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Our goal was to evaluate the diagnostic value of DNA methylation analysis in combination with machine learning to differentiate pleural mesothelioma (PM) from important histopathological mimics.DNA methylation data of PM, lung adenocarcinomas, lung squamous cell carcinomas and chronic pleuritis was used to train a random forest as well as a support vector machine. These classifiers were validated using an independent validation cohort including pleural carcinosis and pleomorphic variants of lung adeno- and squamous cell carcinomas. Furthermore, we performed differential methylation analysis and used a deconvolution method to estimate the composition of the tumor microenvironment.T-distributed stochastic neighbor embedding clearly separated PM from lung adenocarcinomas and squamous cell carcinomas, but there was a considerable overlap between chronic pleuritis specimens and PM with low tumor cell content. In a nested cross validation on the training cohort, both machine learning algorithms achieved the same accuracies (94.8%). On the validation cohort, we observed high accuracies for the support vector machine (97.8%) while the random forest performed considerably worse (89.5%), especially in distinguishing PM from chronic pleuritis. Differential methylation analysis revealed promoter hypermethylation in PM specimens, including the tumor suppressor genes BCL11B, EBF1, FOXA1, and WNK2. Deconvolution of the stromal and immune cell composition revealed higher rates of regulatory T-cells and endothelial cells in tumor specimens and a heterogenous inflammation including macrophages, B-cells and natural killer cells in chronic pleuritis.DNA methylation in combination with machine learning classifiers is a promising tool to reliably differentiate PM from chronic pleuritis and lung cancer, including pleomorphic carcinomas. Furthermore, our study highlights new candidate genes for PM carcinogenesis and shows that deconvolution of DNA methylation data can provide reasonable insights into the composition of the tumor microenvironment.

Prediction of prognosis is a key step of malignant pleural mesothelioma (MPM) management and treatment assignment. Aim of this study was to identify simple prognostic factors, focusing on inflammation-related parameters.Baseline clinical and laboratory data were extracted from a single-center 20-year cohort of consecutive patients exhibiting a proven MPM. Inflammation-related ratios and composite scores were evaluated as prognostic indicators.468 patients were identified. Mean age and BMI were 73.0 years and 25.1 kg/mThe prognosis of MPM is strongly influenced by systemic inflammation and patients exhibiting higher NLR, SII and lower ALI have shorter survival, which strengthens the level of evidence about the major role played by inflammation in MPM.

The role of PET and integrated PET-CT in the diagnostic workup of suspected malignant pleural effusions is unknown. Earlier systematic reviews (published 2014 and 2015) both included pleural pathology without effusion, and reached contradictory conclusions. Five studies have been published since the latest review. This systematic review and meta-analysis aims to summarise the evidence of PET and integrated PET-CT in predicting pleural malignancy in patients suspected of having malignant pleural effusions. A meta-analysis based on a systematic literature search in Cochrane Library, Medline, EMBASE and Clinicaltrials.gov was performed. Diagnostic studies evaluating the performance of PET or PET-CT in patients with suspected malignant pleural effusion, using pleural fluid cytology or histopathology as the reference test, and presenting sufficient data for constructing a 2x2 table were included. The quality of the studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 score. Subgroup analyses on image modality, interpretation method and known malignancy status pre index-test application were planned. Seven studies with low risk of bias were included. The pooled ability to separate benign from malignant effusions varied with image modality, interpretation method and known malignancy status pre index-test application. In studies using PET-CT, visual/qualitative image analysis was superior to semi-quantitative with positive (LR + ) and negative likelihood ratio (LR-) of 9.9 (4.5–15.3) respectively 0.1 (0.1–0.2). There was considerable heterogeneity among studies. In conclusion, visual/qualitative image analysis of integrated PET-CT seems to add relevant information in the work-up of suspected malignant pleural effusions with LR + and LR- close to rigorous pre-set cut-offs of > 10 and < 0.1. However, the quality of evidence was low due to inter-study heterogeneity, and inability to assess meta-bias. Clinical Trial Registration: The protocol was uploaded to the PROSPERO database (CRD42020213319) on the 13th of October 2020.

