba University, Chiba, JAPAN, 2Chiba Cancer Center Research Institite, Chiba, JAPAN, 3Chiba University, Chiba, JAPAN, 4Department of Surgery, School of Medicine, Toho University, Tokyo, JAPAN, 5Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, JAPAN, 6Tokyo Women`s Medical University, Yachiyo Medical Center, Yachiyo, JAPAN 1 Objectives: Metformin has been widely used as an oral drug for type 2 diabetes mellitus. Recent reports showed that metformin exhibited an anti-tumor effects for a variety of malignancies. However its effect for malignant pleural mesothelioma (MPM) remains unknown. Therefor we investigated its impact on mesothelioma cell lines in aspects of cell growth and viability. We also examined anti-tumor effects of metformin in combination with nutlin-3a (an inhibitor of p53-degradation). Methods: We examined the anti-proliferative effect of metformin and/ or nutlin-3a in the effect for eight MPM cell lines. RNA interference was conducted to clarify the relevance of p53 status and the anti-tumor effects of metformin and nutlin-3a. Results: Metformin suppressed cell growth of MPM cells in a p53-independent mechanism. Flow cytometric analysis showed that metformin treatment markedly induced cell cycle arrest at G2/M phase and nutlin-3a produced G1 cell cycle arrest. The apoptotic effect of combination of metformin with nutlin- 3a in MPM involved multiple mechanism and was dependent to the cell type. Conclusion: Metformin suppressed growth of MPM cells in a p53-independent mechanism. Combinatory use of metformin and nutlin-3aproduced synergetic inhibitory effects for cell proliferation. PP02.53: COMPARED HIGH-RESOLUTION WHOLE GENOME SCREENING OF MESOTHELIOMA AND BENIGN ASBESTOS PLEURISY Tunç Tuncel1, Guntulu Ak2, Hasan Veysi Guneş1, Selma Metintas3 , Irfan Değirmenci1, Muzaffer Metintas2 Department of Medical Biology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, TURKEY, 2Lung and Pleural Cancers Research Aand Clinical Center And Medical Faculty Department of Chest Diseases, Eskisehir Osmangazi University, Eskisehir, TURKEY, 3Lung and Pleural Cancers Research and Clinical Center and Medical Faculty Department of Public Health, Eskisehir Osmangazi University, Eskisehir, TURKEY 1 the body and etiologicialy linked to asbestos exposure. Although genetic basis of MPM tumors commonly charecterized with deletions on several cancer related genes like CDKN2A (9p21), NF2 (22q12), BAP1 (3p21), WT1 (11p13), BCL10 (1p22), majority of cases exhibits tumor spesific genetic alterations with great genomic heterogenity. Also pathological effect of asbestos exposure on this genomic complexity still remains unknown. In this study we aimed to determine which asbestos related genomic alterations can lead malignant transformation on bening asbestos related diseases and help us to determine better diagnosis and new personalized treatment options. To clarify these issues, we used high resolution genomic approaches to detect if there is an asbestos related genomic signature which can intersect in or distinguish between malignant and bening diseases. Methods: A total of 55 MPMs and 18 cases with Benign Asbestos Pleurisy (BAP) as control group were included in the study. BAP genomes compared with asbestos related-MPM genomes to find out genetic factors which are spesific to asbestos damage. Genomic DNAs isolated from pleural tumor samples for MPM group and pleural tissues from patients with BAP. Affymetrix CytoScan HD whole genome SNP array was assessed in these 73 individuals. According to their complex genomic architecture, three of these MPM patients selected to whole genome sequencing (Illumina HiSeq platform) for confirmation SNP array findings and further detailed investigation for novel complex structural alterations. Data implemantation and Bioinformatic analysis carried with Nexus Copy Number Discovery Edition 7,5. Through Nexus 7.5, We analyzed copy number frequencies with combining GISTIC (Genomic Identification of significant targets in cancer) analysis. Compared CNV analysis between malign and benign group was conducted with a %40 genomic aberration frequency difference threshold. Most frequent and significant copy number changes selected in combination with these analyses. Results: Deletion of Interferon locus on 9p21.3 genes including IFNA7, IFNA10, IFNA16, IFNA17, IFNA14 was detected as most frequent aberrations among all MPM samples (%65) but not in benign group. Genomic gains are predominantly found in different parts of 8q, 5p, 7p and 20q and losses are 22q, 10q, 14q, 13q, 4p-4q, 16p. Both losses and gains are detected in 1p, 3p-3q, 15q, 19p-19q in MPMs. MPM genomes exhibits allelic imbalance on chromosomal regions like 6q, 9p, 10q, 22q and 3p with ≥%50 frequency. Complex structural alterations like Chromothripsis patterns was detected as a novel finding on MPM and it is seen mostly affecting on Chromosome 15. Conclusion: We detected some genetic alterations between MPM and BAP patients. We think that these alterations may be important to understand the pathogenesis of the diseases and some of them can give opportunites to make new diagnostic and therapeutic researchs. *This study was carried out with the biological samples collected in the study named as “Network cooperation for the management of environmental and occupational exposure to mineral fibers induced pulmonary pathologies” which was supported by General Directorate of Health Researches, Republic of Turkey, Ministry of Health. Keywords: genetic, mesothelioma, Biology, pathogenesis Objectives: Malignant Pleural Mesothelioma (MPM) is a highly aggressive tumour generally originating from serosal linings of iMig2016.ORG 145 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP mesothelioma and could be a therapeutic target. This work PP02.54: ANALYSIS OF GENE-EXPRESSION CHANGES IN 3D SPHEROIDS HIGHLIGHTS A SURVIVAL ROLE FOR ASS1 IN MESOTHELIOMA Dario Barbone1, Carlo Follo1, Loes Van Dam2, Puthen V. Jitesh3 , Shu Dong Zhang4 , William G. Richards5, Raphael Bueno5, Dean Fennell6 , Courtney Broaddus1 University of California, San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 2University Medical Center, Utrecht, Utrecht, NETHERLANDS, 3Sidra Medical and Research Center, Doha, QATAR, 4Queen’s University of Belfast, Belfast, UNITED KINGDOM, 5Brigham and Women’s Hospital, Boston, MA, UNITED STATES OF AMERICA, 6University of Leicester, Leicester, UNITED KINGDOM was supported by a Mesothelioma Applied Research Foundation (MARF) grant to DB (A121342) and by the Simmons Mesothelioma Foundation. CF is supported by a Simmons Fellowship in Mesothelioma Research. Keywords: spheroids, arginine, ASS1, chemoresistance 1 Objectives: Understanding the mechanisms of chemoresistance of malignant pleural mesothelioma may help identify novel therapeutic avenues. We have previously studied how the 3D environment confers increased chemoresistance (multicellular resistance) and wondered if this could be understood by studying the genes differentially expressed in 3D. Methods: Using Affymetrix arrays, we investigated the gene-expression differences between monolayers (2D) and 3D spheroids grown from three mesothelioma cell lines, M28, REN and VAMT. The differentially expressed genes were then compared to genes shown to be upregulated in human mesothelioma, in two publicly available datasets comprising data from 100 patients. The staining of one differentially expressed gene, argininosuccinate synthase or ASS1, was measured in two sets of tumor microarrays, one containing 88 tumor samples and one containing samples from 88 additional mesotheliomas with their paired normal tissues. The difference between the ASS1 of the tumor and the normal matched control was correlated with patient outcome. RNA interference was used to ablate ASS1 in 3D spheroids to determine its effect on chemoresistance in that setting. Results: A total of 209 genes were differentially expressed in 3D (138 up-regulated and 71 down-regulated) compared to 2D. Of 3 genes initially found to be upregulated in both 3D spheroids and patient tumors, only ASS1 was found to be consistently upregulated, both at the mRNA and protein level. In the tumor microarray containing samples from 88 mesothelioma patients, ASS1 expression was found in 90% of samples; only 8 tumors (~10%) showed no ASS1 staining. In the matched pairs (tumor vs normal tissue control obtained from the same patients), ASS1 expression was found to be significantly higher in mesothelioma than in normal tissue. Moreover, the tumors that showed the highest difference between ASS1 in the tumor compared to the paired normal tissue (top quartile, n=24) had significantly shorter survival than those with a smaller difference (lower 3 quartiles, n=64) (10.6 vs 20.2 months, p= 0.0004). Ablation of ASS1 by RNA interference significantly reduced the multicellular resistance of the spheroids. Conclusion: We have shown that ASS1 is expressed in most mesothelioma tumors and may play a survival role in a 3D setting. ASS1, which catalyzes the penultimate step of the biosynthetic pathway of the essential amino acid arginine, may thereby assist tumor survival. We propose that ASS1 contributes to the multicellular resistance acquired by mesothelioma cells in 3D, may contribute to a poor clinical outcome of patients with PP02.55: MYOSIN II-DEPENDENT CELL CONTRACTILITY DRIVES SPONTANEOUS NODULE FORMATION OF MESOTHELIOMA CELLS Julia Tarnoki-Zach1, Dona Greta Isai2, Elod Mehes1, Sandor Paku3 , Zoltan Neufeld4 , Balazs Hegedus3 , Balazs Dome5, Andras Czirok1 Department of Biological Physics, Eotvos Lorand University, Budapest, HUNGARY, 2Department of Anatomy & Cell Biology, University of Kansas School of Medicine, Kansas City, KS, UNITED STATES OF AMERICA, 3Mta-se Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, HUNGARY, 4School of Mathematics and Physics, University of Queensland, Brisbane, ACT, AUSTRALIA, 5Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, AUSTRIA 1 Objectives: Despite recent advances in its treatment, malignant pleural mesothelioma (MPM) still has a poor prognosis with almost all patients succumbing to disease. A pathognomonic feature of MPM is the formation of multiple, macroscopic pleural tumor nodules, which may pinch off, and contribute to the local spreading of the disease. In this study we focus on the role of cell contractility in MPM nodule formation in vitro. Methods: Several human patient-derived MPM cell lines were cultured up to three weeks. The time course of nodule formation was observed by videomicroscopy. Actin and beta-catenin labelled samples were analyzed by confocal laser scanning microscopy. To interfere with normal actomyosin function, we utilized Y27632, the rho kinase (ROCK) inhibitor and blebbistatin, an inhibitor of actomyosin crosslinking. Results: Macroscopic multicellular aggregates develop when MPM cell lines are cultured at high cell densities. Surprisingly, the nodule-like aggregates do not arise by excessive local cell proliferation, but by myosin II-driven cell contractility. Accordingly, nodule formation can be prevented or reversed by pharmacological inhibitors of myosin II activity. Contractile nodules contain actin cables that can span multiple cells. Several features of the in vitro MPM nodule development, e.g. characteristic pattern size and density or speed of appearance of aggregates, can be explained by a computational model that assumes uniform and steady intercellular contractile forces within a monolayer of cells, and a mechanical load-dependent lifetime of cell-cell contacts. Conclusion: Our study indicated the presence of multicellular stress cables, structures that MPM cells can utilize for longrange communication within the mechanically interlinked tumor nodules. The cellular contractile activity can exert forces that iMig2016.ORG 146 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP can internalize parts of the host tissue environment including preexisting blood vessels. The demonstrated ability of myosin II inhibitors to scatter mesothelioma nodules may open novel combined therapeutic methods. Keywords: Malignant pleural mesothelioma, actomyosin contractility, multicellular stress cables, computational model PP02.57: IDENTIFICATION OF CIS- AND TRANSACTING ELEMENTS REGULATING CALRETININ EXPRESSION IN MESOTHELIOMA CELLS Jelena Kresoja-Rakic1, Esra Kapaklikaya1, Gabriela Ziltener1, Damian Dalcher2, Raffaella Santoro2, Brock C. Christensen3 , Kevin C. Johnson3 , Beat Schwaller4 , Walter Weder1, Rolf Stahel5, Emanuela Felley-Bosco1 University of Zurich, Laboratory of Molecular Oncology, Division of Thoracic Surgery, Zurich, SWITZERLAND, 2Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, SWITZERLAND, 3Departments of Epidemiology, Pharmacology and Toxicology and Community and Family, Hanover, NH, UNITED STATES OF AMERICA, 4Department of Medicine and Anatomy, Department of Medicine and Anatomy, University of Fribourg, Fribourg, SWITZERLAND, 5Clinic For Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 PP02.56: POST-TRANSCRIPTIONAL REGULATION OF CALRETININ EXPRESSION Jelena Kresoja-Rakic1, Merve Sulemani1, Michaela B. Kirschner2, Glen Reid3 , Steven Kao3 , Beat Schwaller4 , Rolf Stahel5, Walter Weder1, Emanuela Felley-Bosco1 University of Zurich, Laboratory of Molecular Oncology, Division of Thoracic Surgery, Zurich, SWITZERLAND, 2University Hospital Zurich, Division of Thoracic Surgery, Zurich, SWITZERLAND, 3Asbestos Diseases Research Institute, Sydney, AUSTRALIA, 4Department of Medicine and Anatomy, Department of Medicine and Anatomy, University of Fribourg, Fribourg, SWITZERLAND, 5Clinic For Oncology, University Hospital Zurich, Zurich, SWITZERLAND Objectives: Calretinin (CALB2) is a diagnostic marker for epithelioid mesothelioma. It is also a prognostic marker since patients with tumors expressing high calretinin levels have better overall survival. Silencing of calretinin decreases viability of epithelioid mesothelioma cells. Our aim was to elucidate mechanisms regulating calretinin expression in mesothelioma. Objectives: Calretinin (CALB2) is a diagnostic and prognostic marker in malignant pleural mesothelioma (MPM). The CALB2 3’UTR contains several putative microRNA target sites. Our aim was to investigate the role of the CALB2 3’-UTR in the post-transcriptional regulation of calretinin expression in MPM. Methods: To investigate human calretinin (CALB2) promoter, ~1kb of genomic sequence surrounding the transcription start site (TSS) +1 was analyzed using luciferase reporter pGL3-basic vector. Transcriptional activity of 5’-deletion CALB2 promoter constructs in mesothelioma cells was measured via dual luciferase assay. Mutant constructs were created by site-directed mutagenesis. Electrophoretic mobility shift (EMSA) assay and chromatin immunoprecipitation (ChIP) assay were used to show binding of functional transcription factors (TF). To demonstrate cell-cycle regulated calretinin expression, mesothelioma cells were synchronized using double thymidine treatment followed by nocodazole treatment. 1 Methods: Using the pmirGLO Dual-Luciferase expression vector, the complete CALB2 3‘-UTR fragment was inserted 3‘ of the firefly luciferase gene. Activity of the CALB2 3‘-UTR was quantified after transient transfection into ACC-MESO-4, ZL55 and ONE-58 MPM cells. In silico analysis was employed to predict potential microRNAs targeting the CALB2 3’-UTR. Subsequently, luciferase activity and calretinin expression were evaluated after the transfection-mediated overexpression of the predicted microRNAs. In addition, calretinin protein, assessed by immunohistochemistry, and miR-30 expression, were investigated in a cohort of MPM patients (N=48). Results: The addition of the CALB2 3’-UTR significantly downregulated the luciferase activity in the three tested MPM cell lines. Analysis of the CALB2 3’-UTR using the TargetScan online database predicted target sites for the miR-30 family members, miR-9 and miR-384. Transient delivery of a miR-30e mimic into CALB 3’UTR stably-transfected ACC-MESO-4 cells resulted in an even further decrease of the activity of the luciferase reporter as well as a decrease in calretinin protein expression. Finally, expression of miR-30e was found to negatively correlate with the calretinin expression in a cohort of MPM patient samples. Conclusion: Our data shows for the first time the role of miR30e in the post-transcriptional negative regulation of calretinin expression via interaction with its 3’-UTR. Keywords: calretinin, mesothelioma, 3’-UTR, microRNA Results: Analysis of calretinin transcript and protein suggested a control at the mRNA level. Treatment with 5-aza-2’-deoxycytidine and analysis of TCGA data indicated that promoter methylation is not likely to be involved. Therefore, we investigated the CALB2 promoter by analyzing ~1kb of genomic sequence surrounding the transcription start site (TSS) +1 using promoter reporter assay Deletion analysis of the CALB2 proximal promoter showed that sequence spanning the -161/+80bp region sustained transcriptional activity. Site-directed analysis identified important cis-regulatory elements within this -161/+80bp CALB2 promoter. EMSA and ChIP assays confirmed binding of NRF-1 and E2F2 to the CALB2 promoter and siRNA knockdown of NRF-1 led to decreased expression of calretinin. Cell synchronization experiment showed that calretinin expression was cell cycle regulated with a peak of expression at G1/S phase. Conclusion: Our study identified the transcription factors NRF-1 and E2F2 to bind to the human CALB2 promoter and we demonstrated cell cycle-dependent regulation of calretinin expression in mesothelioma cells providing the first insight into the regulation of CALB2 expression in mesothelioma cells. Keywords: calretinin, promoter, NRF-1, E2F, cell-cycle iMig2016.ORG 147 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.58: DECREASED PROLIFERATION AND CELL MIGRATION OF PRIMARY MESOTHELIAL CELLS FROM CALRETININ-DEFICIENT (CR-/-) MICE Walter Blum1, Emanuela Felley-Bosco2, Laszlo Pecze3 , Beat Schwaller1 Department of Medicine and Anatomy, Department of Medicine and Anatomy, University of Fribourg, Fribourg, SWITZERLAND, 2Department of Molecular Oncology, University Hospital Zurich, Zurich, SWITZERLAND, 3Medicine, University of Fribourg, Fribourg, SWITZERLAND 1 Objectives: Calretinin (CR; human gene symbol: CALB2) is one of the most sensitive and specific markers for the diagnosis of malignant pleural mesothelioma (MPM). Interestingly also reactive human mesothelial cells (proliferating, non-transformed cells) show strong expression of CR. CR’s exact function in mesothelioma formation and its putative molecular involvement is still unknown. In order to investigate CR’s possible role in the reactive mesothelium and in the presumed first steps of tumor development, we investigated the role of CR in mouse primary mesothelial cells (prMC). Our objective was to compare prMC from wildtype (WT) and from CR knockout (CR-/-) mice concerning growth, proliferation, cell cycle length and migration and the effect of artificially (via-lentivirus) up-regulating CR. Methods: prMC from WT and CR-/- mice were analyzed for morphological, proliferative and migratory characteristics. Fluorescent cell-cycle indicators (Fucci) allowed to determining cell cycle parameters. Efficient over-expression of CR and NLS-CR (nuclear localization signal) was achieved using lentiviral-mediated transduction of prMC. Mouse embryos at an age of 14.5 and 16.5 days were collected and investigated by IHC for CR expression. Results: Analysis of the mesothelium from WT and CR-/- mice showed no noticeable macroscopic and histologic differences. PrMC derived from both genotypes were isolated and grown in vitro. Their in vitro morphology was “cobblestone-like”, they expressed the mesothelial markers mesothelin, cytokeratin and vimentin and TEM analysis revealed the presence of microvilli. In CR-/- cells we observed a statistically significantly decreased proliferation rate. By up-regulating CR in prMC (WT and CR-/-) the proliferation rate and the wound closure (mobility) rate was increased; the up-regulation also induced a more pronounced epithelial morphology. The prMC originating from CR-/- animals had a prolonged G1 phase, but an unchanged S/G2/M phase. In the scratch assay the wound closure time of CR-deficient prMC was significantly longer. Artificial over-expression of CR and NLS-CR in prMC (WT and CR-/-) led to a change in cell morphology, an increased proliferation rate and mobility. WT cells closed the wound in the scratch assay much faster and this was due to a combined effect of increased proliferation rate and higher cell mobility of the cells at the wound borders. Immunohistological analysis of embryos (E14.5 and 16.5) showed transient CR expression in cells of the embryonic connective tissue (mesenchyme) and in mesothelial precursor cells surrounding the developing lung. Differentiated mesothelial cells (flat morphology) showed no longer immunostaining for CR. Conclusion: The absence of CR during the embryonic development in CR-/- mice results in long-lasting changes in mesothelial cell characteristics evidenced by differences in vitro in the proliferation and mobility of prMC from WT and CR-/- mice. We make the hypothesis that CR plays an important role during the normal development of mesothelial cells in vivo. Understanding mechanistically the involvement of CR in normal mesothelial cells and in reactive mesothelium is expected to help to understand the process of mesotheliomagenesis. Knowledge about the affected signaling pathways leading to increased proliferation and cell migration might lead to the identification of novel attractive targets for mesothelioma therapy besides directly targeting the expression of CR. Keywords: Calretinin, primary mesothelial cells, Mesothelium PP02.59: KCNMA1 IS TARGETED BY MIR-175P AND MODULATES CELL MIGRATION IN MALIGNANT PLEURAL MESOTHELIOMA Yuen Yee Cheng1, Casey M. Wright1, Michaela B. Kirschner2, Marissa Williams1, Kadir H. Sarun1, J J. Edelman3 , Michael P. Vallely3 , Brian C. Mccaughan4 , Sonja Klebe5, Nico Van Zandwijk1, Ruby C. Lin6 , Glen Reid1 Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA, 2Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 3The Baird Institute and Faculty of Medicine, The University of Sydney, Sydney, NSW, AUSTRALIA, 4Sydney Cardiothoracic Surgeons, RPA Medical Centre, Sydney, NSW, AUSTRALIA, 5Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, SA, AUSTRALIA, 6Cardiothoracic Genomics, Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA 1 Objectives: Mesothelioma has poor prognosis with little therapeutic progress, thus identification of new therapeutic targets for MPM is urgently needed. We and others have shown that microRNAs play an important role in mesothelioma biology and have potential as therapeutic agents. Here we attempt to identify dysregulated microRNAs with functional roles by: utilising publicly available gene expression datasets on MPM, in combination with our transcriptomics studies; validating candidate targets in our relatively large biobank collection of MPM tumours and normal pleural samples; and investigating the functional roles of these candidates. Methods: Candidate targets were identified bioinformatically by systematic interrogation of mRNA-microRNA differential gene expression correlations using Gene Set Enrichment Analysis. Candidates (mRNA, microRNA and protein) were validated using RT-qPCR and immunofluorescent assays in mesothelioma and normal mesothelium samples. Functional significance of candidate genes was confirmed by a number of assays including SYBR green proliferation assay, colony formation assay, cell cycle analysis, apoptosis assay (annexin V and PI staining), migration assay and agarose spot invasion assay. Results: We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumours and cell lines. RT-qPCR revealed that members of both families were significantly down-regulated in MPM tumours and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epitheliiMig2016.ORG 148 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP oid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the immortalised mesothelial line MeT-5A, and was also up-regulated in patient tumour samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. Conclusion: These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets. Keywords: mesothelioma, miR-17-5p, therapeutic targets, KCNMA1, KCal.1, calcium-activated potassium channel subunit alpha 1 PP02.60: ENGINEERED, LIGHT-CONTROLLED GROWTH FACTOR RECEPTORS FOR MESOTHELIOMA RESEARCH Karin Schelch1, Alvaro Ingles-Prieto2, Eva Reichhart2, Stephanie Kainrath2, Mir A. Hoda3 , Walter Berger1, Harald Janovjak2, Michael Grusch1 Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, AUSTRIA, 2Institute of Science and Technology (IST) Austria, Klosterneuburg, AUSTRIA, 3Medical University of Vienna, Vienna, AUSTRIA 1 Objectives: In the field of optogenetics researchers use genetically encoded signaling molecules that can be activated or inactivated by light. Our group focuses on the role of growth factors and their receptors for the malignant behaviour of mesothelioma cells. Our aim was therefore to generate synthetic growth factor receptors that can be activated by light and allow to control growth factor-associated signal transduction pathways with superior spatiotemporal precision. Methods: To generate RTKs that can be optically activated (Opto-RTKs), intracellular domains of mammalian RTKs were fused to light-sensitive protein domains of the light-oxygen voltage (LOV) family from various species. The resulting chimeric receptors were tested for light-dependent activation of signal transduction by reporter gene assays, immunoblotting, and various cell biological tests assessing DNA synthesis, epithelial mesenchymal transition (EMT), and sprout formation. Results: Three different LOV domains were identified that were capable of inducing light-dependent dimerisation and activation of signal transduction when fused to the intracellular domain of murine fibroblast growth factor receptor 1 (mFGFR1). Similar results were obtained for additional RTKs including human EGFR, RET or c-Met. Light-induced activation of Opto-mFGFR1 enabled control of the MAPK, PI3K and PLCγ pathways. Signal activation could be spatially confined to illuminated regions of cell cultures and signals rapidly subsided after cessation of illumination. Functionally, light could replace FGF2 for the induction of cell proliferation and EMT in mesothelioma cells. In endothelial cells, light could replace VEGF for the stimulation of angiogenic sprouting. Conclusion: Our optogenetic approach enables fine-tuned, light-mediated control of growth factor receptors kown to be important for mesothelioma growth. Opto-RTKs will be valuable tools for a number of