Objectives Second-line immune checkpoint inhibition (ICI) was recently shown to have a survival advantage over placebo in malignant pleural mesothelioma (MPM), but the survival comparison to chemotherapy in patients with MPM receiving routine clinical care is unknown. Our objective was to examine the effectiveness of second-line ICI versus chemotherapy on overall survival (OS) outcomes in real-world patients with advanced MPM. Materials and Methods We performed a multicenter retrospective cohort study of real-world adult patients with advanced MPM who received first-line platinum-based chemotherapy and at least two total lines of systemic therapy. Patients received either second-line chemotherapy (gemcitabine and/or vinorelbine) or ICI therapy (pembrolizumab or nivolumab ± ipilimumab). The primary outcome was OS, defined as the time from second-line therapy initiation to death or end of the observation period. We used Kaplan-Meier methods and Cox proportional hazards modeling with adjustment for relevant patient demographic and clinical variables to compare OS between the two second-line treatment groups. Results Of the 176 patients with MPM, the median age was 75 years (IQR: 69–79.5 years), and most were white (77%), male (74%), and had epithelioid histology (67%). Thirty-five percent (61) received second-line chemotherapy and 65% (1 1 5) ICI therapy (80 pembrolizumab, 31 nivolumab, and 4 nivolumab + ipilimumab). Treatment with ICI was associated with significantly longer median OS compared to chemotherapy (8.7 vs 5.0 months, p=0.001; adjusted hazard ratio: 0.52, 95% CI: 0.34–0.81). The estimated 12-month OS probability was 36.7% (95% CI: 27.6%-45.8%) and 15.6% (95% CI: 7.7%-26.1%) in the ICI and chemotherapy groups, respectively. Conclusion In this “real-world” population of patients with MPM, treatment with ICI was associated with improved OS outcomes compared to chemotherapy in the second-line setting, in contrast with a recent clinical trial. Our findings suggest that ICI may benefit patients with advanced MPM and progression after initial platinum-based chemotherapy.

The aim of adoptive T-cell therapy is to promote tumor-infiltrating immune cells following the transfer of either tumor-harvested or genetically engineered T lymphocytes. A new chapter in adoptive T-cell therapy began with the success of chimeric antigen receptor (CAR) T-cell therapy. T cells harvested from peripheral blood are transduced with genetically engineered CARs that render the ability to recognize cancer cell-surface antigen and lyse cancer cells. The successes in CAR T-cell therapy for B-cell leukemia and lymphoma have led to efforts to expand this therapy to solid tumors. Herein, we discuss the rationale behind the preclinical development and clinical trials of T-cell therapies in patients with malignant pleural mesothelioma. Furthermore, we highlight the ongoing investigation of combination immunotherapy strategies to synergistically potentiate endogenous as well as adoptively transferred immunity.

Objectives Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy. Materials and methods Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy. Results A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p Conclusions Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally.

No standard treatment option is available for patients with unresectable malignant pleural mesothelioma (MPM) progressing after upfront chemotherapy. We aimed to explore the role of focal radiotherapy (FRT) as a treatment modality for oligo-progressive MPM.In this retrospective study, consecutive patients pretreated with ≥1 lines of chemotherapy were included. Oligo-progressive MPM was defined as an unresectable disease with radiological progression at ≤3 sites according to a chest-abdominal contrast-enhanced computed tomography. Patients were treated with either stereotactic body radiotherapy (SBRT, ≥5 Gy per fraction) or hypo-fractionated radiotherapy (hypoRT,5 Gy per fraction). Time to further systemic therapy (TFST) and local control (LC) after FRT were the primary endpoints. Biologically effective dose (BED) was calculated using three different alpha/beta models (1.5 Gy, 3 Gy and 10 Gy).From April 2006 to March 2019, 37 patients were treated on 43 pleural lesions; 16/37 (43 %) had undergone upfront multimodality treatment (MMT) including surgery. FRT was given in 22/37 (59.5 %) after one line of chemotherapy. SBRT was delivered for 26/43 lesions (60.5 %), hypoRT for 17/43 (39.5 %). Median TFST was 6 months (95 % CI 4.9-7.1). LC at 6 months and 1 year was 84 % and 76 %, respectively. Median TFST was longer in patients treated after 1 vs1 line of chemotherapy (9 vs 4 months, p = 0.001) and in patients pretreated with MMT (6 vs 3 months, p = 0.021). Six-month LC was better in patients treated with a BED 100 using alpha/beta 1.5 and 3. No ≥ G3 acute or late toxicities were reported.FRT was feasible in selected patients with oligo-progressive MPM, allowing delay of further systemic therapies, with no severe toxicity. FRT was more effective when performed at progression after one line of systemic therapy. Our results suggest a radio-resistant behavior of MPM.

Objectives Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM. Materials and methods Patients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response. Results Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naive. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks. Conclusions Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

Objectives Distinguishing pleural sarcomatoid mesotheliomas from true sarcomas is challenging because the former does not always express the mesothelial markers, and diagnosis is often made on the basis of keratin expression. Consequently, sarcomas such as angiosarcomas that express keratin complicate the differential diagnosis. Furthermore, some mesotheliomas have been reported to express endothelial markers. The aim of this study is to identify useful markers for distinguishing pleural sarcomatoid mesothelioma from angiosarcoma. Materials and methods This study enrolled 147 patients with pleural mesothelioma—93 with epithelioid, 25 with biphasic, and 29 with sarcomatoid subtypes—and 41 patients with angiosarcomas in various organs. The expression levels of cytokeratin, mesothelial, and endothelial markers were assayed in both groups to identify the markers that could assist in distinguishing mesothelioma from angiosarcoma. Cytokeratin (AE1/AE3, CAM 5.2), endothelial (CD31, CD34, ERG, factor VIII, and claudin-5), and mesothelial (calretinin, WT-1, podoplanin (D2-40), EMA, and CK5/6) markers were immunohistochemically assayed using tissue blocks. Results More than 90% of the mesotheliomas and less than 20% of the angiosarcomas expressed cytokeratin. Calretinin was expressed in 82% of all types of mesotheliomas but in only 48% of sarcomatoid mesotheliomas. Endothelial markers were expressed in mesothelioma tissues—CD31 in 10.3%, CD34 in 3.5%, ERG in 29%, and factor VIII in 3.4%—and the positivity was higher in sarcomatoid than in epithelioid and biphasic mesotheliomas. Claudin-5 was expressed in all the angiosarcomas, but not in any of the mesotheliomas. Conclusion We found overlapping immunophenotypes in pleural mesotheliomas and angiosarcomas, but the sensitivity and specificity of claudin-5 expression were sufficient to distinguish between them. The differential diagnosis of mesothelioma should therefore include claudin-5 in a panel of immunohistochemical markers to distinguish mesothelioma from angiosarcoma.

Objectives Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1–3 inhibitor, as a second or third-line treatment. Materials and Methods We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon’s two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. Results 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. Conclusions The FGFR 1–3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

Objective Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in a subset of malignant cells. However, it remains unknown whether ROR1 is targetable in malignant mesothelioma (MM). Therefore, in this study, we investigated the effects of ROR1 inhibition in mesothelioma cells. Materials and methods Growth inhibition, colony formation, apoptosis, and mRNA/protein levels using siRNA-transfected MM cells were evaluated. Cluster analysis using Gene Expression Omnibus repository of transcriptomic information was also performed. Results Our results indicated that in three (H2052, H2452, and MESO-1) among four MM cell lines, ROR1 inhibition had anti-proliferative and apoptotic effects and suppressed the activation of AKT and STAT3. Although growth inhibition by siROR1 was minimal in another mesothelioma cell line (H28), colony formation was significantly suppressed. Microarray, quantitative polymerase chain reaction, and Western blot analyses showed that there were differences in the suppression of mRNA and proteins between H2452 and H28 cells transfected with siROR1 compared with those transfected with control siRNA. Cluster analysis further showed that MM tumors had relatively high ROR1 expression, although the cluster in them was different from that in MM cell lines. Thymidylate synthase, a target of pemetrexed, was downregulated in H2452 cells transfected with siROR1. Accordingly, a combination of pemetrexed with siROR1 was found to be effective in the three MM cell lines we studied. Conclusion Our findings may provide novel therapeutic insight into the treatment of advanced MM.

Objectives CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies. Material and methods The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs). Results Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response. Conclusions YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.