applications in mesothelioma research including dissection of signalling dynamics with increased spatiotemporal precision in single cell experiments, targeting signal activation to specific cell populations in co-culture systems and experimental animals, and facilitation of drug screening procedures. Keywords: optogenetic, signal transduction, growth factor receptor, receptor tyrosine kinase PP02.61: PRECLINICAL INVESTIGATION OF THE THERAPEUTIC POTENTIAL OF NINTEDANIB IN MALIGNANT PLEURAL MESOTHELIOMA Viktoria Laszlo1, Judit Ozsvar1, Thomas Klikovits1, Dora Lakatos2, Mir A. Hoda1, Tamas Garay3 , Walter Berger4 , Michael Grusch4 , Walter Klepetko1, Frank Hilberg5, Balazs Dome1, Balazs Hegedus1 Surgery, Medical University Vienna, Vienna, AUSTRIA, 2Department of Biological Physics, Eotvos University, Budapest, HUNGARY, 32nd Department of Pathology, Semmelweis University, Budapest, HUNGARY, 4Department of Internal Medicine, Medical University Vienna, Vienna, AUSTRIA, 5Boehringer Ingelheim Austria, Vienna, AUSTRIA 1 Objectives: Malignant pleural mesothelioma (MPM) is a devastating malignancy with still rising incidence worldwide. Its aggressive biological behavior and therapy resistance result in a median overall survival (OS) of 9 to 17 months only. Currently, platinum-based chemotherapy in combination with antifolate agents is the standard front-line therapy for MPM and to date no molecularly targeted therapeutic approaches have been approved in the clinics. Nintedanib is an indolinone derivative that has been demonstrated to efficiently inhibit the activity of VEGFR, PDGFR and FGFR tyrosine kinase isoforms and thus to be capable to suppress angiogenesis and tumor growth. Here, we report the antitumor activity of nintedanib in MPM. Methods: 21 MPM cell lines were treated with nintedanib and SRB assays were performed to determine the IC50 values for each cell line. 4 sensitive cell models were selected for further in vitro analysis: BrdU, TUNEL and clonogenic assays were performed to investigate the impact of the drug on the proliferation, apoptosis and colony formation capacity of MPM cells, respectively. The migratory activity of MPM cells was analyzed with 2D videomicroscopy. The downstream signaling of the target receptors was investigated by Western blot analysis. Drug interactions with cisplatin were assessed in the p31 MPM cell line and in its cisplatin-resistant subline (p31cis) iMig2016.ORG 149 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP by using the CalcuSyn software. The in vivo anti-MPM activity of nintedanib was studied in an orthotopic human MPM xenograft model in SCID mice. The effect of nintedanib as single agent at a dose of 50 mg/kg daily, administered intraperitoneally and in combination with the cisplatin/pemetrexed regimen, was investigated. Survival, total tumor weight and microvessel density were evaluated Results: Nintedanib exerted a growth inhibitory effect on MPM cell lines in both short- and long-term viability assays. The inhibition of proliferation was observed in all MPM cell models analyzed, whereas significant apoptosis induction was only found in half of them. Migratory activity strongly decreased upon nintedanib treatment. Down-regulation of Erk1/2 phosphorylation was evident within 10 min of treatment and was present even after 24h. Nintedanib, however, had no inhibitory effect on the activation of Akt or S6. Additive, but no synergistic effect on cell viability was detected in the p31 and p31cis MPM cells when nintedanib was combined with cisplatin. In vivo, nintedanib significantly prolonged the survival of mice (vs. control, log-rank test, p=0.0008) and inhibited tumor growth as a single agent (p=0.003 vs control), as well as in combination with cisplatin and pemetrexed (0.005 vs cisplatin-pemetrexed). Moreover, nintedanib inhibited angiogenesis in the xenograft tumors. Conclusion: Our data suggest that nintedanib exerts antitumor activity in MPM both in vitro and in vivo and thus may represent a promising novel therapeutic option in this malignancy Keywords: angiogenesis, targeted therapy, Nintedanib content in comparison with normal rats. Primary tumors and metastases were fixed, embedded in paraffin and analysed for histopathology and immunohistochemistry. Results: In vitro, the M5-T2 cell line differed from the three others by a low saturation density (1.1 x 105 / cm2), low mobility and a myofibroblast-like morphology. In vivo, the tumor was mainly restricted to the omentum without metastases to normal tissues. Conversely, F4-T2, F5-T1 and M5-T1 cell lines shared in common a high saturation density (> 2 x 105 / cm2), a high mobility, a propensity to produce metastasis to normal tissues and positivity for vimentin in IHC. Among these cells, M5-T1 presented the shortest doubling time, highest saturation density and was the only cell line producing spheroids in culture. It also exhibited the highest expression of Fra-1, which has been associated with cell migration in both rat and human mesothelioma. In vivo, M5-T1 tumor was also characterized by considerable tumor heterogeneity and a very high mitotic index. Analyses of chemokine content in peritoneal fluids revealed that M5-T1 and F5-T1 presented elevated levels of MCP-1, relative to controls, while F4-T2 and M5-T2 did not present any change in the content of any of the eight chemokines. F5-T1 tumor differed from M5-T1 by an additional elevation of MCP-3, MIP-1 α, and IP-10. Conclusion: These four experimental rat tumor models represent interesting new tools for basic research on tumor microenvironment and oncoimmunology, with potential prospects for the evaluation of new therapeutic strategies for MM. Keywords: Cell lines, Rat tumor model, Vimentin, Chemokines PP02.62: COMPARATIVE ANALYSIS OF 4 EXPERIMENTAL MESOTHELIOMAS IN F344 RATS: A PRELIMINARY STUDY OF THEIR TUMOR BIOLOGY FEATURES Joëlle Nader1, Myriam Robard2, Marc Grégoire1, Daniel L. Pouliquen1 UMR 892 INSERM / 6299 CNRS, Nantes, FRANCE, 2Plateforme MicroPICell, SFR F. Bonamy, Nantes, FRANCE 1 PP02.63: THBS2, A NOVEL GENE INVOLVED IN THE MALIGNANT PROGRESSION OF PLEURAL MESOTHELIOMA Elisa Barone1, Stefan J. Marciniak2, Doris M. Rassl3 , Julia Knight3 , James Wason4 , Luciano Mutti5, Alessandra Bonotti6 , Rudy Foddis6 , Alfonso Cristaudo6 , Ombretta Melaiu1, Giovanni Giangreco1, Federica Gemignani1, Stefano Landi1 Objectives: Malignant mesothelioma (MM) develops in complex microenvironments where molecular interactions between tumor cells and the immune system of the host play a crucial role. Given the diversity of biologic situations found among MM, in-depth study of the parameters involved might lead to formulation of new principles in tumor biology as well as new therapeutic strategies. Department of Biology, University of Pisa, Pisa, ITALY, 2Cambridge Institute For Medical Research (cimr), University of Cambridge, Cambridge, UNITED KINGDOM, 3Department of Pathology, Papworth Hospital NHS Foundation Trust, Cambridge, UNITED KINGDOM, 4MRC Biostatistics Unit, Cambridge, UNITED KINGDOM, 5School of Environment and Life Sciences, University of Salford, Manchester, UNITED KINGDOM, 6School of Medicine and Surgery, University of Pisa, Section of Occupational Medicine, Pisa, ITALY Methods: The cell lines used in this study were established from Fischer F344 rats, 378 to 392 days after induction with a single intraperitoneal inoculation of crocidolite fibers (UICC analytical sample, Neyco). The growth pattern of each cell line (doubling time, saturation density) was determined in culture in 6-well plates, and expression profiles of genes of interest determined by RT-qPCR. Fifteen to thirty five days after orthotopic (i.p.) injection of tumor cells into syngeneic rats, peritoneal fluids and plasmas were collected for analyses of GRO alpha, Eotaxin, IP-10, MIP-1 α, MIP-2, MCP-1, MCP-3 and Rantes Objectives: The identification of novel diagnostic/prognostic biomarkers and therapeutic targets for Malignant Pleural Mesothelioma (MPM) is of extreme importance. Following previous studies, we identified genes up-regulated and potentially involved in the carcinogenetic process of MPM. Among them, THBS2 was found up-regulated in MPM tissues and in Mero-14, Mero-25, and Istmes2 MPM cell lines. Aims: to evaluate the functional role of THBS2 in MPM cell lines and its use as a prognostic biomarker. 1 iMig2016.ORG 150 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Methods: In order to investigate the role of THBS2 in the carcinogenesis of MPM, we employed RNA interference techniques. Following transient transfection, we performed a phenotypic screening through the Sulphorhodamine-b, the Colony Formation, the Wound-Healing, and the Caspase luminescence assays. For evaluating the protein expression of THBS2 as prognostic biomarker we performed immuno-histochemistry on Tissue Microarray (TMA) composed by 135 cases of MPM and we correlated the staining scores with the patients’ overall survival. Results: THBS2-silencing caused a statistical significant increase of apoptosis (+30% in Mero-14; p-value= 0.032), a reduced proliferation (-41% in IstMes2; p-value = 0.044), and a decreased clonogenicity (-66% in Mero14 cells; p-value = 0.020). No significant association between protein expression and overall survival was found. Conclusion: Present results suggest a potential of targeting THBS2 as a novel therapeutic approach for the treatment of MPM, whereas data from TMA do not support the use of THBS2 as a prognostic biomarker. Keywords: THBS2, silencing, novel target, mesothelioma PP02.64: GROWTH FACTOR-INDUCED MORPHOLOGY AND EXPRESSION CHANGES IN CELL MODELS REFLECTING THE HISTOLOGICAL MESOTHELIOMA SUBTYPES treatment with FGF2 and EGF induced phenotypical changes reminiscent of EMT. Changes in cell shape were accompanied by scattering, increased migration, growth and invasiveness and required signaling along the mitogen-activated protein kinase (MAPK) pathway. Inhibition of the fibroblast growth factor receptors (FGFR) or the MAPK axis could prevent these changes and, in MPM cell lines with sarcomatoid morphology, reverse scattering and induce a more epithelioid morphology. Gene and microRNA expression analyses demonstrated an overlap with previously established EMT markers such as CDH1 or VIM, but also identified several novel potential markers such as MMP1, ESM1, ETV4, PDL1, ITGA6 or BDKRB2. Blockage of the FGFR or the MAPK pathway resulted in the opposite regulation of these genes. Inhibition of MMP1 but not of ESM1 or ETV4 via siRNAs or pharmacological inhibitors prevented FGF2-induced scattering and invasiveness. In unsupervised clustering, the gene expression profiles of solvent- or cytokine-treated cells were associated with those of epithelioid and sarcomatoid MPM, respectively. Pathway enrichment analysis of the targets of altered microRNAs (fold change >10) as well as differentially expressed genes (fold change >3) after FGF2 treatment showed that the regulated genes are assigned to categories such as transcriptional misregulation in cancer, MAPK, Wnt and Hippo pathway, interaction with extracellular matrix, focal adhesions and tight junctions. Conclusion: These findings enhance our understanding of the morphological and behavioral plasticity of mesothelioma cells and the link to the MPM histological subtypes and their influence on patient outcome. Keywords: Epithelial-mesenchymal transition, MAPK Signals, MPM histological subtypes Karin Schelch1, Christina Wagner2, Ruby Lin3 , Mir A. Hoda2, Balazs Hegedus2, Balazs Dome2, Walter Berger2, Glen Reid3 , Michael Grusch2 University of Sydney, Asbestos Diseases Research Institute, Sydney, AUSTRALIA, 2Medical University of Vienna, Vienna, AUSTRIA, 3Asbestos Diseases Research Institute, Sydney, AUSTRALIA 1 Objectives: The three main histological subtypes of malignant pleural mesothelioma (MPM), epithelioid, sarcomatoid and biphasic are characterized by differences in aggressiveness and patient prognosis. However, the mechanisms and causes responsible for the different cell morphologies are poorly understood. Epithelial-mesenchymal transition (EMT) has been implicated in progression and chemoresistance of numerous tumors but its role in MPM is not well characterized. The aim of this study was to analyze growth factor-induced morphological and phenotypical changes in MPM cell lines and the associated gene expression and signal transduction cascades in more detail. Methods: Morphological and behavioral changes of cell models treated with cytokines and inhibitors or transfected with siRNAs were analyzed by morphometry, immunoblotting, migration, invasion and soft agar assays. Alterations in gene or microRNA expression were evaluated via qPCR and array hybridization. Pathway enrichment analysis was based on KEGG. Results: In several cell models established from biphasic MPM, PP02.65: THE H3K27ME3 DEMETHYLASE KDM6B AS AN EPIGENETIC REGULATOR OF ERΒ EXPRESSION IN HUMAN MALIGNANT PLEURAL MESOTHELIOMA Arcangela G. Manente1, Giulia Pinton1, Luca Pavesi1, Daniela Tavian2, Puthen V. Jithesh3 , Dean Fennell4 , Stefan Nilsson5, Laura Moro1 Pharmaceutical Sciences, University of Piemonte Orientale, Novara, ITALY, 2Cellular Biochemistry and Molecular Biology, Catholic University of the Sacred Heart, Milano, ITALY, 3Sidra Medical and Research Center, Doha, QATAR, 4Cancer Studies, University of Leicester, Leicester, UNITED KINGDOM, 5Biosciences and Nutrition, Karolinska Institutet, Huddinge, SWEDEN 1 Objectives: To determine the correlation between the demethylase KDM6B and the estrogen receptor β (ERβ) expression in human malignant pleural mesothelioma (MPM). Methods: We have evaluated the correlation between KDM6B and ERβ expression in MPM tumor samples and derived cell lines grown in normoxic and hypoxic conditions. Results: In this study, we report a strong positive correlation between high expression of the H3K27 demethylase KDM6B iMig2016.ORG 151 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP and the ERβ coding genes in MPM tumor samples. Furthermore, we demonstrate a role for KDM6B in the control of ERβ expression in MPM derived cell lines, independent from the expressed levels of the methyltransferase EZH2. Parallel induction of KDM6B and ERβ occurs in estrogen receptor negative cells from biphasic MPM, grown in chronic hypoxia or packed in spheroids, where the presence of a hypoxic core is confirmed by HIF2 immunofluorescence staining. Real-time and Western blot analyses confirm the HIF2-dependent hypoxic induction of KDM6B and the KDM6B-dependent expression of ERβ. The activation of KDM6B in hypoxia is confirmed by reduced histone H3K27 tri-methylation. Importantly, the expression of ERβ and the less aggressive phenotype, acquired in hypoxia, are maintained when cells return to normoxia if treated with the selective ERβ agonist KB9520, even though HIF2 and KDM6B decrease to basal levels. Conclusion: The possibility to reverse the more aggressive biphasic cell phenotype by targeting ERβ with a selective agonist could represent a new strategy to effectively treat this histological subtype of MPM. Keywords: ERbeta, hypoxia, KDM6B, Malignant pleural mesothelioma PP02.66: COMBINATION OF NUTLIN-3A AND HSP90 INHIBITORS PRODUCES SYNERGISTIC CYTOTOXICITY ON MESOTHELIOMA WITH THE WILD-TYPE P53 Masatoshi Tagawa1, Shinya Okamoto1, Takao Morinaga1, Masato Shingyoji2, Ikuo Sekine3 , Toshio Suzuki4 , Yuji Tada4 , Koichiro Tatsumi4 , Hideaki Shimada5, Kenzo Hiroshima6 Chiba Cancer Center Research Institite, Chiba, JAPAN, 2Division of Respirology, Chiba Cancer Center, Chiba, JAPAN, 3Department of Medical Oncology, University of Tsukuba, Tsukuba, JAPAN, 4Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, JAPAN,5Department of Surgery, School of Medicine, Toho University, Tokyo, JAPAN, 6Department of Pathology, Tokyo Women’s Medical University, Yachiyo, JAPAN 1 Objectives: A majority of malignant mesothelioma lacks the INK4A/ARF locus which contains the p14ARF and p16INK4A genes but possesses the wild-type p53 genotype. The genetic defect activates MDM2 that facilitates p53 degradation processes, and consequently induces a functional loss of p53 activities together with uninhibited cell cycle progression. Activation of the endogenous p53 pathways by inhibiting MDM2 can be crucial for cell death of mesothelioma. We therefore investigated a possible therapeutic strategy of the p53 activation with an inhibitors for MDM2 and MDM4, a MDM2-like molecule involved in suppression of p53-mediated transactivation. Methods: We examined cytotoxicity of nutlin-3a which blocked the MDM2-p53 interaction and subsequently suppressed proteasome-mediated p53 degradation, and that of heat shock protein 90 (HSP90) inhibitors which repressed p53-inactivating MDM4 and receptor-type tyrosine kinases. Cytotoxicity was assessed with a colorimetric assay and the CalcuSyn software, and cell cycle was analyzed with flow cytometry. Expression levels of p53-associated proteins were examined with Western blot analysis. Results: Nutlin-3a produced cytotoxicity on mesothelioma with the wild-type p53 but not with mutated p53, whereas HSP90 inhibitors, 17-AAG and 17-DMAG, achieved cytotoxicity in a p53-independent manner. Cells treated with nutlin-3a increased sub-G1 fractions, and showed phosphorylation of p53 and activation of the p53 down-stream pathways. HSP90 inhibitors-treated cells exhibited up-regulation of p53 expression and down-regulation of AKT phosphorylation although knock-down of p53 with the si-RNA did not influence the cytotoxicity. Combination of nutlin-3a with HSP90 inhibitors produced synergistic cytotoxicity with further increased sub-G1 fractions through augmented p53 expression levels and enhanced caspase cleavages but not through down-regulated AKP phosphorylation. Nutlin-3a produced synergistic cytotoxic activities with NSC207895, a specific MDM4 inhibitor, but not with MK-2206, an AKT inhibitor. The combinatory use of nutlin-3a with HSP90 inhibitors achieved suppression of tumor growth greater than a single agent in an orthotopic mouse model. Conclusion: Nutlin-3a and HSP90 inhibitors produced synergistic cytotoxic effects on mesothelioma through inhibiting both MDM2 and MDM4 functions. Activation of the endogenous p53 by inhibiting the MDM2-mediated p53 degradation processes and intensifying p53-mediated transcriptional activation due to MDM4 suppression is favorable for cell death of mesothelioma bearing the wild-type p53 genotype. Keywords: HSP90, MDM4, p53, MDM2 PP02.67: SHED SYNDECAN-1 ALTERS ANGIOGENESIS IN MALIGNANT MESOTHELIOMA Ghazal Heidari-Hamedani1, Angelika Schmalzl1, Tünde Szatmari1, Muzaffer Metintas2, Anders Hjerpe1, Katalin Dobra1 KI, Stockholm, SWEDEN, 2Osmangazi University, Eskisehir, TURKEY 1 Objectives: Angiogenesis is important in mesothelioma progression, and so far anti-angiogenic therapies have not shown significant improvement in patients’ survival, highlighting the further need of novel treatment options. Syndecan-1 is a transmembrane heparan sulfate proteoglycan that acts as a regulatory co-receptor in different cellular processes including angiogenesis. The angiogenesis regulatory mechanism of syndecan-1 is known to be through shedding of extracellular domain of syndecan-1 into body fluids through matrix metalloproteinases (MMPs), and interacting with growth factors including VEGF. Also SDC1 activates integrins and insulin like growth factor-1 receptor (IGF-1R). There is a unique sequence on syndecan-1 extracellular domain known as synstatin that regulates the signaling pathways involved in angiogenesis. The expression of syndecan-1 is low on MPM cells and it has been shown that decrease of syndecan-1 deteriorates the prognosis. Methods: Syndecan-1 was over-expressed in a human MPM iMig2016.ORG 152 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP cell line and conditioned mediums from syndecan-1 over-expressing cells and mock controls were collected. Expression of soluble angiogenic factors was measured using Proteome Profiler Array. In order to see if proteins modulated by syndecan-1 overexpression affect endothelial cell proliferation, endothelial cells were treated with conditioned mediums from syndecan-1 overexpressing cells and controls. Cell proliferation, tube formation and chemotaxis were assessed using WST1 proliferation assay, 3D tube formation and transwell assays. MMP-7 was silenced by siRNA to inhibit the shedding. Soluble syndecan-1 and VEGF levels were measured using ELISA in pleural effusions from mesothelioma patients (n=39) or in vitro. Results: A number of angiogenesis-related proteins were altered by syndecan-1, including both pro-angiogenic Angiopoietin-1 (Fold change ± SD: 0.65± 0.07), FGF-4 (0.8±0.02), HGF (1.33±0.07), NRG1-β1 (1.35±0.08), and anti-angiogenic proteins TSP-1 (0.8±0.02), TIMP-1 (0.89±0.01) and controversial pro/anti-angiogenic proteins such as TGF-β1 (1.35±0.01). These factors collectively led to inhibition of endothelial cell proliferation and tube formation. There was no significant change in endothelial cells chemotactic migration in presence of SDC1 overexpressing cells conditioned medium compared to controls. We found a significantly fair correlation between VEGF and shed SDC1 levels in these patients (r = 0.4; p <0.05). Median survival time of mesothelioma patients with VEGF level <2.125 ng/mL was 14 months (n= 11), compared to 6 months in patients with higher VEGF levels (n=19; hazard ratio: 2.83, 95% CI: 1.26 to 6.37). Conclusion: Syndecan-1 overexpression on MPM cells can change angiogenicity by affecting the growth factors gradient and inhibiting endothelial cells proliferation and tube formation. Combination of shed syndecan-1 and VEGF could be a better prognostic evaluation in mesothelioma patients. Keywords: angiogenesis, mesothelioma, Shed SDC1 PP02.68: UTILISING MICRORNAS TO SENSITISE MESOTHELIOMA TO CISPLATIN AND GEMCITABINE by seeding 10,000 cells per well in a 96-well round-bottom suspension culture plate. MPM cells were grown as (2D) monolayers using standard cell culturing methods. MicroRNA gene expression in 2D & 3D cell culture was profiled using TaqMan Low Density Arrays and validated using RT-qPCR and digital PCR. Drug cytotoxicity to cisplatin and gemcitabine was investigated in both 2D and 3D cultures. Candidate microRNA mimics were transfected in both cultures individually to test for involvement in drug resistance. Results: We confirmed that MPM cells grown as spheroids are more resistant to cisplatin and gemcitabine when compared to MPM cells grown in 2D cultures. Immunofluorescence studies showed a gradient of hypoxia from the centre of the spheroids where high Hif1α expression is observed (Fig.1). We also identified significant up-regulation of miR-210-3p, miR-378a-3p, miR-195-5p and miR-146b-5p, and down-regulation of miR320b and miR-1225b-5p in 3D spheroids. Transfecting MPM cells in 2D culture with a miR-210-3p mimic resulted in increased drug resistance. Conclusion: We observed that MPM spheroids are more resistant to cisplatin and gemcitabine than 2D cultures. Hif1α is highly expressed in the spheroids and all of the significantly differentially expressed microRNAs listed above are involved in the downstream cascade of Hif1α regulatory pathway. Increasing the levels of miR-210 using a mimic resulted in increased resistance of MPM cells to chemotherapy, suggesting this microRNA plays a role in drug resistance observed in MPM. Keywords: Hif1a, mesothelioma, 3D tumour spheroids, microRNA Yuen Yee Cheng1, Kadir Sarun1, Michaela B. Kirschner2, Nico Van Zandwijk1, Glen Reid1, Ruby C. Lin1 Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA, 2University Hospital Zurich, Division of Thoracic Surgery, Zurich, SWITZERLAND 1 Objectives: Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related thoracic cancer. Chemotherapy is an important palliative treatment option but almost every patient will be confronted with recurrence of disease and drug resistance. We have shown that microRNAs are involved in drug response in MPM cells. To better understand the potential role of microRNAs in drug resistance and sensitisation in MPM we have used monolayer (2D) and spheroid (3D) cell culture models. Methods: Tumour spheroids (a 3D in vitro model) were grown iMig2016.ORG 153 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.69: TRABECTEDIN IS ACTIVE AS SINGLE AGENT AND SYNERGIZES WITH CHEMOTHERAPY AND BCL-2 INHIBITION IN MALIGNANT PLEURAL MESOTHELIOMA Mir A. Hoda , Yawen Dong , Christine Pirker , Thomas Klikovits2, Karin Schelch3 , Petra Heffeter1, Kushtrim Kryeziu1, Viktoria Laszlo2, Balazs Hegedus2, Balazs Dome2, Walter Klepetko2, Michael Grusch1, Walter Berger1 1 2 1 Institute of Cancer Research, Medical University of Vienna, Vienna, AUSTRIA, 2Division of Thoracic Surgery, Medical University of Vienna, Vienna, AUSTRIA, 3Asbestos Diseases Research Institute, Sydney, AUSTRALIA 1 Objectives: Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study we evaluated the antineoplastic potential of trabectedin as a single agent and in combination with cisplatin and bcl-2 inhibition in human MPM. Methods: Activity of trabectedin alone and in combination was established in an extended panel of MPM cell lines (N=6) and primary cell cultures from MPM (N=13) and non-malignant tissues samples (N=2) using chemosensitivity, migration, spheroid growth, cell cycle distribution and cell death assays. Trabectedin activity in vivo was evaluated in an orthotopic xenograft model. Results: Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or non-adherent spheroids with IC50 values ≤ 10 nM. Non-malignant mesothelial cells were significantly less responsive. This strong anti-mesothelioma activity was based on cell cycle perturbation and apoptosis induction synergistically enhanced by cisplatin. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl-2 expression. Accordingly, bcl-2 inhibitors (obatoxlax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bim, bax, Mcl-1 and bcl-xL. Trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Conclusion: These data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors. Thus, it represents a promising new therapeutic option for MPM. Keywords: novel therapeutics, synergism, trabectedin PP02.70: LIVE CELLS MESOTHELIOMA BIOBANK TO EXPLORE MECHANISMS OF TUMOR PROGRESSION Emanuela Felley-Bosco1, Gabriela Ziltener2, Isabelle Opitz3 , Walter Weder3 , Rolf Stahel4 Laboratory of Molecular Oncology/thoracic Surgery, Zürich University Hospital, Zürich, SWITZERLAND, 2University of Zurich, Laboratory of Molecular Oncology, Division of Thoracic Surgery, Zurich, SWITZERLAND, 3Division of Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 4Clinic For Oncology, University Hospital Zurich, Zurich, SWITZERLAND 1 Objectives: We recently observed that loss of epithelioid phenotype occurring in some of the patients at tumor progression is associated with worst outcome. In order to carry out functional investigations, primary cultures were established. Our aims were to secure a live cell biobank and obtain proof of principle that primary cultures chemoresistant models, mimicking tumor progression observed in the patient, can be obtained in vitro, providing a useful tool to investigate underlying mechanisms. Methods: Primary mesothelioma cultures were established from 210 patients between 2007 and 2014. Some primary cultures were obtained from the same patient at different times: diagnosis, at surgery after cisplatin/pemetrexed therapy and recurrence. Cultures were characterized by analysis of mesothelioma markers using Western blot and gene expression and compared to original tumor. A primary culture from a chemo naïve patient was exposed to increasing doses of cisplatin/ pemetrexed during 3 months and the resulting in vitro treated cells were compared to control in a cytotoxicity assay and by selected gene profiling. Results: Three hundred twenty one primary cultures were established and expanded to collect RNA, protein and frozen stocks. Eighty six cultures could be grown in complete absence of serum and 3% oxygen and some of them have been used to investigate developmental pathways, which are rapidly lost in serum containing medium and growth in 20% oxygen. Selected cultures from a same patient were further characterized for the expression of calretinin, mesothelin, N-cadherin, podoplanin, YAP, survivin and found to reflect tumor of origin. Development of chemoresistance toward cisplatin/pemetrexed was observed in the in vitro treated culture compared to control untreated cultures grown in parallel. Selected gene expression revealed a profile similar to parental cultures established before and after chemotherapy. Conclusion: The establishment of a large live cell mesothelioma biobank contributes to the international efforts aimed at improving the handling of this disease since they can be used to test novel therapeutic approaches. In addition, they may help understanding mechanisms underlying tumor progression observed in vivo. Keywords: chemoresistance, mesothelioma live cell biobank, tumor progression iMig2016.ORG 154 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.71: ANALYSIS OF NOVEL RHOA MUTATIONS IN MALIGNANT PLEURAL MESOTHELIOMA Assunta De Rienzo1, Antonios Sideris2, Daniele Sciaranghella1, Nhien Dao1, William G. Richards1, Raphael Bueno1 Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA, 2Surgery, Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA 1 Objectives: Malignant Pleural Mesothelioma (MPM) is a rare asbestos-induced cancer with poor prognosis (median survival ~4-12 months). Treatment is hampered by the lack of early detection strategies and effective novel therapeutic approaches. We found that the RHO -family GTPase RHOAis a target of mutations in MPM (Cancer Res., 2016). RHOA resides on 3p21.3 near BAP1 (3p21.1), a gene frequently deleted in MPM. The objective of this study was to define the role of RHOA as a novel putative driver gene in MPM. RHOA regulates the actin cytoskeleton during stress fiber and focal adhesion formation, and contributes to cancer signaling cascades. It has been implicated as an oncogene in multiple hematologic and solid cancers, such as angioimmunoblastic T-cell lymphoma and diffuse gastric cancer. Methods: Ten MPM and matched normal genomic DNA samples were analyzed by whole-genome sequencing using a Complete Genomics platform and novel potential driver genes were identified. RHOA was further investigated in 147 additional MPM cases by targeted re-sequencing. Ten MPM cell lines were selected for functional studies. To determine the biological impact of the novel mutations on their protein products, the mutant variants were systematically introduced into established MPM cell lines. The impact of mutated RHOA was assessed by in vitro assays. To further analyze the properties of the mutated protein, downstream targets were selected and evaluated by immunoblotting. Results: Analyses of a total of 157 MPM identified three novel somatic mutations (2%) in RHOA. Microarray analysis revealed that RHOA expression levels were significantly associated with overall survival indicating an adverse effect of elevated expression of this gene. Immunoblotting analyses showed expression of RHOA at different levels in all 10 MPM cell lines. Pharmacological and genetic inhibition of RHOA appeared to alter the migratory ability of MPM cell lines. Conclusion: RHOA was found to be mutated in 2% of MPMs. Preliminary functional analyses suggest a potential role of RHOA in the tumorigenesis of MPM. Assays evaluating cell motility, migratory ability, invasiveness and anchorage-independent growth of the transduced MPM cell lines are in progress to further characterize the role of mutated RHOA in MPM. This study may lead to novel anti-tumor interventions and patient stratification criteria for future trials. Keywords: Malignant pleural mesothelioma, RHOA PP02.72: CELL ASSAYS AND SAXS INDICATE THAT BAMLET IS A POTENTIAL TREATMENT FOR CHEMOTHERAPY-RESISTANT MESOTHELIOMA Emma M. Rath1, Yuen Yee Cheng2, Amanda L. Hudson3 , Chris Weir3 , Kadir Sarun2, Anders P. Håkansson4 , Viive Howell3 , Robert B. Knott5, Anthony P. Duff5, Guo J. Liu5, Glen Reid2, W B. Church1 Faculty of Pharmacy, University of Sydney, Sydney, NSW, AUSTRALIA, 2Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA, 3Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, Sydney, NSW, AUSTRALIA, 4Experimental Infection Medicine, Lund University, Malmö, SWEDEN, 5Australian Nuclear Science and Technology Organisation, Lucas Heights, NSW, AUSTRALIA 1 Objectives: BAMLET and related HAMLET-like (Human Alpha-lactalbumin Made Lethal to Tumours) complexes have demonstrated broad-spectrum anti-cancer activity in vitro to over 50 cancer cell lines at concentrations that do not harm some primary and immortalised non-cancer cells. In vivo experiments carried out for HAMLET and BAMLET in humans, rats and mice for bladder cancer, colon cancer and glioblastoma demonstrated anti-tumour efficacy and non-toxicity. The HAMLET family of compounds was discovered during studies on the properties of human milk. Their structure is a novel protein-lipid structure consisting of an aggregation of partially unfolded protein making up the majority of the compound’s mass, with fatty acid molecules bound in the hydrophobic core. The cytotoxicity of HAMLET-like compounds has not previously been investigated for mesotheliomas. This study tested BAMLET compounds on many mesothelioma cell lines and a few non-cancer cell lines from human and rat. The compound structures were also investigated by small-angle X-ray scattering (SAXS). Methods: Multiple BAMLET compounds were created from bovine alpha-lactalbumin and beta-lactoglobulin proteins with varying amounts of oleic acid. Sybr and Alamar Blue cell death assays were performed to investigate BAMLET and chemotherapy (cisplatin, pemetrexed, gemcitabine, and vinorelbine) toxicity towards chemo-sensitive and chemo-resistant mesothelioma (human MM05, MSTO, REN, H28, H226, H2452, H2052, VMC20, VMC23, VMC33, and VMC40, and rat II-45, II-45-CisR, -PemR, -GemR, -VLBR, and -ComboR) and non-cancer cell lines (human fibroblasts and MeT5A, and rat 4/4RM.4). To investigate the role of the active agent oleic acid in its structure as a function of the amount of oleic acid incorporated, SAXS was performed on multiple BAMLET compounds using a Bruker NanoStar II and the Australian Synchrotron SAXS/WAXS beamline. Results: In vitro, BAMLET killed all 11 human epithelial-like and biphasic mesothelioma (IC50 = 33±2 µM) and rat mesothelioma cell lines (IC50 = 30±2 µM) at similar concentrations. This concentration range was not toxic to some primary non-cancer human cells. Cisplatin and pemetrexed killed the mesothelioma cell lines at the same dose ranges that they killed some non-cancer cells (cisplatin IC50 = 5.9±2.8 µM). Chemo-resistant rat mesothelioma cells were just as sensitive to BAMLET as the chemo-sensitive cells (IC50 = 35±17 µM). The BAMLET structures as revealed by SAXS are well-correlated with the amount of incorporated oleic acid and are correlated with the toxicity results of the cell death assays. iMig2016.ORG 155 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Conclusion: The results show that BAMLET may be an effective and non-toxic treatment option for mesothelioma patients whose disease no longer responds to chemotherapy and thus who currently do not have a drug treatment option. Keywords: mesothelioma, BAMLET, chemotherapy resistance, SAXS Transfection of 1nM miR-137 sensitised MPM cell to both cisplatin and gemcitabine. Pathway enrichment analysis revealed a number of potential targets of miR-137, including YB-1, which plays a role in MPM cell proliferation. In vitro experiments showed miR-137 mimic transfection significantly down-regulated YB-1 mRNA (p < 0.05) and protein, which was attributed to its role as a growth suppressor. Conclusion: miR-137 acts as a tumour suppressor in MPM and is significantly down-regulated in both MPM cell lines and tumour samples. Additionally, miR-137 suppresses the expression of YB-1, which in part explains its tumour suppressive properties. PP02.73: TUMOUR SUPPRESSOR MICRORNA-1373P TARGETS ONCO-PROTEIN YB-1 IN MALIGNANT PLEURAL MESOTHELIOMA Keywords: microRNA-137-3p, mesothelioma, therapeutic targets, YB-1 Thomas Johnson1, Yuen Yee Cheng1, Marissa Williams1, Brian C. Mccaughan2, Sonja Klebe3 , Nico Van Zandwijk1, Ruby C. Lin4 , Glen Reid1 Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA, 2Sydney Cardiothoracic Surgeons, RPA Medical Centre, Sydney, NSW, AUSTRALIA, 3Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, SA, AUSTRALIA, 4Cardiothoracic Genomics, Asbestos Diseases Research Institute, Sydney, NSW, AUSTRALIA 1 Objectives: Deletion on a number of chromosomal regions is a common characteristic observed in malignant pleural mesothelioma (MPM), notably within regions 9p21-22 and 1p21-22. Specifically, studies have shown that the deletion of region 1p21-22 occurs in approximately 74-85% of MPM cases. Since this region has been implicated in tumour suppression, we set out to investigate this phenomenon. MicroRNA-137 (miR-137) resides within this region and has been shown to modulate tumour suppression in a number of cancers including breast, lung and gastric cancer. However, its role in MPM is not yet clear. Here we investigate whether miR-137 can act as a tumour suppressor and propose the therapeutic potential of miR-137 in MPM. We also determine the regulatory nature of miR-137 on the onco-protein YB-1. Methods: Gene expression of miR-137 was determined in 10 MPM cell lines, one normal mesothelial line, 125 Formalin-Fixed Paraffin-Embedded (FFPE) MPM tissue samples and 24 normal mesothelial samples using TaqMan probes. Cell proliferation and colony formation assays were conducted following transfection with miR-137 or control mimics to determine the effect of miR-137 on MPM cell growth. microRNA-137 mimic and control transfection was also used to test drug sensitisation. Pathway enrichment analyses based on predicted target gene lists of miR-137 extracted from TargetScan and miRDB respectively were determined to explore the effect of miR-137 at a systems level. Validation of miR-137 gene targets by RT-qPCR and Western Blot were carried out. Results: miR-137 was significantly down-regulated in four MPM cell lines (p < 0.01). It is also significantly down-regulated in FFPE MPM samples compared to the normal mesothelial samples (p < 0.0001). Proliferation assays revealed growth inhibition of miR-137 in all ten MPM cell lines, albeit to variable degrees. Four cell lines exhibited statistically significant growth retardation (p < 0.05). Colony formation assay results further supported the suppressive role of miR-137 in MPM proliferation. PP02.74: IFN REGULATORY FACTOR 9 PLAY KEY ROLE IN MESOTHELIOMA GROWTH Yidan D. Zhao1, Licun Wu1, Hana Z. Yun1, Ming Tsao2, Marc De Perrot1 Thoracic Surgery Labs, University Health Network, Toronto, ON, CANADA, 2Pathology, Tgh, University Health Network, Toronto, ON, CANADA 1 Objectives: Interferons (IFNs) are a family of cytokines that potently demonstrate antitumor, antiviral, immunomodulatory and antiproliferative activities. Although the complex mechanisms of action remain unclear, IFNs are used the treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkins lymphoma. IFN regulatory factor 9 (IRF9) is an IFN regulatory factor that mediates signaling by type I IFNs (IFNα and IFNγ). IRF9-RNA interference (RNAi) has a key role completely inhibited the antiproliferative activity, but its possible roles in mesothelioma are not established. In the present study, we investigated the effect of host genetic deletion of IRF9 in the mouse on the growth of mesothelioma. Methods: We developed an asbestos induced mesothelioma in C57 B/6 mouse in the abdominal cavity 9-14 months after peritoneal introduction of chrysotile and crocidolite asbestos. We have also cultured cells derived from these tumors and established Z1P3 cell line with a variety of epithelioid features and doubling times around 72 -98 hours. The Z1P3 cells were then given a dermal injection in both IRF9-deficient and wild type mice. Results: The MSLN-imunostaining positive tumors were strikingly similar to epithelioid-like tumor, which resemble to those occurring in man with regard to histologic features and growth patterns. In the Z1P3 cells injected groups, tumor growth were significantly accelerated strongly in IRF9-deficient mice compared with wild-type (wt) mice.Our results showed that host IRF9 expression was critical to support an antitumor immune response and to restrict tumor growth. Conclusion: In conclusion, we have established a mesothelioma-like Z1P3 cell line and our study shows that in an animal iMig2016.ORG 156 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP innate immunity-related model genetically deleted of an IRF9, tumor growth are accelerated, suggesting a complex role of inflammation in host–tumor interaction. Keywords: asbestos, tumor growth, IFN regulatory factor 9, MSLN positive PP02.76: ‘ARE THE PSYCHOLOGICAL NEEDS OF PATIENTS WITH MESOTHELIOMA THE SAME AS THOSE WITH ADVANCED LUNG CANCER?’ Hannah Ball Oxford Pleural Unit, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, LE, UNITED KINGDOM PP02.75: PRO-ONCOGENIC EFFECTS OF PATHOGENIC FIBRES ON MESOTHELIAL CELLS Joaquin Zacarias-Cabeza1, Tatyana Chernova1, Fiona A. Murphy1, Sara Galavotti1, Xiao-Ming Sun1, Ian R. Powley1, Stefano Grosso1, Jonathan Bennett2, Apostolos Nakas2, Martin Bushell1, Anne E. Willis1, Marion Macfarlane1 MRC Toxicology Unit, Leicester, UNITED KINGDOM, 2Glenfield Hospital, UHL NHS Trust, Leicester, UNITED KINGDOM 1 Objectives: Malignant mesothelioma (MM) is an aggressive, fatal tumour of the pleura or peritoneum and strongly related to asbestos exposure. Malignant pleural mesothelioma (MPM) is the most common and occurs with a latency of up to 40 years. Long pathogenic fibres fail to clear through the lymph system and are retained in the pleura of the exposed individuals. During the long latency period, mesothelial cells remain exposed to paracrine signalling from the inflammatory cells recruited to the fibre-retaining areas of the pleura, as well as directly to fibres. However, the mechanism of malignant transformation of mesothelial cells is not well understood. Methods: To examine the effects of paracrine pro-inflammatory factors and cyto- and geno-toxic effects of pathogenic fibres we used an in-vitro cellular model in which normal untransformed mesothelial cells were exposed to conditioned media from fibre-activated macrophages or to pathogenic fibres. Molecular and functional readouts included changes in gene and protein expression as well as epigenetic changes. Results: We show that paracrine factors from fibre-activated macrophages increased proliferation rate and migration ability in normal mesothelial cells. Moreover, cell death induced by H2O2 in mesothelial cell culture was reduced by pro-survival paracrine factors released from fibre-activated macrophages. Additionally, direct exposure of normal mesothelial cells to pathogenic fibres with a high-aspect ratio induced changes in tumour suppressor genes favouring malignant transformation. Conclusion: Direct exposure of mesothelial cells to fibres as well as exposure to a pro-inflammatory microenvironment contribute to the development of pathogenic changes in target mesothelial cells. Keywords: Malignant Mesothelioma, Pathogenic Fibres, Pro-oncogenic, Pro-Inflammatory Factors Objectives: Mesothelioma is a devastating disease characterised by a poor prognosis, high symptom burden and lack of effective treatment. Psychological distress which adversely affects a person’s experience of cancer has been shown to be highly prevalent in patients with mesothelioma. Historically, care for those with mesothelioma has been provided by the existing infrastructure and services in place for lung cancer and with assumptions having been made that the evidence guiding the supportive care needs for lung cancer is relevant to those with mesothelioma. This poster presents the findings of a systematic literature review with the objective of answering the question ‘Are the psychological needs of patients with mesothelioma the same as those with advanced lung cancer?’, which was submitted as the authors dissertation as part of her MSc. Methods: An electronic search of the databases MEDLINE, CINAHL, PsycARTICLES, Psychology and Behavioural Sciences Collection, PsycINFO, and the Cochrane Library of Systematic Reviews was run. Grey literature was identified and relevant reference lists searched. Studies meeting a predefined inclusion criterion were read and critically appraised for quality. Data relating to psychological experiences was extracted which was then synthesised narratively and through a process of Meta ethnography. Results: 17 studies were included in the review. Critical appraisal identified methodological or reporting weaknesses across 15 of the studies. Common themes identified across the studies created 10 key concepts. These were uncertainty, normality, hope/hopelessness, stigma/blame/guilt, family/carer concern, physical symptoms, experience of diagnosis, iatrogenic distress, financial/legal and death and dying. Key similarities and differences were identified between the mesothelioma and lung cancer evidence. Conclusion: Conclusions include that there is limited research exploring the lived experiences of those with mesothelioma and lung cancer, with the majority of them having methodological and/or reporting concerns compromising the findings/conclusions made. However, reoccurring themes in the evidence was found suggesting a number of areas where the psychological experience of mesothelioma differs from that of advanced lung cancer. These findings warrant more research to explore further and if proven, the need for the provision of specialist mesothelioma care services is affirmed. Specialist nurses should be regularly screening for psychological distress and adapting supportive care accordingly to meet these needs. Keywords: Systematic review, nursing, psychological distress, Supportive care iMig2016.ORG 157 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP PP02.77: “AROUND AUSTRALIA IN 80 DAYS” ARD/MPM is a small speciality that is competing with a wide range of other health diseases and therefore has diminished priority status within many health professionals scope of learning. Judy Rafferty The vast variances in practices/resources within the country Cancer Services/Nurse Educator, Canberra Hospital/Lung Foundation Australia, Canberra/Brisbane, ACT, AUSTRALIA Timely promotion was difficult. Objectives: Objectives: Australia has one of the highest incidence rates of malignant mesothelioma in the world[1]. There is increasing evidence that a third; non-occupational wave of mesothelioma cases has developed in Australia, with a projected increase of 79% by 2020[2] . Thus given the vast nature of the Australian continent, it was believed that it was necessary to provide health professionals with current best practice guidelines and resources about asbestos related diseases and specifically malignant pleural mesothelioma (ARD & MPM). A national tour was conducted and included workshops/ forums for health professionals utilising a multidisciplinary team approach. [1] https://www.mesothelioma-australia.com/media/10743/ amr-data-report_final-for-publication2013-1-.pdf [2] Kao SC, Reid G, Lee K, Vardy J, Clarke S, van Zandwijk N. Malignant Mesothelioma. Internal Medicine Journal. [Review]. 2010; 40:742–50 Accessing rural/remote staff to attend workshops due to staffing levels was a major challenge and required workshops timing to be altered. Conclusion: As the Australian mesothelioma projected figures increase over the next decade, we as a nation wish to be prepared to provide personalised care to this cohort of patients and carers. The Australian tour presented evidence based, one day workshops to health professionals across the nation to improve their understanding of diagnosis, treatments, legal matters and how and where to access available resources for ARD/MPM patients, carers and families to provide professional “personalised care”. Keywords: Mesothelioma, Australia, personalised care, Australian, health professional, tour, successful, Australian first, education Methods: To meet the personalised needs of this increasing number of patients who are scattered extensively across the nation, two Australian organisations collaborated to provide workshops based on Best Practice Guidelines, current research and clinical practice to health professionals. These one day workshops were conducted in each capital city and one rural/ regional destination in each state and territory. There were modified workshops for indigenous health professionals and GP’s. In each destination suitable venues were identified, advertising conducted and catering organised. Presenters with clinical expertise were sought in each area from local respiratory physicians, medical and radiation oncologists, palliative care specialist nurses, surgeons, allied health and the legal fraternity. Specialists were flown in where local specialists were not available. The program consisted of: introduction/history of ARD/MPM; diagnosis, pathology, staging and treatment; palliative care needs; the psychological impact and the legal considerations for patients and their carers with MPM. All sessions were evaluated by participants and all attendees were awarded certificates of attendance. Results: A total of 18 workshops/forums were conducted in Australia for health professionals with an attendance of 551 participants. Eight were conducted in the capital cities, ten in rural/regional There were modified workshops for indigenous health professional and GP’s. The most valued features of the workshops as identified by the participant’s evaluations were: Quality of the workshop content and the relevance to daily practice Quality, knowledge and enthusiasm of the speakers Multidisciplinary approach Opportunity for professional networking Quality of the written resources Challenges for the project: iMig2016.ORG 158 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP AUTHOR INDEX Authors highlighted in bold = Presenting Author for this abstract A Abal, Mariana.....................................................................................PP01.33 Abate-Daga, Daniel............................................................................MS04.04 Abdel-Rahman, Abdel-Rahman M.......................PP01.35, PP01.42, PP01.53 Abdelrahman, Abdelrahman M..........................................................PP02.09 Aboelazm, Omnia............................................................................... PP01.61 Achard, Carole...................................................................................MS04.02 Acuña, Claudia.................................................................................... PP01.33 Aderca, Ileana....................................................................................MS04.06 Adusumilli, Prasad S.......................................................................... PL05.01 Aerts, Joachim.................................................. MS16.03, PP02.21, PP02.22, .......................................................................................... PP02.33, PP02.36 Aeschlimann, Beat............................................................................. MS15.05 Agostini, Lorenzo...............................................................................MS05.05 Ahiskali, Rengin.................................................................................. PP02.47 Ahmed, Jaylan.................................................................................... PP01.61 Aigner, Clemens................................................................................. MS15.02 Ak, Guntulu....................................... MS06.04, PP01.25, PP02.47, PP02.53 Akın Kabalak, Pınar............................................................................ PP01.25 Al-Taei, Saly.......................................................................................MS16.05 Albelda, Steven............................................... MS04.05, MS04.06, MS16.01, ...........................................................................................PL06.05, PP01.28 Aldieri, Elisabetta............................................................................... PP01.72 Alexander, Laura................................................................................. PP01.02 Alfieri, Roberta................................................................................... MS13.02 Aliverti, Andrea....................................................................................PP01.14 Allcock, Richard J............................................................................... PP01.70 Allen, Louise........................................................................................ PP01.12 Alley, Evan.......................................................... MS03.02, PL06.05, PP02.08 Allione, Alessandra............................................................................. PP01.72 Almutairi, Abdulhadi......................................................................... PP02.29 Altomonte, Maresa............................................................................ MS10.03 Alves Das Mercês, Nen Nalú.............................................................. PP01.60 Alì, Greta............................................................................................MS08.04 Ambrogi, Marcello C...........................................................MS15.03, PP01.17 Ambrogi, Vincenzo............................................................................ PP02.46 Ambrosi, Jean-Paul............................................................................. PP01.50 Amodio, Rosalba................................................................................. PP01.59 Ampollini, Luca..................................................................................PP01.20 Ananthanarayanan, Viju....................................................................MS08.05 Anbunathan, Hima............................................................................. MS07.02 Ancona, Laura....................................................................MS08.06, PP01.44 Andersen, Claus B.............................................................................. PP01.69 Andersen, Morten............................................................................... PP01.69 Andreassen, Trygve............................................................................ PP01.21 Angelillo, Italo..................................................................................... PP01.59 Annesi, Diego..................................................................................... MS10.03 Antoine, Daniel J................................................................................MS05.03 Aoe, Keisuke........................................................................................PP02.04 Aou El-Kasem, Fatma M.A.............PP01.35, PP01.42, PP01.53, PP02.09 Aprile, Vittorio.................................................................................... MS15.03 Ardissone, Francesco......................................................................... PP01.56 Arif, Qudsia......................................................................................... PP01.22 Armato, Sam......................................................................................MS03.06 Armstrong, Bruce............................................................................... PP01.43 Arni, Stephan......................................................................................MS11.01 Arns, Madeleine.................................................................................. PP01.62 Asano, Michiko................................................................................... PP01.34 Ascoli, Valeria............................... MS07.03, MS08.06, PP01.59, PP01.64 Ashizawa, Kazuto................................................................................PP02.04 Ashton, Miranda J.............................................................................MS14.02 Aspesi, Anna....................................................................................... PP01.64 Aston, Wayne J..................................................... PP01.77, PP01.78, PP02.26 Atagi, Shinji........................................................................................ MS10.07 Atinkaya Ozturk, Cansel..................................................................... PP01.25 Avella Patino, Diego............................................................................ PL05.06 Aziz Shokralla, Hala........................................PP01.29, PP01.35, PP01.37, ..........................................................................PP01.38, PP01.39, PP01.53 B Baas, Paul.......................................................... MS04.07, PP02.33, PP02.36 Bakó, Szilvia.......................................................................................MS02.05 Baldassarre, Antonio.......................................................................... PP01.44 Ball, Hannah......................................................................................PP02.76 Ballarino, Paola................................................................................. MS12.03 Baratti, Dario....................................................................................MS12.01 Barba, Adalberto................................................................................ MS10.02 Barbieri, Pietro G...............................................................................MS06.03 Barbiero, Fabiano..............................................................................MS06.02 Barbone, Dario................................................................... MS02.07, PP02.54 Barbone, Fabio...................................................................................MS06.02 Bareggi, Claudia................................................................................. PP01.07 Barlow, Julianne................................................................................ MS10.04 Barnes, Daniel T..................................................................................PP02.06 Barone, Elisa..................................................................................... PP02.63 Bates, Gleneara E...........................................MS12.02, MS15.07, PP02.02 Bathen, Tone F.................................................................................... PP01.21 Batirel, Hasan.................................................................. PP01.26, PP02.47 Battistini, Francesca........................................................................... PP01.59 Baumann, Francine...........................................MS05.03, MS07.04, PP01.50 Baumgartner, Bernhard...................................................................... PP01.62 Bearz, Alessandra............................................................................... PP01.31 Beatty, Gregoary................................................................................. PP01.28 Behner, Dusty.................................................................................... MS07.04 Bella, Francesca................................................................................. PP01.59 Belvedere, Ornella........................................................................... MS06.02 Bendell, Johanna C............................................................................ MS10.01 Benepal, Taqdir.................................................................................. MS07.02 Benfatto, Lucia.................................................................................... PP01.59 Bennett, Jonathan.......................................... MS02.02, MS02.06, MS11.03, ............................................................................ MS11.06, PL01.06, PP02.75 Benziane, Sarah.................................................................................PP01.11 Bérard, Karima...................................................................MS11.01, PP01.06 Berardi, Rosanna................................................................................PP02.33 Berger, Ian B.................................................................... MS03.02, PP02.08 iMig2016.ORG 159 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Berger, Walter..................................... PP02.60, PP02.61, PP02.64, PP02.69 Bertazzi, Pier Alberto.......................................................................... PP01.41 Bertocci, Erica................................................................................... MS10.03 Bertoglio, Pietro................................................................ MS15.03, PP01.17 Bertulli, Rossella................................................................................ MS12.01 Betti, Marta..........................................................PP01.56, PP01.64, PP01.72 Bezemer, Koen................................................... MS16.03, PP02.21, PP02.22 Biasi, Alessandra................................................................ PP01.56, PP01.64 Biesma, Bonne....................................................................................PP02.36 Biffo, Stefano..................................................................................... MS13.02 Bijou, Fontanet.................................................................................... PL04.03 Bilancia, Rocco..................................................................................MS09.04 Bilgi, Zeynep....................................................................................... PP02.47 Birembaut, Philippe............................................................ PP01.08, PP02.28 Bishop, Paul........................................................................................ PP01.68 Bitanihirwe, Byron K.Y........................................................................ PP01.06 Bittinger, Mark................................................................................... MS10.04 Blakemore, Stephen J........................................................................ PL04.03 Blanquart, Christophe.....................................MS02.03, PP01.09, PP01.11 Blazek, Gertrude................................................................................. PP01.62 Blum, Walter......................................................PP02.15, PP02.19, PP02.58 Blum, Yuna....................................................................................... MS08.08 Blumenschein, Jr, George R.............................................................. MS10.01 Blyth, Kevin.................................................. MS03.03, MS04.08, MS10.06, .............................................................................................PP01.01, PP01.02 Boisgerault, Nicolas..........................................................................MS04.02 Boissard, Alice.................................................................................... PP01.08 Boldorini, Renzo................................................................. MS05.04, PP01.64 Bolitschek, Josef................................................................................. PP01.62 Bollati, Valentina................................................................................. PP01.07 Bölükbas, Servet............................................................................... PP02.44 Bolyard, Chelsea................................................................................MS04.08 Bomalaski, John................................................................................ MS10.02 Bommeli, Cordelia............................................................................. MS15.05 Bonotti, Alessandra...........................................................MS05.04, PP02.63 Booton, Richard................................................................. MS05.01, PP01.68 Bordini, Lorenzo.................................................................................. PP01.07 Borg, Elaine....................................................................................... MS13.04 Borroni, Ester..................................................................................... MS11.02 Boss, Andreas.....................................................................................MS11.01 Botta, Laura........................................................................................ PP01.59 Botticella, Angela..............................................................................MS03.04 Bowcock, Anne M.............................................................................. MS07.02 Boyer, Michael.................................................................. MS04.03, MS10.05 Bradbury, Penelope............................................................................ PL02.03 Braggio, Cesare.................................................................................. PP01.20 Brahmbhatt, Himanshu..................................................................... MS10.05 Braidwood, Lynne..............................................................................MS04.08 Brcic, Luka......................................................................... MS08.03, PP01.40 Brentisci, Carol................................................................................... PP01.59 Bressan, Vittoria..................................................PP01.30, PP01.44, PP01.59 Bressler, Yaakov............................................... MS12.02, MS15.07, PP02.02 Brina, Daniela.................................................................................... MS13.02 Broaddus, Courtney..........................................................MS02.07, PP02.54 Brochard, Patrick...............................................................................MS08.07 Broggini-Tenzer, Angela......................................................................MS11.01 Broome, Richard................................................................................MS06.05 Brozik, Jan..........................................................................................PP02.06 Bruno, Caterina................................................................................... PP01.46 Bruno, Rossella................................................................................ MS08.04 Bryant-Greenwood, Peter.................................................................. MS07.04 Buck, Brenda...................................................................................... PP01.50 Bueno, Raphael...............................................MS02.07, MS07.01, MS10.04, ............................................................................ PP01.06, PP02.54, PP02.71 Buikhuisen, Wieneke..........................................MS04.07, PP02.27, PP02.36 Burgers, Sjaak..................................... MS04.07, PP01.19, PP02.27, PP02.36 Burton, Kimberley.............................................................................. MS13.01 Busacca, Sara......................................................................PP01.71, PP01.73 Bushell, Martin.................................. MS02.02, MS11.06, PL01.06, PP02.75 Bydder, Sean.......................................................................................PP02.23 C Cabras, Antonello D........................................................................... MS12.01 Caglar, Hale B..................................................................................... PP02.47 Cain, Kelvin...................................................... MS02.02, MS02.06, MS11.06 Calabro’, Luana.................................................................................MS10.03 Caldarella, Adele................................................................................ PP01.59 Cale, Alexander...................................................................................PP02.48 Campanini, Nicoletta.......................................................................... PP01.20 Candela, Pina...................................................................................... PP01.59 Canino, Claudia.................................................................................MS05.03 Capocaccia, Riccardo......................................................................... PP01.59 Carbognani, Paolo.............................................................................. PP01.20 Carbone, Michele..........................MS05.03, MS07.04, PP01.50, PP01.76 Carlson, Sephanie.............................................................................MS04.06 Carnovale Scalzo, Caterina...............................................................MS08.06 Casadio, Caterina............................................................... PP01.56, PP01.64 Casalone, Elisabetta.........................................PP01.56, PP01.64, PP01.72 Casbard, Angela.................................................................................PP02.34 Cascione, Luciano.............................................................................MS05.04 Case, Bruce W....................................................................................PP01.66 Casey, Thomas................................................................................... MS16.07 Cassetti, Paolo...................................................................................MS06.02 Cattaneo, Monica..............................................................................MS06.02 Cavaletto, Maria................................................................................ MS11.02 Cavalleri, Tommaso............................................................................ PP01.07 Cellerin, Laurent................................................................................. PP01.09 Cena, Tiziana.......................................................................PP01.31, PP01.44 Cengel, Keith A................................................MS03.02, MS14.01, PP02.08 Cerkl, Peter......................................................................................... PP01.62 Chalmers, Anthony............................................................MS14.02, MS14.03 Chang, Yu-Yin...................................................................................... PP01.47 Chaturvedi, Anshuman...................................................... MS05.06, PP01.68 Chaudhry, Ikram.................................................................................PP02.29 Chaudhry, Mubarak............................................................................PP02.48 Chauhan, Anoop................................................................................ MS05.01 Cheah, Hui Min...................................................................................MS11.07 Chee, Jonathan...................................................................MS16.02, PP02.14 Cheema, Ahsan...................................................................................PP02.29 Chella, Antonio.................................................................................. MS15.03 Chellini, Elisabetta.............................................................. PP01.44, PP01.59 Chen, Tianhui................................................................................... MS06.06 Cheng, Yuen Yee.............................................MS04.03, MS11.04, PP02.59, ...........................................................................PP02.68, PP02.72, PP02.73 Chernova, Tatyana.......................................... MS02.02, MS02.06, MS11.03, ...........................................................................MS11.06, PL01.06, PP02.75 Chirieac, Lucian R...............................................................................MS07.01 iMig2016.ORG 160 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Cho, Bc John....................................................................................... PL02.03 Christensen, Brock C..........................................................................PP02.57 Church, W B........................................................................................ PP02.72 Chéné, Anne-Laure..............................................................................PP01.11 Ciammella, Patrizia...........................................................................MS05.05 Cirilli, Claudia..................................................................................... PP01.59 Clarke, Stephen................................................................................. MS10.05 Clayson, Helen................................................ MS01.04, MS01.05, MS01.06 Cleaver, Amanda.................................................................................PP02.26 Clive, Amelia O................................................................................... MS14.05 Cocchioni, Mario................................................................................. PP01.59 Cognetti, Francesco........................................................................... PP01.31 Coindre, Jean-Michele....................................................................... PL04.03 Collins, Colin....................................................................................... PP01.65 Colombo, Enrico................................................................................. PP01.64 Comba, Pietro..................................................................................... PP01.46 Conner, Joe....................................................................... MS04.08, MS10.06 Consonni, Dario............................... PP01.07, PP01.41, PP01.59, PP01.60 Conti, Susanna..................................................................................PP01.46 Contiero, Paolo................................................................................... PP01.59 Cook, Alistair M................................................................................ PP02.23 Cookson, William O........................................................................... MS07.02 Coolen, Johan.................................................................................. MS03.04 Coonar, Aman..................................................................................... PP02.31 Cooper, Wendy A...............................................................................MS04.03 Coosemans, Willy..............................................................................MS03.04 Copin, Marie-Christine...................................................... MS08.08, PL02.05 Coqueret, Olivier................................................................................. PP01.08 Cornelissen, Robin..............................................................PP02.22, PP02.36 Corti, Mariangela................................................................................ PP01.59 Costa, Chrisostome...........................................................................MS02.04 Cowan, Katherine.............................................................................. MS01.05 Cowell, Gordon W..............................................................................MS03.03 Cowen, Michael..................................................................................PP02.48 Cozzi, Ilaria....................................................................... MS07.03, MS08.06 Creaney, Jenette................. MS11.07, MS16.02, PP01.23, PP01.70, PP02.14 Creech, Lorraine.............................................................................. MS05.06 Cristaudo, Alfonso.............................................................MS05.04, PP02.63 Croce, Carlo M................................................................................... MS13.02 Crosbie, Philip..................................................................................... PP01.68 Cuccaro, Francesco............................................................................ PP01.44 Cucevic, Branka.................................................................................. PP01.40 Cusimano, Rosanna............................................................................ PP01.59 Czirok, Andras.....................................................................................PP02.55 D D’Angelo, Massimo.............................................................MS12.03, PP01.31 Daga, Antonio.................................................................................... MS11.02 Daimon, Takashi................................................................................ MS13.05 Dalcher, Damian.................................................................................PP02.57 Dallari, Barbara...................................................................PP01.41, PP01.59 Dammeijer, Floris..............................................................MS16.03, PP02.21 Danielli, Riccardo.............................................................................. MS10.03 Danson, Sarah................................................................................... MS10.06 Dao, Nhien.......................................................................................... PP02.71 Dao, Tao.............................................................................................. PL05.05 Dayal, Saurabh.................................................................................. MS14.03 De Angelis, Roberta............................................................................ PP01.59 De Fonseka, Duneesha......................................................................PP01.12 De Giorgi, Anna Maria........................................................................ PP01.59 De Klerk, Nicholas.............................................................................PP01.30 De Koning, Leanne............................................................................. PL04.05 De La Maza-Borja, Luis....................................................................MS14.04 De Leyn, Paul.................................................................... MS03.04, MS15.01 De Lima, Vinicius................................................................................ PP01.27 De Matteis, Sara................................................................................. PP01.41 De Perrot, Marc............................................... MS14.04, PL02.03, PP02.15, .............................................................................PP02.18, PP02.19, PP02.74 De Reyniès, Aurélien..........................................................................MS08.08 De Rienzo, Assunta........................................................... MS07.01, PP02.71 De Santi, Chiara............................................................................... MS05.04 De Smet, Ruben.................................................................................MS05.02 De Waele, Jorrit.................................................................................. PP02.10 De Wever, Walter................................................................................MS03.04 Decaluwé, Herbert.............................................................................MS03.04 Degiovanni, Daniela...........................................................MS12.03, PP01.31 Dekeyser, Melanie............................................................................. MS15.01 Dekeyzer, Frederik.............................................................................MS03.04 Delanghe, Joris R...............................................................................MS05.02 Delanghe, Sigurd...............................................................................MS05.02 Delaunay, Tiphaine............................................................................MS04.02 Della Gatta, Andrew.......................................................................... MS11.04 Delvenne, Philippe.............................................................................MS02.04 Demery, Amr....................................................................................... PP01.53 Depypere, Lieven...............................................................................MS03.04 Deraco, Marcello............................................................................... MS12.01 Deshayes, Sophie...............................................................MS02.03, PP01.11 Devo, Perry........................................................................................PP02.11 Değirmenci, Irfan...............................................................................PP02.53 Dhalluin, Xavier...................................................................................PP02.37 Dhanasingh, Immanuel...................................................................... PP01.04 Dhont, Ludovic................................................................................. MS02.04 Di Gaetano, Cornelia...........................................................PP01.56, PP01.72 Di Giacomo, Anna Maria.................................................................... MS10.03 Di Pietrantonj, Carlo........................................................................... PP02.41 Dianzani, Caterina.............................................................................. PP01.64 Dianzani, Irma................................................... PP01.56, PP01.64, PP01.72 Diaz, Monica...................................................................................... MS10.02 Dick, Craig.........................................................................................MS03.03 Dick, Ian M.......................................................................................... PP01.70 Dieckmann, Karin.............................................................................. MS15.02 Dietz, Allen.........................................................................................MS04.06 Dini, Paolo.......................................................................................... MS15.03 Dinsdale, David..................................................MS02.06, MS11.06, PL01.06 Dioni, Laura........................................................................................ PP01.07 Djearaman, Madava............................................................................PP01.14 Dobbs, Adrian....................................................................................PP02.17 Dobra, Katalin.................................................... PP01.05, PP01.13, PP02.67 Dogan, A. Umran................................................................................ PP01.50 Dogan, Meral...................................................................................... PP01.50 Dome, Balazs...................................... MS15.02, PP01.15, PP01.17, PP01.18, .............................................PP01.19, PP02.55, PP02.61, PP02.64, PP02.69 Donaldson, Ken...................................................................................PL01.06 Dong, Yawen......................... PP01.15, PP01.17, PP01.18, PP01.62, PP02.69 Dongel, Isa.......................................................................................... PP01.25 Dooms, Christophe........................................................... MS03.04, MS15.01 iMig2016.ORG 161 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Driscoll, Tim........................................................................................ PP01.43 Dubbeldam, Adriana..........................................................................MS03.04 Dudek, Kate....................................................................................... MS11.06 Duff, Anthony P................................................................................... PP02.72 Dujmovic, Tomislav............................................................................. PP01.40 Durkin, Amy........................................................................................ PL05.06 Duysinx, Bernard...............................................................................MS02.04 E Eberlein, Michael................................................................................PP02.44 Ebert, Martin.......................................................................................PP02.23 Eckmayr, Josef.................................................................................... PP01.62 Edelman, J J........................................................................................PP02.59 Edwards, John...................................................MS05.01, MS10.06, PP02.31 El Bastawisy, Ahmed.........................................................................PP01.61 El Soud Youssef, Magdolen................................................................PP02.36 Elarouci, Nabila.................................................................................MS08.08 Eldemery, Amr M.............................................................................. PP02.09 Elshafie, Ghazi...................................................................................PP01.14 Emi, Mitsuru....................................................................................... MS07.04 Errhalt, Peter....................................................................................... PP01.62 Ersoz, Elcin......................................................................................... PP01.25 Evison, Matthew................................................................ MS05.06, PP01.68 Fisichella, Pietro M.............................................................................PP02.39 Flicker, Martin..................................................................................... PP01.62 Flores, Erin..........................................................................MS07.04, PP01.50 Foddis, Rudy......................................................................MS05.04, PP02.63 Follador, Alessandro..........................................................................MS06.02 Follo, Carlo...................................................................... MS02.07, PP02.54 Fontanini, Gabriella...........................................................................MS08.04 Fonteneau, Jean-François.................................................................MS04.02 Foot, Heather..................................................................................... MS01.05 Forastiere, Francesco........................................................ MS08.06, PP01.59 Formisano, Debora............................................................................MS05.05 Forte, Iris M......................................................................................... PP02.13 Foschi, Roberto................................................................................... PP01.59 Foster, Helen...................................................................................... MS10.05 Foster, John E.................................................................... MS03.03, PP01.02 Fox-Rushy, Julia.................................................................................. PP02.31 Francis, David..................................................................................... PP01.63 Francis, Roslyn....................................................................................PP02.23 Franklin, Peter..................................................................................... PP01.30 Frasca, Graziella................................................................................. PP01.59 Frauenfelder, Thomas.......................................................MS03.05, MS09.02 Friedberg, Joseph...............................................................................PP02.08 Friess, Martina................................................ MS03.05, MS09.02, MS15.05, ............................................................................................ PP01.06, PP01.24 Fuchimoto, Yasuko.............................................................................. PP01.34 Fujimoto, Nobukazu...........................................................PP01.34, PP02.04 Furukawa, Masashi.............................................................................PP02.05 Fusco, Mario....................................................................................... PP01.59 G F Facciolo, Francesco........................................................................... MS07.03 Falcini, Fabio....................................................................................... PP01.59 Falco, Francesco................................................................................MS05.05 Falzon, Mary...................................................................................... MS13.04 Fanetti, Anna Clara............................................................................. PP01.59 Fanucchi, Olivia................................................................................. MS15.03 Fasola, Gianpiero...............................................................................MS06.02 Favero, Chiara..................................................................................... PP01.07 Fazzo, Lucia........................................................................................ PP01.46 Feld, Ronald........................................................................................ PL02.03 Felley-Bosco, Emanuela.................................... MS11.01, PP01.06, PP02.15, ............................................................................PP02.19, PP02.56, PP02.57, ...........................................................................................PP02.58, PP02.70 Fennell, Dean....................................MS05.01, MS11.02, MS11.03, PP01.71, ............................................................PP01.73, PP01.74, PP02.33, PP02.34, ............................................................................................PP02.54, PP02.65 Feola, Daniela..................................................................................... PP01.59 Ferrante, Daniela................................PL01.04, PP01.44, PP01.56, PP01.64 Ferroni, Patrizia.................................................................................MS04.04 Filice, Angelina..................................................................................MS05.05 Findik, Gokturk................................................................................... PP01.25 Fisher, Patricia................................................................................... MS10.06 Fisher, Scott....................................................MS13.01, MS16.07, PP01.77, ...........................................................................PP01.78, PP02.23, PP02.26 Gaafar, Rabab M.................................................PP01.35, PP01.37, PP01.38, .............................................................PP01.39, PP01.53, PP02.09, PP02.32 Galanis, Evanthia...............................................................................MS04.06 Galateau-Sallé, Françoise............... MS08.07, MS08.08, PL02.05, PP02.37 Galavotti, Sara...............................................MS02.02, MS02.06, MS11.03, .............................................................................................PL01.06, PP02.75 Galeone, Carla...................................................................................MS05.05 Gallan, Alexander J............................................................................MS08.05 Gallizzi, Giulia.................................................................................... MS12.03 Gangemi, Manuela............................................................................. PP01.59 Gao, Zhi Bin........................................................................................MS08.02 Garassino, Marina Chiara................................................................... PP01.59 Garay, Tamas...................................................................................... PP02.61 Garcia Gerardi, Carlos........................................................................ PP01.33 Gardner, Georgina..............................................................................PP02.34 Gasparini, Pierluigi........................................................... MS05.04, MS13.02 Gatta, Gemma..................................................................................... PP01.59 Gaudino, Giovanni............................................................................. MS07.04 Geltner, Christian................................................................................ PP01.62 Gemba, Kenichi...................................................................................PP02.04 Gemignani, Federica..........................................................MS05.04, PP02.63 Gennaro, Valerio................................................................................. PP01.59 Gennatas, Spyridon..........................................................................MS07.02 Gercovich, Felipe Gustavo.................................................................. PP01.33 Ghaly, Galal......................................................................................... PP01.37 iMig2016.ORG 162 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Giangreco, Adam................................................................................ PL04.06 Giangreco, Giovanni...........................................................................PP02.63 Giangreco, Manuela..........................................................................MS06.02 Giannarelli, Diana.............................................................................. MS10.03 Giannini, Riccardo.............................................................................MS08.04 Giavarra, Marco.................................................................................MS06.02 Gil Deza, Ernesto................................................................................ PP01.33 Gilg Soit Ilg, Anabelle........................................................................MS08.07 Gill, Ritu............................................................................................. MS10.04 Gilmour, Lesley.................................................................................MS14.03 Ginsberg, Michelle...............................................................PL05.01, PL05.05 Giordano, Antonio............................................................................... PP02.13 Girardi, Paolo.....................................................................................MS06.03 Gironi, Laura C.................................................................................... PP01.64 Gittins, Jacki...................................................................................... MS05.01 Giuliani, Orietta................................................................................... PP01.59 Giurdanella, Maria Concetta.............................................................. PP01.59 Glodic, Goran...................................................................................... PP01.40 Gnetti, Letizia...................................................................................... PP01.20 Godfrey, Jack..................................................................................... MS11.06 Gola, Gemma...................................................................................... PP01.59 Goldoni, Matteo.................................................................................. PP01.20 Gomez, Daniel R................................................................................. PL05.01 Goparaju, Chandra M........................................................................MS05.03 Grauslund, Morten.............................................................................. PP01.69 Greaves, Peter......................................................................................PL01.06 Greillier, Laurent.................................................................................PP02.37 Grillo, Lucia Rosalba.......................................................................... MS07.03 Groen, Harry.......................................................................................PP02.36 Grosso, Federica..............................................MS12.03, PP01.31, PP01.64 Grosso, Stefano............................................. MS02.02, MS11.03, MS11.06, ............................................................................MS13.02, PL01.06, PP02.75 Großer, Christian.................................................................................PP02.43 Grusch, Michael................................................ PP01.19, PP02.60, PP02.61, ...........................................................................................PP02.64, PP02.69 Grutters, Jan.......................................................................................PP02.27 Grégoire, Marc................................................. MS02.03, MS04.02, PP01.08, .............................................................PP01.09, PP01.11, PP02.28, PP02.62 Guadagni, Fiorella.............................................................................MS04.04 Guaglio, Marcello............................................................................... MS12.01 Guarrera, Simonetta............................................PP01.56, PP01.64, PP01.72 Guaschino, Roberto............................................................................ PP01.56 Guazzelli, Alice................................................................................... MS13.06 Gudmundsson, Eyjolfur................................................................... MS03.06 Guenther, Detlef................................................................................. MS15.05 Guette, Catherine............................................................................... PP01.08 Gueugnon, Fabien............................................................................... PP01.09 Guneş, Hasan Veysi............................................................................PP02.53 Guo, Holly........................................................................................... PP02.18 Gustafson, Mike.................................................................................MS04.06 H Hagmolen Of Ten Have, Wanda....................................................... PP02.27 Håkansson, Anders P.......................................................................... PP02.72 Hamaidia, Malik.................................................................................PP02.12 Hamasaki, Makoto.............................................................................MS08.01 Harries, Lauren..................................................................................PP01.68 Hasegawa, Mizue..............................................................MS08.02, PP01.32 Hasegawa, Seiki............................................. MS09.06, MS13.05, PP02.07, ............................................................................ PP02.49, PP02.50, PP02.51 Hashimoto, Masaki............................ MS09.06, PP02.49, PP02.50, PP02.51 Hassan, Raffit............................... MS04.04, MS10.01, PP02.16, PP02.35 Hastings, Robert..................................................................PP01.71, PP01.73 Hatz, Rudolf A.................................................................................... MS15.04 Hayashi, Tatsurou...............................................................................PP02.05 Heffeter, Petra.....................................................................................PP02.69 Hegedus, Balazs..................................................PP01.15, PP01.17, PP01.18, ............................................................................PP01.19, PP02.55, PP02.61, ............................................................................................PP02.64, PP02.69 Hegmans, Joost................................. MS16.03, PP02.21, PP02.22, PP02.33 Heidari-Hamedani, Ghazal.................................................................PP02.67 Hemminki, Kari..................................................................................MS06.06 Hendriks, Rudi................................................................................... MS16.03 Hens, Niel........................................................................................... PP02.10 Hermans, Christophe......................................................................... PP02.10 Hesdorffer, Mary............................................................................... MS07.04 Hida, Tomoyuki..................................................................................MS08.01 Hilberg, Frank..................................................................................... PP02.61 Hill, Kate...........................................................................................MS01.05 Hill, Kate M........................................................................................ MS01.06 Hillerdal, Carl-Olof.............................................................................PP01.13 Hillerdal, Gunnar.............................................................. MS06.07, PP01.05 Hillinger, Sven...................................................................MS03.05, MS09.02 Hiroshima, Kenzo...........................................MS08.02, MS08.05, PP01.32, ............................................................................................PP02.52, PP02.66 Hjerpe, Anders................................................... PP01.05, PP01.13, PP02.67 Hmeljak, Julija..................................................................................MS13.03 Ho, Peter T.........................................................................................PL04.03 Hoda, Mir A......................................MS15.02, PP01.15, PP01.17, PP01.18, .......................................................... PP01.19, PP01.62, PP02.60, PP02.61, .......................................................................................... PP02.64, PP02.69 Hodgson, Clare................................................................................... PP01.68 Hoffman, Harriet................................................................................ MS07.04 Hoffman, Kimberly.............................................................................PP02.35 Hofman, Paul..................................................................... MS08.08, PL02.05 Hofmann, Hans-Stefan.......................................................................PP02.43 Holme, Jayne..................................................................... MS05.06, PP01.68 Hope, Danika E................................................................................... PP01.77 Hosteler, B.......................................................................................... PP01.23 Howell, Viive....................................................................................... PP02.72 Huang, Quin........................................................................................PP02.39 Hubert, Pascale.................................................................................MS02.04 Hudson, Amanda L............................................................................. PP02.72 Humphreys, Catherine A...................................................................MS03.03 Husain, Aliya.................................... MS08.05, MS16.06, PL05.06, PP01.22 Hussain, Michelle.............................................................................. MS13.06 Huynh, Yennie.................................................................................... MS10.05 Hveem, Kristian.................................................................................. PP01.21 Hylebos, Marieke...............................................................................PP01.67 Haas, Andrew.....................................................................MS03.02, PP02.08 Haas, Andrew R.................................................................................. PP01.28 Hagan, Sarah..................................................................................... MS14.01 iMig2016.ORG 163 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP I Iannuzzi, Carmelina A.......................................................................PP02.13 Imbeaud, Sandrine............................................................................. PL02.05 Inai, Kouki...........................................................................................PP02.04 Inal Cengiz, Tuba................................................................................ PP01.25 Inci, Ilhan..........................................................................MS03.05, MS09.02 Indovina, Paola................................................................................... PP02.13 Ingles-Prieto, Alvaro...........................................................................PP02.60 Isai, Dona Greta..................................................................................PP02.55 Ishibashi, Hironori............................................................. MS15.06, PP02.45 Italiano, Antoine.................................................................................. PL04.03 Iwasaki, Ainori...................................................................................MS08.01 J Jackson, Andrew................................................................................PL05.02 Jackson, Sue......................................................................................MS05.06 Jakopovic, Marko...............................................................................PP01.40 Janes, Sam........................................................................ MS13.04, PL04.06 Janevski, Zoran................................................................................... PP01.40 Janovjak, Harald.................................................................................PP02.60 Jarrold, Ian......................................................................................... MS01.05 Jaurand, Marie Claude...................................... MS08.08, PL02.05, PL04.05 Jean, Didier........................................................ MS08.08, PL02.05, PL04.05 Jennings, Cormac............................................................................... PP01.50 Jetter, Alexander................................................................................ MS15.05 Jitesh, Puthen V..................................................................................PP02.54 Jithesh, Puthen V............................................................... MS11.02, PP02.65 Johnson, Kevin C................................................................................PP02.57 Johnson, Thomas...............................................................................PP02.73 Johnson, Todd.................................................................................... MS07.04 Johnston, Amanda............................................................................. MS10.02 Jones, Carolyn................................................................................... MS11.06 Jørnild, Alina....................................................................................... PP01.69 June, Carl............................................................................................ PP01.28 K Kadota, Yoshihisa.............................................................................. MS10.07 Kaijen-Lambers, Margaretha............................................ MS16.03, PP02.22 Kainrath, Stephanie............................................................................PP02.60 Kamata, Toshiko................................................................................. PP01.32 Kamel, Mohamed............................................................................... PP01.39 Kamikonya, Norihiko......................................................... MS09.06, PP02.51 Kaneda, Yasufumi.............................................................................. MS10.07 Kanteti, Rajani..................................................................................... PP01.22 Kanteti, Rajani P.................................................................................PP01.04 Kao, Steven....................................................... MS04.03, MS10.05, PP02.56 Kapaklikaya, Esra...............................................................................PP02.57 Kasa, Alma......................................................................................... MS12.03 Kato, Katsuya.................................................................................... PP02.04 Katou, Katsuya....................................................................................PP02.05 Katsura, Hideki................................................................................... PP01.32 Katz, Sharyn.......................................................................................PP02.08 Katz, Sharyn I.................................................................................. MS03.02 Kaur, Balveen.....................................................................................MS04.08 Kawahara, Kunimitsu........................................................................MS08.01 Kazan, Steven.................................................................. PP01.36, PP01.75 Keating, Jane...................................................................MS03.01, MS04.05 Keilhack, Heike................................................................................... PL04.03 Kelly, Caroline..................................................................................... PP01.02 Kenkel, David......................................................................................MS11.01 Kern, Izidor.........................................................................................MS08.03 Kerr, Naseem...................................................................................... PP01.28 Khadeir, Ramsay................................................................................ MS10.02 Khalid, Urooj......................................................................MS03.02, PP02.08 Khalil, Mohammed........................................................................... PP02.48 Khanna, Swati.................................................................... MS04.04, PP02.16 Kharazmi, Elham...............................................................................MS06.06 Khattri, Arun...................................................................................... MS16.06 Khong, Andrea....................................................................................PP02.26 Kindler, Hedy...................................................MS03.06, MS10.01, MS16.06, .............................................................................PL05.06, PP01.04, PP01.22 Kirchbacher, Klaus............................................................................. PP01.62 Kircheva, Diana................................................................................... PL05.06 Kirschner, Michaela........................................................................... MS07.04 Kirschner, Michaela B.................................... MS04.03, MS15.05, PP01.19, ...........................................................PP01.24, PP02.56, PP02.59, PP02.68 Kirwan, Marie....................................................................................MS05.06 Kishimoto, Takumi.............................................PP01.34, PP02.03, PP02.04 Kızılgöz, Derya.................................................................................... PP01.25 Klabatsa, Astero................................................................................PL06.05 Klebe, Sonja....................................................... MS04.03, PP02.59, PP02.73 Klepetko, Walter..................................................MS15.02, PP01.15, PP01.17, ............................................................................ PP01.18, PP01.19, PP01.62, ............................................................................................ PP02.61, PP02.69 Klikovits, Thomas.............................MS15.02, PP01.15, PP01.17, PP01.18, ............................................................. PP01.19, PP01.62, PP02.61, PP02.69 Klotz, Laura V....................................................................................MS15.04 Knight, Julia........................................................................................PP02.63 Knott, Robert B................................................................................... PP02.72 Kobayashi, Masashi..........................................................MS15.06, PP02.45 Kodnar, Julia....................................................................................... PP01.15 Koh, Eitetsu......................................................................................... PP01.32 Koller, Francisco José......................................................................... PP01.60 Kolluri, Krishna.................................................................MS13.04, PL04.06 Kondo, Nobuyuki............................ MS09.06, PP02.49, PP02.50, PP02.51 Korasidis, Stylianos........................................................................... MS15.03 Korse, Catharina M............................................................................. PP01.19 Kossenkov, Andrew............................................................................. PL06.05 Kratzke, Robert..................................................................................MS04.06 Krausz, Thomas.................................................................................MS08.05 Kresoja-Rakic, Jelena......................................................PP02.56, PP02.57 Krowczynska, Małgorzata...................................................PP01.51, PP01.54 Krstic-Demonacos, Marija................................................................MS13.06 Krug, Lee..............................................................................PL05.01, PL05.05 Kryeziu, Kushtrim...............................................................................PP02.69 Kucharczuk, John.............................................................................. MS03.01 Kudo, Tomoo...................................................................................... MS13.05 Kukulj, Suzana.................................................................................... PP01.40 iMig2016.ORG 164 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Kumar, Neelam.................................................................MS13.04, PL04.06 Kumar, Prem........................................................................................PP01.14 Kumazawa, Sachiko.......................................................... MS15.06, PP02.45 Kuo, Licheng....................................................................................... PL05.02 Kuribayashi, Kozo............................................. PP01.03, PP01.52, PP02.07, ............................................................................................ PP02.49, PP02.51 Kuroda, Ayumi................................... MS09.06, PP02.49, PP02.50, PP02.51 Kusamura, Shigeki............................................................................. MS12.01 L Labby, Zacariah E..............................................................................MS03.06 Lacey, Simon...................................................................................... PP01.28 Lacin, Tunc.......................................................................................... PP02.47 Ladanyi, Marc.................................................................................... MS13.03 Lagani, Vincenzo................................................................................. PP01.21 Lagniau, Sabrina................................................................................PP01.16 Laird, Barry........................................................................................ MS14.02 Lakatos, Dora...................................................................................... PP02.61 Lake, Richard.....................................................MS13.01, MS16.07, PP01.77, .............................................................PP01.78, PP01.79, PP02.23, PP02.26 Lam, Vincent..................................................................................... PP02.06 Lamote, Kevin................................................................... MS05.02, PP01.16 Landi, Stefano....................................................................MS05.04, PP02.63 Lando, Cecilia Francesca................................................................... PP01.59 Lang, Georg....................................................................................... MS15.02 Lansley, Sally M................................................ MS11.07, MS16.07, PP02.23 Lantuejoul, Sylvie..............................................................................MS08.07 Larson, David...................................................................................... PP01.50 Larus, John......................................................................................... PL04.03 Laszlo, Viktoria...................MS15.02, PP01.15, PP01.17, PP02.61, PP02.69 Lathrop, Mark.................................................................................... MS07.02 Lauk, Olivia...................................... MS07.04, MS09.02, MS11.01, MS15.05 Le Pimpec-Barthes, Françoise...........MS08.08, PL02.05, PL04.05, PP02.37 Le Quesne, John................................MS11.03, MS11.06, PL01.06, PP01.63, ..............................................................................PP01.71, PP01.73, PP01.74 Le Stang, Nolwenn............................................................................MS08.07 Learmonth, Kirsty..............................................................................MS04.08 Lebenthal, Abraham......................................................................... PP02.39 Lee, Chunman...................................................................................MS10.07 Lee, Lukas J.......................................................................................PP01.47 Lee, Yc Gary........................................................................................MS11.07 Legittimo, Patrizia............................................................................... PP01.44 Leigh, James....................................................................................... PP01.43 Leighl, Natasha................................................................................... PL02.03 Lennon, Frances E.............................................................................. PP01.04 Leslie, Felicity.................................................................................... MS10.05 Lester, Jason F....................................................................................PP02.34 Lesterhuis, Willem J........................................ MS13.01, MS16.07, PP01.77, ..........................................................PP01.78, PP01.79, PP02.23, PP02.26 Li, Feng...............................................................................................MS03.06 Libener, Roberta................................................................. PP01.56, PP01.64 Liddell, Charly..................................................................................... PP01.09 Lievens, Yolande................................................................................ MS15.01 Lievense, Lysanne........................................... MS16.03, PP02.21, PP02.22 Lim, Eric............................................................................MS07.02, PP02.30 Lin, Ruby............................................................................ MS11.04, PP02.64 Lin, Ruby C.......................................................... PP02.59, PP02.68, PP02.73 Lind, Michael J................................................................................... MS11.05 Lindner, Michael................................................................................ MS15.04 Linton, Anthony...............................................MS04.03, MS06.05, MS10.05 Litzky, Leslie....................................................................................... PL06.05 Liu, Guo J............................................................................................ PP02.72 Lizotte, Patrick................................................................................... MS10.04 Lo, Albert............................................................................................ MS16.01 Loay, Eman.........................................................................................PP02.09 Loay, Iman........................................................................................... PP01.38 Locatelli, Myriam................................................................................PP02.37 Lococo, Filippo..................................................................................MS05.05 Loembe, Arsene-Bienvenu.................................................................PP02.32 Lou, Jianlin.........................................................................................MS06.06 Loubani, Mahmoud.............................................................................PP02.48 Louis, Renaud....................................................................................MS02.04 Lowe, Val............................................................................................MS04.06 Lu, Shir Kiong.................................................................................... MS07.02 Luberto, Ferdinando........................................................................... PP01.44 Lucchi, Marco.................................................. MS05.04, MS08.04, MS15.03 Lum, Trina..........................................................................................MS04.03 M Ma, Shaokang.....................................................................MS16.02, PP02.14 Maceyko, Steve.................................................................................. MS16.01 Macfarlane, Marion........................................ MS02.02, MS02.06, MS11.03, ............................................................................ MS11.06, PL01.06, PP02.75 Machan, Barbara................................................................................ PP01.62 Macleod, Nicholas............................................................................. MS14.02 Madore, Jason...................................................................................MS04.03 Maffè, Antonella................................................................................. PP01.64 Magnani, Corrado..............................................PL01.04, PP01.31, PP01.44, ............................................................PP01.56, PP01.64, PP01.72, PP02.41 Maher, Stephen G.............................................................................. MS11.05 Maio, Michele.................................................................................... MS10.03 Malcervelli, Gabriela.......................................................................... PP01.33 Maldonado, Fabien............................................................................MS04.06 Mallone, Sandra................................................................................. PP01.59 Mandrekar, Sumithra.........................................................................MS04.06 Manente, Arcangela G....................................................... MS11.02, PP02.65 Mangone, Lucia.................................................................................. PP01.59 Manno, Valerio.................................................................................... PP01.46 Mansano Sarquis, Leila Maria........................................................... PP01.60 Mansfield, Aaron S...........................................................MS04.06, PP01.10 Mantovani, Maria De Fátima.............................................................. PP01.60 Marchevsky, Alberto..........................................................................MS08.05 Marciniak, Stefan J............................................................ MS05.01, PP02.63 Marcq, Elly.........................................................................................PP02.10 Margery, Jacques...............................................................................PP02.37 Marinaccio, Alessandro...................................................................... PP01.44 Markaki, Maria.................................................................................... PP01.21 Martinson, Luke.................................................................................PP01.74 Mascaux, Céline................................................................................MS02.04 Maskell, Nick....................................MS05.01, MS14.05, PP01.12, PP02.31 Massard, Christophe.......................................................................... PL04.03 Matsuda, Tsuyoshi............................................................................. MS01.04 Matsumoto, Seiji................................................ MS09.06, PP02.49, PP02.51 Matsumoto, Shinji..............................................................................MS08.01 iMig2016.ORG 165 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Mattioli, Stefano................................................................................. PP01.44 Mattone, Silvia.................................................................................... PP02.41 Matullo, Giuseppe................................................PP01.56, PP01.64, PP01.72 Maza, Luis D.L.................................................................................... PP02.18 Mazuranic, Anton................................................................................ PP01.40 Mazuranic, Ivica................................................................................. PP01.40 Mccaughan, Brian C.......................................... MS04.03, PP02.59, PP02.73 Mcclanahan, Terri............................................................................... PL06.05 Mcdiarmid, Jennifer........................................................................... MS10.05 Mcdonald, Alice.................................................................................. PL04.03 Mcdonnell, Alison...............................................................................PP02.23 Mcgarvey, Maureen............................................................................ PP01.28 Mcgettrick, Michael...........................................................................PP01.01 Mcgregor, Stephanie.........................................................................MS08.05 Mclaughlin, Megan.............................................................................PP02.35 Mclaurin, Brett.................................................................................... PP01.50 Mclean, Jocelyn................................................................................ PP02.42 Meduri, Stefano.................................................................................MS06.02 Meerang, Mayura........................... MS11.01, MS15.05, PP01.06, PP01.24 Mehes, Elod........................................................................................PP02.55 Meiller, Clément.................................................................................. PL02.05 Melaiu, Ombretta..............................................................MS05.04, PP02.63 Melenhorst, Jos.................................................................................. PP01.28 Melfi, Franca......................................................................................MS08.04 Menegozzo, Simona........................................................................... PP01.44 Mensi, Carolina.....................................PP01.07, PP01.41, PP01.59, PP01.60 Meristoudis, Christos......................................................................... MS07.05 Merkler, Doug..................................................................................... PP01.50 Merler, Enzo.....................................................................MS06.03, PP01.30, ............................................................................................ PP01.44, PP01.59 Mesopath, Experts Pathologists.......................................................MS08.07 Metintas, Muzaffer.........................................MS06.01, MS06.04, PP01.25, .............................................................................PP02.47, PP02.53, PP02.67 Metintas, Selma................................................MS06.04, PP01.25, PP02.53 Miccoli, Sara....................................................................................... PP01.64 Michiara, Maria................................................................................... PP01.59 Michot, Jean-Marie............................................................................. PL04.03 Middleton, Gary.................................................................................. PP02.16 Mikami, Koji.......................................................PP01.03, PP01.52, PP02.07 Miles, Gareth J................................................. MS02.02, MS02.06, MS11.06 Miligi, Lucia......................................................................................... PP01.44 Millward, Michael J............................................................................. PP01.79 Miluzio, Annarita................................................................................ MS13.02 Minaai, Michael................................................................................. MS07.04 Minelli, Giada..................................................................... MS08.06, PP01.46 Mineo, Tommaso Claudio...................................................................PP02.46 Minkiewicz, Anna............................................................. PP01.51, PP01.54 Mirabelli, Dario...................................................PL01.04, PP01.44, PP01.56, .............................................................................................PP01.59, PP01.64 Miyamoto, Yosuke............................................................................... PP01.34 Mjelle, Robin....................................................................................... PP01.21 Moffatt, Miriam.................................................................................. MS07.02 Mohamed, Abdelrahman.....................................PP01.37, PP01.38, PP01.39 Molina, Julian....................................................................................MS04.06 Montero, Angeles.............................................................. MS07.02, MS08.05 Moody, Hannah L.............................................................................MS11.05 Moon, Edmund................................. MS14.01, MS16.01, PL06.05, PP01.28 Moons, Johnny................................................................................... MS15.01 Moore, David A................................... PP01.63, PP01.71, PP01.73, PP01.74 Moore, Kathleen N............................................................................ MS10.01 Mora, Marco......................................................................................MS05.04 Morahan, Grant................................................................................. MS13.01 Morgenfeld, Eduardo.......................................................................... PP01.33 Morinaga, Takao.................................................................PP02.52, PP02.66 Moro, Laura.....................................................MS02.05, MS11.02, PP02.65 Morra, Aldo........................................................................................ MS10.03 Morre, Dj............................................................................................. PP01.23 Morre, Dm........................................................................................... PP01.23 Morris, Paul......................................................................................... PP01.50 Morrow, Betsy.................................................................... MS04.04, PP02.16 Moseley, Jennifer................................................................................PP02.39 Moser, Justin........................................................................................PP01.10 Motas, Natalia.................................................................................... PP02.41 Munck, Camille....................................................................................PP01.11 Murer, Bruno..................................................................... MS05.04, MS13.02 Murphy, Erin....................................................................................... PL06.05 Murphy, Fiona A...................................................................PL01.06, PP02.75 Musk, Arthur W................................................................... PP01.23, PP01.30 Mussai, Francis................................................................................... PP02.16 Mussi, Alfredo....................................................MS08.04, MS15.03, PP01.17 Musti, Marina...................................................................................... PP01.44 Mutti, Antonio..................................................................................... PP01.20 Mutti, Luciano.................................. MS05.04, MS13.02, MS13.06, PP02.63 Muzio, Alberto.....................................................................MS12.03, PP01.31 N Nabavi, Noushin................................................................................PP01.65 Nabeshima, Kazuki..........................................................MS08.01, MS08.05 Nackaerts, Kristiaan......................................................... MS03.04, MS15.01 Nader, Joëlle................................... MS04.02, PP01.08, PP02.28, PP02.62 Nafteux, Philippe.............................................................MS03.04, MS15.01 Nagamatsu, Yasuko S.......................................................................MS01.04 Naidu, Babu.........................................................................................PP01.14 Nakamichi, Toru................................MS09.06, PP02.49, PP02.50, PP02.51 Nakano, Takashi.............................. MS09.06, MS10.07, MS13.05, PP01.03, ............................................................. PP01.52, PP02.07, PP02.49, PP02.51 Nakas, Apostolos............................................ MS02.02, MS02.06, MS09.01, ......................................................... MS09.04, MS11.03, MS11.06, PL01.06, ..............................................................PP01.71, PP01.73, PP01.74, PP02.75 Napolitano, Andrea............................................MS05.03, MS07.04, PP01.50 Nasu, Masaki..................................................................................... MS07.04 Nawrocki-Raby, Béatrice.................................................... PP01.08, PP02.28 Neelature Sriramareddy, Sathya......................................................MS02.04 Nelson, Annemarie............................................................................. PP01.28 Nelson, Gill........................................................................................PP01.57 Nemunaitis, John............................................................................... MS10.01 Neu, Reiner.........................................................................................PP02.43 Neufeld, Zoltan...................................................................................PP02.55 Newick, Kheng................................................................................... MS16.01 Nguyen, Jean-Michel.......................................................................... PP01.09 Nguyen-Kim, Thi Dan Linh...............................................MS03.05, MS09.02 Nicholson, Andrew............................................................................. MS07.02 Nicolson, Marianne............................................................................ PP02.41 Niewiadomsky, Dario.......................................................................... PP01.33 Nilsson, Stefan.................................................................. MS11.02, PP02.65 Nims, Sarah...................................................................... MS03.01, MS04.05 iMig2016.ORG 166 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Nishi, Hideyuki.................................................................................... PP01.34 Nixon, Lisette S................................................................................. PP02.34 Nowak, Anna.........................PP01.77, PP01.78, PP01.79, PP02.23, PP02.32 Numico, Gianmauro............................................................MS12.03, PP01.31 O O’Brien, Shaun................................................................................... MS16.01 O’Brien, Mary E.................................................................................. MS07.02 O’Hara, Mark...................................................................................... PP01.28 O’Rourke, Noelle................................................................................ MS14.02 Oda, Yoshinao....................................................................................MS08.01 Oddone, Enrico................................................................................... PP01.44 Oehler, Rudolf..................................................................................... PP01.15 Ogliara, Paola..................................................................................... PP01.64 Ojo, Anthonia...................................................................................... PL05.02 Okabayashi, Asako............................................................................. PP01.32 Okabe, Kazunori............................................................................... PP02.05 Okamoto, Shinya................................................................................PP02.66 Okubo, Kenichi..................................................................MS15.06, PP02.45 Okumura, Meinoshin......................................................................... MS10.07 Okumura, Yoshitomo......................................................... MS09.06, PP02.51 Oledzka, Gabriela................................................................PP01.51, PP01.54 Oliveto, Stefania...............................................................................MS13.02 Olschweski, Horst............................................................................... PP01.62 Oneglia, Barbara................................................................................ MS12.03 Op De Beeck, Ken............................................................................... PP01.67 Opitz, Isabelle.............................................. MS03.05, MS07.04, MS09.02, .........................................................................MS11.01, MS15.05, PP01.06, ............................................................................. PP01.19, PP01.24, PP02.70 Orlandi, Augusto................................................................................MS04.04 Otsuki, Taiichiro..................................PP01.03, PP01.52, PP02.07, PP02.51 Ottolini, Barbara..................................................................................PP01.74 Ötvöss, Rita......................................................................................... PP01.13 Own, Sulaf A....................................................................................... PP01.05 Ozaki, Daisuke...................................................................................MS08.02 Ozaki, Shinji........................................................................................ PP01.34 Ozsvar, Judit....................................................................................... PP02.61 Ozturk, Akın........................................................................................ PP01.25 P Pacey, Simon..................................................................................... MS10.02 Pachter, Jonathan...............................................................................PP02.21 Paci, Massimiliano.............................................................................MS05.05 Pagano, Ian........................................................................................MS05.03 Pairon, Jean Claude...........................................................................MS08.07 Paku, Sandor......................................................................................PP02.55 Palleschi, Alessandro......................................................................... PP01.07 Panageas, Katherine.......................................................................... PL05.05 Panou, Vasiliki...................................................................................MS07.05 Papotti, Mauro....................................................................MS07.03, PP01.64 Pardini, Barbara.................................................................................. PP01.72 Parhar, Preeti...................................................................................... PL05.01 Pascucci, Cristiana............................................................................. PP01.59 Pasini, Barbara................................................................................... PP01.64 Pass, Harvey I....................................................MS05.03, MS07.04, PP01.50 Passaro, Carmela............................................................................... PP02.13 Pastan, Ira........................................................................................... PP02.16 Pastorino, Sandra..............................................MS05.03, MS07.04, PP01.50 Patel, Akash.......................................................................MS03.02, PP02.08 Patel, Manish.....................................................................................MS04.06 Pattison, Scott................................................................................... MS10.05 Paul, Jim............................................................................................. PP01.02 Pauwels, Patrick................................................................................. PP02.10 Pavesi, Luca........................................................................................PP02.65 Pavlakis, Nick..................................................................................... MS10.05 Pavone, Venere................................................................................... PP01.44 Paz-Ares, Luis..................................................................................... PP02.41 Pearson, John..................................................................................... PP01.70 Pecze, Laszlo......................................................................................PP02.58 Pedrazzoli, Paolo................................................................................ PP01.31 Peek, Ann............................................................................................ PP01.02 Peeters, Stephanie........................................................... MS03.04, MS15.01 Peikert, Tobias..................................................................MS04.06, PP01.10 Pellegrini, Laura................................................................. MS05.03, PP01.50 Pellizzari, Giacomo............................................................................MS06.02 Pennati, Marzia.................................................................................. MS12.01 Pentimalli, Francesca......................................................................... PP02.13 Pernazza, Fausto............................................................................... MS12.03 Perrone, Federica.............................................................................. MS12.01 Perticaroli, Patrizia............................................................................. PP01.44 Pesatori, Angela C.............................................................................. PP01.07 Pesce, Elisa........................................................................................ MS13.02 Petel, Fabien......................................................................................MS08.08 Peters, Susan...................................................................................... PP01.30 Petrucci, Maria Saba.......................................................................... PP01.59 Pettinari, Aldo..................................................................................... PP01.44 Phillips, Melissa................................................................................. MS10.02 Piccolini, Ezio..................................................................... MS12.03, PP01.56 Piffer, Silvano...................................................................................... PP01.59 Pinto, Carmine.................................................................................... PP01.31 Pinton, Giulia................................................. MS02.05, MS11.02, PP02.65 Pirastu, Roberta.................................................................................. PP01.44 Pirker, Christine..................................................................................PP02.69 Piro, Roberto...................................................................... MS05.05, PP01.59 Pisa, Frederica...................................................................................MS06.02 Pissaloux, Daniel...............................................................................MS08.07 Planchard, David.................................................................PP02.37, PP02.41 Plesa, Gabriela.................................................................................... PP01.28 Plestina, Sanja.................................................................................... PP01.40 Pohl, Wolfgang.................................................................................... PP01.62 Poland, Craig A....................................................................................PL01.06 Popat, Sanjay..................................................................... MS07.02, PP02.32 Popper, Helmut................................................................................... PP01.62 Portella, Giuseppe.............................................................................. PP02.13 Postel-Vinay, Sophie........................................................................... PL04.03 Pouliquen, Daniel L........................ MS04.02, PP01.08, PP02.28, PP02.62 Powers, Amy.......................................................................MS07.04, PP01.50 Powley, Ian R..................................................MS02.02, MS02.06, MS11.03, .............................................................................................PL01.06, PP02.75 Predina, Jarrod................................................................MS03.01, MS04.05 Pringle, J. H........................................................................................ MS11.03 iMig2016.ORG 167 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Prokrym, Kirill....................................................................................MS05.03 Proto, Claudia..................................................................................... PP01.59 Puchalski Kalinke, Luciana................................................................ PP01.60 Q Qadri, Syed.........................................................................................PP02.48 Quetel, Lisa........................................................................ PL02.05, PL04.05 Quirke, Phillip......................................................................PP01.71, PP01.73 Quispel-Janssen, Josine................................................. MS04.07, PP02.36 R Rafferty, Judy.....................................................................................PP02.77 Rahman, Naj....................................................................................... PP02.31 Rahoma, Mohamed.............................................PP01.35, PP01.42, PP01.53 Rahouma, M..........................................PP01.37, PP01.38, PP01.39, PP01.61 Rahouma, Mohamed.......................................................................... PP01.29 Rajagopalan, Prabhu......................................................................... MS10.01 Ranucci, Alessandra........................................................................... PP01.44 Rapicetta, Cristian........................................................................... MS05.05 Rassl, Doris M.................................................................... MS05.01, PP02.63 Rath, Emma M.................................................................................... PP02.72 Ravn, Jesper........................................................................................ PP01.69 Rea, Federico...................................................................................... PP01.31 Reck, Martin........................................................................................PP02.32 Reichhart, Eva.....................................................................................PP02.60 Reid, Alison......................................................................................... PP01.30 Reid, Glen........................................MS04.03, MS10.05, MS11.04, PP01.19, ........................................................... PP01.24, PP02.56, PP02.59, PP02.64, ...........................................................................PP02.68, PP02.72, PP02.73 Renier, Annie...................................................... MS08.08, PL02.05, PL04.05 Ribich, Scott........................................................................................ PL04.03 Riboldi, Luciano.................................................................................. PP01.41 Ribrag, Vincent................................................................................... PL04.03 Ricciardi, Sara.................................................................................... MS13.02 Rice, David.......................................................................................... PL05.01 Richards, Cathy................................................................................... PP01.63 Richards, William................................................................MS10.04, PP01.06 Richards, William G........................... MS02.07, MS07.01, PP02.54, PP02.71 Ried, Michael.................................................................................... PP02.43 Riehm, Jacob J.................................................................................... PP01.04 Righi, Luisella.....................................................................MS07.03, PP01.64 Rimanti, Anita..................................................................................... PP01.59 Rimner, Andreas................................................................ PL05.01, PL05.02 Rinaldi, Catherine A.............................................MS11.07, PP01.78, PP01.79 Rintoul, Robert C............................................................ MS05.01, PP02.31 Rizzello, Roberto Vito......................................................................... PP01.59 Robard, Myriam.................................................MS04.02, PP02.28, PP02.62 Robinson, Bruce............................MS13.01, MS16.02, MS16.07, PP01.23, ........................................................... PP01.70, PP02.14, PP02.23, PP02.26 Robinson, Cleo.................................................................................... PP01.50 Roche, Maria....................................................................................... PL04.03 Roden, Anja........................................................................ MS04.06, PP01.10 Røe, Oluf D........................................................................ MS07.05, PP01.21 Roglic, Mihovil.................................................................................... PP01.40 Rolli, Luigi........................................................................................... PP01.20 Romanelli, Antonio............................................................................. PP01.59 Romeo, Elisa...................................................... MS08.06, PP01.44, PP01.59 Rooijackers, Jos..................................................................................PP02.27 Rosato, Simonetta.............................................................................. PP01.64 Rose, Buerkley................................................................... MS03.06, PL05.06 Rosenzweig, Kenneth E...................................................................... PL05.01 Rosolen, Valentina.............................................................................MS06.02 Roulois, David....................................................................................MS02.03 Roveta, Annalisa.................................................................MS12.03, PP01.31 Ruffini, Enrico..................................................................................... PP01.56 Ruiz, William F..................................................................................... PP01.36 Rullo, Emma.......................................................................................MS08.06 Rusca, Michele................................................................................... PP01.20 Rusch, Valerie......................................................................PL05.01, PL05.05 Rush, Hannah.................................................................................... MS10.02 S Sagan, Christine................................................................................. PP01.09 Sage, Beth........................................................................................... PL04.06 Sage, Elizabeth.................................................................................. MS13.04 Saito, Atsuhiro................................................................................... MS10.07 Sala, Orietta........................................................................................ PP01.44 Salgia, Ravi......................................................................... PP01.04, PP01.22 Salimu, Josephine............................................................................. MS16.05 Samarzija, Miroslav............................................................................ PP01.40 Santin, Alessandro D......................................................................... MS10.01 Santoni-Rugiu, Eric............................................................................PP01.69 Santoro, Armando.............................................................................. PP01.31 Santoro, Raffaella...............................................................................PP02.57 Sarapa, Nenad................................................................................... MS10.01 Sarun, Kadir........................................................................ PP02.68, PP02.72 Sarun, Kadir H....................................................................................PP02.59 Sato, Akitoshi...................................................................................... PP01.32 Sato, Ayuko....................................................................... MS08.01, MS13.05 Sblattero, Daniele..............................................................................MS02.05 Scagliotti, Giorgio V........................................... PP01.31, PP02.32, PP02.41 Scarnato, Corrado.............................................................................. PP01.44 Scheinberg, David.............................................................................. PL05.05 Schelch, Karin.....................................................PP02.60, PP02.64, PP02.69 Schenk, Peter...................................................................................... PP01.62 Scherpereel, Arnaud.........................................MS02.04, MS08.07, PP01.11, .......................................................................................... PP02.33, PP02.37 Schinwald, Anja...................................................................................PL01.06 Schlom, Jeffrey..................................................................................MS04.04 Schmalzl, Angelika.............................................................................PP02.67 Schmid-Bindert, Gerald...................................................................... PP02.41 Schmidt, Anna.................................................................................... PL04.03 Schneiter, Didier................................................................................MS09.02 Schwaller, Beat...................................................PP02.15, PP02.19, PP02.56, ............................................................................................ PP02.57, PP02.58 iMig2016.ORG 168 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Schwartz, Jean-Marc......................................................................... MS13.06 Sciacca, Salvatore.............................................................................. PP01.59 Sciaranghella, Daniele....................................................................... PP02.71 Scolyer, Richard A..............................................................................MS04.03 Scuderi, Tiziana.................................................................................. PP01.59 Seifert, Burkhardt............................................. MS03.05, MS09.02, PP01.06 Seiwert, Tanguy Y.............................................................................. MS16.06 Seiwerth, Sven.................................................................................... PP01.40 Sekido, Yoshitaka...............................................................................PL01.09 Sekine, Ikuo........................................................................................PP02.66 Sekine, Yasuo..................................................................... MS08.02, PP01.32 Seward, Shelly M............................................................................... MS10.01 Sgarbi, Giorgio...................................................................................MS05.05 Sgargi, Paolo....................................................................................... PP01.59 Shah, Rajesh...................................................................... MS05.06, PP01.68 Sharkey, Annabel J...................................... MS09.01, MS09.04, PP01.71, ........................................................................................... PP01.73, PP01.74 Sharples, Linda................................................................................... PP02.31 Shaw, Jacqui........................................................................................PP01.74 Sheaff, Michael.................................................................................. MS10.02 Shen, Ronglai...................................................................................... PL05.01 Sherlock-Brown, Graham................................................................... PP02.31 Shibata, Eisuke................................................................... PP01.03, PP02.07 Shimada, Hideaki..............................................MS08.02, PP02.52, PP02.66 Shimizu, Shigeki................................................................................ MS13.05 Shingyoji, Masato...............................................................................PP02.66 Shinohara, Yoshiyasu........................................................................ MS13.05 Shrestha, Raunak............................................................................... PP01.65 Sideris, Antonios................................................................................PP02.71 Siegert, Charles J...............................................................................PP02.39 Signorelli, Diego................................................................................. PP01.59 Silini, Enrico Maria............................................................................. PP01.20 Silvestri, Stefano................................................................................. PP01.44 Simone, Charles B.............................................MS03.02, MS14.01, PP02.08 Singhal, Sunil................................................... MS03.01, MS03.02, MS04.05 Siozopoulou, Vasiliki........................................................................... PP02.10 Sivasothy, Pasupathy.......................................................................... PP02.31 Sklarek, Jürgen.................................................................................. MS15.04 Skubiszewska, Agnieszka....................................................PP01.51, PP01.54 Smeele, Patrick....................................................................................PP01.11 Smit, Egbert........................................................................................ PP02.41 Smits, Evelien..................................................................................... PP02.10 Smojver-Jezek, Silvana....................................................................... PP01.40 Sneddon, Sophie...............................................................................PP01.70 Soeberg, Matthew J..........................................................MS06.05, PP01.43 Solin, Jessica......................................................................MS16.07, PP02.26 Solinas, Michela................................................................................. PP01.20 Soltermann, Alex................................................................................ PP01.06 Soluri, Maria Felicia...........................................................................MS02.05 Somigliana, Anna B...........................................................................MS06.03 Soria, Jean-Charles............................................................................ PL04.03 Sørensen, Jens B............................................................... PP01.27, PP01.69 Spicer, James..................................................................................... MS10.02 Spraggon, Lee.................................................................................... MS13.03 Spriggs, Ruth..................................................................................... MS11.06 Staal-Vd Brekel, Jeske........................................................................PP02.36 Stahel, Rolf......................................................MS09.02, MS11.01, MS15.05, .............................................................PP01.06, PP02.56, PP02.57, PP02.70 Staumont, Bernard............................................................................MS02.04 Steele, Jeremy................................................................................... MS10.02 Steinberg, Seth..................................................................................MS04.04 Stella, Franco......................................................................................PP02.46 Stephens, Richard............................................................................. MS01.05 Sterman, Daniel................................................................. MS04.05, PL06.05 Stetler-Stevenson, Maryalice............................................................. PP02.16 Stobo, David B...................................................................................MS03.03 Stockhammer, Paul.............................. PP01.15, PP01.17, PP01.18, PP01.62 Storchi, Cinzia..................................................................................... PP01.59 Stracci, Fabrizio.................................................................................. PP01.59 Straus, Christopher M.......................................................................MS03.06 Studnicka, Michael............................................................................. PP01.62 Stura, Antonella.................................................................................. PP01.59 Suh, Hyerim....................................................................................... MS11.04 Sulemani, Merve.................................................................................PP02.56 Sun, Jing............................................................................................ MS16.01 Sun, Xiao-Ming..............................................MS02.02, MS02.06, MS11.03, ............................................................................ MS11.06, PL01.06, PP02.75 Sundquist, Kristina............................................................................MS06.06 Suzuki, Toshio.....................................................................PP02.52, PP02.66 Szatmari, Tände.................................................................................. PP01.13 Szatmari, Tünde..................................................................................PP02.67 Szeto, Kyle.......................................................................................... PP01.22 Szlosarek, Peter............................................................... MS05.01, MS10.02 Szöke, Tamas......................................................................................PP02.43 Sætrom, Pål........................................................................................ PP01.21 T Tabi, Zsuzsanna............................................................... MS16.04, MS16.05 Tada, Yuji.......................................................... MS08.02, PP02.52, PP02.66 Taddei, Sofia......................................................................................MS05.05 Tagawa, Masatoshi.......................................... MS08.02, PP02.52, PP02.66 Taggart, Dj........................................................................................... PP01.23 Taghavi, Shahrokh............................................................................. MS15.02 Tagliabue, Giovanna........................................................................... PP01.59 Takasaki, Chihiro............................................................... MS15.06, PP02.45 Takeshima, Yukio................................................................................PP02.04 Takuwa, Teruhisa............................... MS09.06, PP02.49, PP02.50, PP02.51 Tan, Angelina.....................................................................................MS04.06 Tan, Yi-Hung Carol.......................................................... MS16.06, PP01.22 Tanaka, Fumihiro............................................................... MS09.06, PP02.51 Tanaka, Toshiki...................................................................................PP02.05 Tangy, Frédéric...................................................................................MS04.02 Tanji, Mika........................................................................................... PP01.50 Tanyi, Janos L..................................................................................... PP01.28 Tao, Hiroyuki.......................................................................................PP02.05 Tarnoki-Zach, Julia........................................................................... PP02.55 Tatsumi, Koichiro................................................................PP02.52, PP02.66 Taub, Robert N...................................................MS12.02, MS15.07, PP02.02 Taverna, Giacomo.............................................................................. MS12.03 Tavian, Daniela...................................................................................PP02.65 Taylor, Morag.......................................................................PP01.71, PP01.73 Taylor, Paul......................................................................... MS05.06, PP01.68 Telford, Nick........................................................................................ PP01.68 Tenconi, Sara................................................... MS05.05, MS09.01, MS09.04 Terada, Takayuki..................................................PP01.03, PP01.52, PP02.07 Terracini, Benedetto........................................................................... PL01.04 Tewaternaude, Jim.............................................................................. PP01.57 iMig2016.ORG 169 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Thomas, Anish................................................................... MS04.04, PP02.16 Thomson, Blythe................................................................................. PL04.03 Thurm, Rivka.......................................................................................PP02.02 Tinwell, Brendan................................................................................ MS07.02 Tironi, Andrea....................................................................................MS05.04 Tiseo, Marcello................................................................... PP01.20, PP01.59 Tod, Angela......................................................................................... PP02.31 Todaro, Aldo........................................................................................ PP01.07 Todisco, Liana.................................................................................... MS12.03 Tognelli, Flavio.................................................................................... PP01.33 Torigian, Drew A................................................................. MS03.02, PP01.28 Toulmonde, Maud............................................................................... PL04.03 Trama, Annalisa.................................................................................. PP01.59 Tranchant, Robin................................................................ PL02.05, PL04.05 Truini, Anna........................................................................................MS05.04 Tsamardinos, Ioannis.......................................................................... PP01.21 Tsao, Anne............................................................................PL05.01, PL05.05 Tsao, Ming........................................................................................... PP02.74 Tsim, Selina......................................................MS03.03, PP01.01, PP01.02 Tsubota, Noriaki................................................. MS09.06, PP02.49, PP02.51 Tsujimura, Tohru............................................MS08.01, MS09.06, MS13.05, .............................................................................PP02.07, PP02.49, PP02.51 Tsunoda, Tatsuhiko............................................................................ MS07.04 Tumino, Rosario.................................................................................. PP01.59 Tuncel, Tunç...................................................................................... PP02.53 Tunesi, Sara.........................................................................PL01.04, PP01.56 Turchetti, Daniela............................................................................... PP01.64 V Vaickus, Lou....................................................................................... MS10.04 Vaja, Ricky......................................................................... MS09.01, MS09.04 Valentino, Francesco.......................................................................... PP01.31 Vallely, Michael P................................................................................PP02.59 Van Audenaerde, Jonas...................................................................... PP02.10 Van Camp, Guy................................................................................... PP01.67 Van Dam, Loes....................................................................................PP02.54 Van Den Broek, Daan......................................................................... PP01.19 Van Heemst, Robbert.........................................................................PP02.36 Van Keulen, Virginia...........................................................................MS04.06 Van Meerbeeck, Jan.......................... MS05.02, PP02.10, PP02.32, PP02.33 Van Meerbeeck, Jan P.........................................................PP01.16, PP01.67 Van Nimwegen, Menno...................................................... MS16.03, PP02.21 Van Raemdonck, Dirk........................................................................MS03.04 Van Veer, Hans...................................................................................MS03.04 Van Zandwijk, Nico........................................MS04.03, MS06.05, MS10.05, ............................................................MS11.04, PP01.19, PP01.24, PP01.43, ............................................................ PP02.42, PP02.59, PP02.68, PP02.73 Vandecaveye, Vincent........................................................................MS03.04 Vandermeers, Fabian.........................................................................MS02.04 Vansteenkiste, Johan........................................................ MS03.04, MS15.01 Vatrano, Simona................................................................................ MS07.03 Vattiato, Rosa...................................................................................... PP01.59 Vd Noort, Vincent................................................................................PP02.36 Velema, Derek.....................................................................................PP02.32 Venegas, Ollin................................................................... MS03.01, MS04.05 Ventura, Luigi...................................................................................... PP01.20 Verbeken, Eric....................................................................................MS03.04 Verheij, Marcel................................................................................... MS14.03 Vermaelen, Karim Y.............................................................................PP01.16 Verschakelen, Johny..........................................................................MS03.04 Viberti, Clara........................................................................PP01.56, PP01.72 Vicentini, Massimo............................................................................. PP01.59 Vigneswaran, Wickii...........................................................................MS08.05 Vigneswaran, Wickii T........................................................PL05.06, PP01.22 Villaflor, Christopher........................................................................... PP01.22 Villamizar, Guillermo A......................................................................PP02.01 Visca, Paolo....................................................................................... MS07.03 Vitale, Maria Francesca...................................................................... PP01.59 Vlacic, Gregor.................................................................................. MS08.03 Von Wangenheim, Ute........................................................................PP02.32 Vrugt, Bart........................................................... MS11.01, PP01.06, PP01.24 Vyberg, Mogens................................................................................. MS07.05 W Wada, Sae........................................................................................... PP01.34 Waddell, Nicola................................................................................... PP01.70 Wagner, Christina...............................................................................PP02.64 Wahba, Hisham................................................................... PP01.53, PP02.09 Waithman, Jason................................................................................PP02.23 Walker, Graeme................................................................................. MS13.01 Waller, David.....................................................MS09.01, MS09.04, PP01.71, ............................................................................. PP01.73, PP01.74, PP02.31 Wallin, Bruce A................................................................................. PP02.35 Walter, Annette.................................................................................. MS10.01 Walts, Ann..........................................................................................MS08.05 Wang, Jung-Der.................................................................................. PP01.47 Wang, Yan.......................................................................... MS10.04, PP02.21 Wang, Yuzhuo..................................................................................... PP01.65 Wasielewski, Eric.................................................................PP01.11, PP02.37 Wason, James.....................................................................................PP02.63 Watson, Sydeaka................................................................................ PL05.06 Weaver, David T.................................................................................. MS10.04 Weder, Walter.................................. MS03.05, MS07.04, MS09.02, MS11.01, ........................................................... MS15.05, PP01.06, PP01.19, PP01.24, .............................................................................PP02.56, PP02.57, PP02.70 Weir, Chris........................................................................................... PP02.72 Whiting, Caroline............................................................................... MS01.05 Wilczynska, Ania................................................................................ MS11.06 Wild, Peter........................................................................................... PP01.24 Wilk, Ewa..............................................................................PP01.51, PP01.54 Willemin, Marie C................................................................................PP01.11 Willems, Luc....................................................................... MS02.04, PP02.12 Williams, Marissa........................................... MS04.03, MS11.04, PP01.19, ............................................................................................ PP02.59, PP02.73 Willis, Anne E.................................................. MS02.02, MS02.06, MS11.03, ............................................................................ MS11.06, PL01.06, PP02.75 Woll, Penella..................................................................... MS04.08, MS10.06 Won, Brian M...................................................................................... PP01.22 Wong, Kwok....................................................................................... MS10.04 Woo, Kaitlin M..................................................................................... PL05.01 iMig2016.ORG 170 ABSTRACT BOOK 13TH INTERNATIONAL CONFERENCE OF THE I NTERNATIONAL MESOTHELIOMA INTEREST GROUP Woodward, Rosemary........................................................ MS03.03, PP01.02 Wright, Casey M..................................................................................PP02.59 Wu, Abraham J.................................................................................... PL05.01 Wu, Di................................................................................. MS08.02, PP01.32 Wu, Licun......................................................... MS14.04, PP02.15, PP02.18, ........................................................................................... PP02.19, PP02.74 Wu, Matthew.....................................................................MS14.04, PP02.18 Wu, Ting-Hui....................................................................................... PP01.47 Wuilleret, Guillaume.......................................................................... MS15.05 Zhou, Zhi............................................................................................ MS13.04 Ziino, Antonio...................................................................................... PP01.59 Ziltener, Gabriela.................................................................PP02.57, PP02.70 Zimmerman, Marion..........................................................................MS04.07 Zöchbauer-Müller, Sabine................................................................. MS15.02 Zonca, Sara....................................................................... MS02.05, MS11.02 Zucchi, Luigi.......................................................................................MS05.05 Zucman-Rossi, Jessica...................................... MS08.08, PL02.05, PL04.05 Zuo, Zhixiang...................................................................................... MS16.06 Zwaenepoel, Karen............................................................................. PP02.10 Y Yahia, Maha........................................................................ PP01.61, PP02.09 Yamagishi, Tomoko............................................................................. PP01.34 Yan, Ming............................................................................................ PL05.02 Yang, Haining................................................... MS05.03, MS07.04, PP01.50 Yeap, Beow Y.......................................................................................MS07.01 Yearly, Jennifer H................................................................................ PL06.05 Yehia, Maha........................................................................................ PP01.53 Yildirim, Huseyin................................................................................. PP01.25 Yildizeli, Bedrettin............................................................................... PP02.47 Yilmaz, Senay..................................................................................... PP01.25 Yilmaz, Ulku........................................................................................ PP01.25 Yokohori, Naoko.................................................................................. PP01.32 Yorke, Ellen..........................................................................PL05.01, PL05.02 Yoshida, Kumiko.................................................................................PP02.05 Yoshiyama, Kouichi.............................................................................PP02.05 Young, Jane......................................................................................... PP01.43 Yuan, Constance................................................................................. PP02.16 Yuan, Zhenqiang................................................................................. PL04.06 Yuksel, Mustafa.................................................................................. PP02.47 Yumuk, Fulden.................................................................................... PP02.47 Yun, Hana............................................................................................ PP02.18 Yun, Hana Z......................................................................................... PP02.74 Yun, Zhihong.......................................................MS14.04, PP02.15, PP02.19 Yusa, Toshikazu..................................................................................MS08.02 Z Zacarias-Cabeza, Joaquin................................................MS11.03, PP02.75 Zaffaroni, Nadia................................................................................. MS12.01 Zago, Giulia........................................................................................MS04.07 Zai, Silvia............................................................................................ MS12.03 Zanelli, Francesca.............................................................................MS05.05 Zanin, Tina.........................................................................................MS06.02 Zauderer, Marjorie G.......................................................... PL05.01, PL05.05 Zemek, Rachael M.............................................................................. PP01.79 Zhang, Jingli....................................................................... MS04.04, PP02.16 Zhang, Shu Dong................................................................................PP02.54 Zhang, Xing........................................................................................MS06.06 Zhao, Yidan D.....................................................................................PP02.74 iMig2016.ORG 171