Objectives Negative effusion cytology is more common in certain forms of Malignant Pleural Effusion (MPE) and results in pathway delay. Local Anaesthetic Thoracoscopy (LAT) is extremely sensitive and safe but cannot be offered to all. A stratified pathway, including ‘Direct to LAT’ in selected cases could enhance patient experience but requires reliable baseline predictors of unhelpful cytology, including both negative (no malignant cells) and incomplete results (malignant cells identified but predictive markers failed), since pleural biopsies will be required in the latter for optimal management. This retrospective analysis of a prospective multi-centre study, sought to identify baseline features for pathway rationalization. Materials and methods 363/638 (57%) of patients recruited to the DIAPHRAGM study (ISRCTN10079972) were included. Prospective data, including final diagnoses, asbestos exposure and fluid cytology results were supplemented by retrospective Computed Tomography (CT) and predictive marker reports. Independent predictors of negative and incomplete cytology were determined by multivariable logistic regression. Contingency tables were used to assess diagnostic value of cytology in associated phenotypes. Results 238/363 (66%) patients were diagnosed with MPE (18 tumour types). Fluid cytology was negative in 151/238 (63%) and independently associated with asbestos-exposure (Odds Ratio (OR) 5.34) and a malignant CT (OR 2.25). When both features were recorded the sensitivity and negative predictive value of fluid cytology were 19% (95% CI 11–30%) and 9% (95% CI 4–20%)), respectively. Cytology was incomplete in 34/238 (14%), i.e. 47% of positive cytology cases) but was not associated with any baseline feature. ORs for incomplete cytology in Ovarian, Breast, Renal and Lung Cancer were 83, 22, 21 and 9, respectively. Conclusion Negative cytology is extremely likely in patients with asbestos exposure and a malignant CT report. A ‘Direct-to-LAT’ approach may be appropriate in this setting. No baseline predictors of incomplete cytology were identified.

Objectives Tumor spread through air spaces (STAS) was recently reported as a novel risk factor for the prognosis of patients with resected lung adenocarcinoma that indicates invasive tumor behavior. The purpose of this study was to build a prognostic model consisting of STAS and other pathologic features including visceral pleural invasion (VPI), vascular invasion (VI) and histological subtype (HS) in lung invasive adenocarcinoma. Materials and methods A total of 289 patients with resected lung invasive adenocarcinomas ≤4 cm were analyzed retrospectively to evaluate the potential prognostic value of STAS, VPI, VI and HS for recurrence-free survival (RFS) and overall survival (OS). Results STAS was observed in 143 patients (49.5%). Univariate and multivariate analysis showed that STAS, VPI, VI and HS were significant prognostic factors for poorer RFS and OS. Thus, a prognostic model including STAS, VPI, VI and HS was built using the results of the multivariate analysis. Nomograms were developed to predict the 5-year RFS and OS. The concordance index (C-index) of the prognostic model was 0.8122 for predicting 5-year RFS and 0.8539 for predicting 5-year OS in the internal validation. Moreover, the calibration curves for the 5-year RFS and OS showed that the nomograms were calibrated well. In addition, a similar predicted capability of the prognostic model was observed in the validation cohort. Conclusion STAS, VPI, VI and HS were significant prognostic factors for poorer RFS and OS. The prognostic model including STAS, VPI, VI and HS could effectively predict prognosis.

Mesothelioma patients rely on the information their clinical team obtains from medical imaging. Whether x-ray-based computed tomography (CT) or magnetic resonance imaging (MRI) based on local magnetic fields within a patient’s tissues, different modalities generate images with uniquely different appearances and information content due to the physical differences of the image-acquisition process. Researchers are developing sophisticated ways to extract a greater amount of the information contained within these images. This paper summarizes the imaging-based research presented orally at the 2018 International Conference of the International Mesothelioma Interest Group (iMig) in Ottawa, Ontario, Canada, held May 2-5, 2018. Presented topics included advances in the imaging of preclinical mesothelioma models to inform clinical therapeutic strategies, optimization of the time delay between contrast administration and image acquisition for maximized enhancement of mesothelioma tumor on CT, an investigation of image-based criteria for clinical tumor and nodal staging of mesothelioma by contrast-enhanced CT, an investigation of methods for the extraction of mesothelioma tumor volume from MRI and the association of volume with patient survival, the use of deep learning for mesothelioma tumor segmentation in CT, and an evaluation of CT-based radiomics for the prognosis of mesothelioma patient survival.

A number of key immune regulators show prognostic value in malignant pleural mesothelioma (MPM), but the association between Bridging integrator 1 (BIN1), indoleamine 2,3 dioxygenase 1 (IDO1) and patient outcome has not been investigated. We aimed to determine the expression of BIN1 and IDO1, their association with other markers and impact on overall survival (OS) in MPM.The expression of BIN1, IDO1, CD3, CD20 and CD68 were evaluated by immunohistochemistry in 67 patients who underwent pleurectomy/decortication. Survival analyses were performed using the Kaplan Meier method and significant biomarkers were entered into a Cox Regression multivariate model, accounting for known prognostic factors such as age, gender, histological subtype, PD-L1 expression and neutrophil-to-lymphocyte ratio.Immune markers were variably expressed in tumor cells, ranging from 0% to 100% for BIN1 (median: 89%), and 0% to 77.5% for IDO1 (median: 0%). Expression of markers of tumor-infiltrating lymphocytes (TILs) and macrophages ranged from 0% to more than 50%. BIN1 expression was high in 35 patients (51%) and was associated with increased OS (median: 12 vs 6 months for high and low BIN1 respectively,p = 0.03). Multivariate analysis showed BIN1 remained an independent prognostic indicator (HR 0.39; 95% CI: 0.18-0.82, p = 0.01). The majority of patients had immune inflamed tumors (77%) and there was a significant association between TILs and BIN1 (p = 0 0.01), PD-L1 (p=0.04) and CD68+ macrophages in the tumor (p 0.01). There were no significant associations between PD-L1 and BIN1 or IDO1.High BIN1 expression is a favorable prognostic biomarker and is associated with TILs in MPM.

The pathologist plays a central role in the diagnosis and management of malignant mesothelioma, including definitive tissue-based diagnosis in conjunction with clinical and radiographic data; diverse ancillary studies of diagnostic, prognostic, and predictive importance; and research efforts to better define the pathobiology of mesothelioma and develop novel clinical applications. The pivotal role of pathology in care of mesothelioma patients was on display at the recent meeting of the International Mesothelioma Interest Group (iMig) in Ottawa, Canada. This review summarizes the key findings of the "Molecular Pathways and Diagnosis in Malignant Mesothelioma" plenary session, including a large multi-institutional validation of a composite nuclear grading system for pleural mesothelioma, including incorporation of tumor necrosis as an additional independent prognostic factor; the correlation between nuclear grading in small biopsies and paired resection specimens in pleural mesothelioma; a multi-institutional study of important clinical and pathologic prognostic factors in peritoneal mesothelioma; the diagnostic role of HEG1 immunohistochemistry as a highly sensitive and specific marker of mesothelial lineage; the prevalence and diagnostic significance of MET protein overexpression in mesothelioma, as well as the correlation between MET protein overexpression and MET gene amplification; and the prognostic role of EZH2 protein overexpression in mesothelioma, together with data indicating an important pathogenic role for EZH2 in mesothelioma tumorigenesis. Special consideration is given to the convergence of diagnostic, prognostic, and predictive tools and their role in guiding highly personalized patient-centered management, and to the translation of novel research findings to practical techniques for routine pathologic practice.

Objectives Histologic diagnosis of malignant pleural mesothelioma (MPM) is not always straightforward. Loss of BRCA1-associated protein 1 (BAP1) expression as detected by immunohistochemistry (IHC) (BAP1 IHC) and homozygous deletion (HD) of 9p21 as detected by fluorescencein situ hybridization (FISH) (9p21 FISH) are effective for distinguishing malignant mesothelial proliferation from benign proliferation. We have previously reported that immunohistochemical expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, is correlated with the deletion status of 9p21 FISH in MPM tissues. In this study, we investigated whether a combination of MTAP and BAP1 IHC could distinguish sarcomatoid MPM from fibrous pleuritis. Materials and Methods We examined IHC expressions of MTAP and BAP1 and 9p21 FISH in sarcomatoid/desmoplastic (n = 18) and biphasic MPM (n = 12) and in fibrous pleuritis (n = 17). In biphasic MPM, only sarcomatoid components were evaluated for IHC and FISH. The sensitivity and specificity of each detection assay for discriminating MPM cases from fibrous pleuritis was determined. In addition, we compared the IHC expression of MTAP with the deletion status of 9p21 FISH. Results MTAP IHC and BAP1 IHC showed 80% and 36.7% sensitivity, respectively, and both showed 100% specificity in differentiating MPM from fibrous pleuritis. A combination of MTAP and BAP1 IHC yielded greater sensitivity (90%) than that detected for MTAP IHC alone or BAP1 IHC alone. Moreover, a high degree of concordance was observed between the results of MTAP IHC and HD of 9p21 FISH (κ = 0.63). Conclusions With an accurate interpretation of results, combined MTAP and BAP1 IHC is a reliable and effective method for distinguishing sarcomatoid MPM from fibrous pleuritis.

Objectives Several studies have demonstrated the promise of continuation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) beyond progression in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). The aim of the present study is to clarify the efficacy of continuation of gefitinib in patients with NSCLC beyond progression. Materials and methods A total of 50 patients with EGFR-mutant NSCLC who progressed based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria during gefitinib treatment were eligible. The primary endpoint was progression-free survival-2 (PFS2; time from first gefitinib dose to off-gefitinib progression). Secondary endpoints were PFS1 (time from first gefitinib dose to RECIST 1.1 progression); the difference between PFS2 and PFS1 (PFS2-PFS1); overall survival (OS); and safety. Patients received gefitinib 250 mg/d orally until symptomatic progression or at the investigator’s discretion. Results Between January 2016 and March 2017, 50 patients were enrolled in this study. One patient withdrew consent, leaving a total of 49 patients to be evaluated. The median PFS2-PFS1 was 5.1 months (95% CI, 2.5–7.8), and the median PFS2 was 27.7 months (95% CI, 21.6–33.9). Twelve patients (24.4%) continued gefitinib therapy for 14 months (median value, range 7.2–20.3 months) after RECIST 1.1 progression. The median OS was not reached. Patients were classified by the characteristics of progression at the time of enrollment. PFS2-PFS1 was significantly shorter in patients with pleural metastasis or pleural effusion compared with the other types of progression (1.8 months vs. 7.1 months, p-value = 0.005). Conclusion In patients with EGFR-mutant NSCLC who experience progression, it is beneficial to maintain gefitinib treatment with local treatment such as radiotherapy until symptomatic progression. However, in patients with pleural metastasis or effusion, continuation of gefitinib beyond progression should be carefully determined on a case by case basis.

This study of a large, contemporary national database evaluated postoperative outcomes and overall survival (OS) for malignant pleural mesothelioma (MPM) by facility volume.The National Cancer Database was queried for newly-diagnosed non-metastatic MPM undergoing definitive surgery (extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)). Patients were dichotomized into those receiving therapy at a high-volume facility (HVF), defined a priori at the 90th percentile of case volume, with all others categorized as lower-volume facilities (LVFs). Statistics included multivariable logistic regression, Kaplan-Meier analysis, propensity-matching, and multivariable Cox proportional hazards modeling. Sensitivity analysis varied the dichotomized HVF-LVF cutoff and evaluated effects on postoperative outcomes and OS.Of 1307 patients, 621 (48%) were treated at LVFs and 686 (52%) at HVFs. HVFs were more often in the Middle/South Atlantic regions, and less likely in New England, South, and Midwest. Notably, 75% of procedures at HVFs were P/Ds, versus 84% at LVFs (p 0.001). Patients treated at HVFs experienced shorter length of postoperative hospitalization (p = 0.035), lower 30-day readmission rates (4.6% vs. 6.1%, p = 0.021), and lower 90-day mortality rates (10.0% vs. 14.6%, p = 0.029). Median OS for respective groups were 18 versus 15 months (p = 0.010), which were not significant following propensity-matching (p = 0.540). On multivariable analysis, facility volume did not independently predict for OS. Sensitivity analyses confirmed the postoperative outcomes and OS findings.This is the largest investigation to date assessing facility volume and outcomes following surgery for MPM. Although no independent effects on OS were observed, postoperative outcomes were more favorable at HVFs. These findings have implications for postoperative management, patient counseling, referring providers, and cost-effectiveness.

The 8th edition of malignant pleural mesothelioma (MPM) American Joint Committee on Cancer (AJCC) staging system has been published. The current analysis aims to evaluate its performance in a population-based setting among patients recorded within the surveillance, epidemiology and end results (SEER) database.SEER database (2004-2013) has been accessed through SEER*Stat program and AJCC 8th edition stage groups were reconstructed. Survival analyses (overall and cancer-specific) were conducted according to 6th and 8th editions through Kaplan-Meier analysis. Cox-regression multivariate model was also utilized for pair wise comparisons between different prognostic groups for overall and cancer-specific survival.A total of 5382 patients with MPM were identified in the period from 2004 to 2013. According to the 6th edition, significant pair wise P values for overall survival included: IA vs. III (P=0.027); IA vs. IV: P0.0001; IB vs. IV: P0.0001; II vs. III: P0.0001; II vs. IV: P0.0001; III vs. IV: P0.0001). According to the 8th edition, significant pair wise P values for overall survival included: all stages vs. IV: P0.0001; IA vs. II: P=0.046; IA vs. IIIA: P=0.022; IA vs. IIIB: P0.0001; IB vs. II: P0.0001; IB vs. IIIB: P0.0001; II vs. IIIA: P0.0001; IIIA vs. IIIB: P0.0001). C-index for 6th edition was 0.539 (SE: 0.008; 95% CI: 0.524-0.555); while C-index for 8th edition was 0.540 (SE: 0.008; 95% CI: 0.525-0.556). Based on the above findings, a simplified staging system was proposed and overall and cancer-specific survivals were evaluated according to the simplified system. For overall and cancer-specific survival assessment, P values for all pair wise comparisons among different stages were significant (0.01).The prognostic performance of both the 6th and 8th AJCC editions is unsatisfactory; there is a need for a more practical and prognostically relevant staging system for MPM.

Objectives The relationship between transthoracic needle biopsy (TTNB) and pleural recurrence of cancer after curative lung resection remains unclear. We aimed to assess whether TTNB increases the ipsilateral pleural recurrence (IPR) rate and identify other potential risk factors for pleural recurrence after surgery. Materials and methods This retrospective study included 392 patients with p-stage I non-small cell lung cancer with solid or part-solid nodules after curative lung resection in 2009–2010. Imbalances among the characteristics were adjusted using an inverse probability-weighted method based on propensity scoring. Multivariate Cox’s regression analysis and the Kaplan-Meier method were used to determine independent risk factors for IPR. Results A total of 243 (62%) patients received TTNB, while 149 (38%) underwent an alternate, or no, diagnostic technique. IPR was significantly more frequent in the TTNB group (p = 0.004), while total recurrence was similar between the groups (p = 0.098). After applying the weighted model, diagnostic TTNB (hazard ratio [HR], 5.27; 95% confidence interval [CI], 1.49–18.69; p = 0.010), microscopic visceral pleural invasion (HR, 2.76; 95% CI, 1.08–7.01; p = 0.033) and microscopic lymphatic invasion (HR, 3.25; 95% CI, 1.30–8.10; p = 0.012) were associated with an increased frequency of IPR. Among patients who received TTNB, microscopic lymphatic invasion was a risk factor for IPR (HR, 2.74; 95% CI, 1.10–6.79; p = 0.030). Conclusions The diagnostic TTNB procedure is associated with pleural recurrence but may be unrelated to overall recurrence-free survival in early lung cancer. Moreover, microscopic lymphatic invasion could be a risk factor for pleural recurrence. TTNB should be carefully considered before lung resection and close follow-up to detect if pleural recurrence is needed.

A small proportion of patients with malignant pleural mesothelioma (MPM) achieve pathological complete response (CR) following treatment with current practice induction chemotherapy. Our analysis of 58 patients with MPM treated with platinum-based chemotherapy showed 4 patients (7%) attained pathological CR at subsequent extrapleural pneumonectomy (EPP). Patient and tumour factors such as age, gender, smoking habit, histological subtype, and clinical stage were not found to be associated with pathological CR. Patients with pathological CR had longer disease-free survival (29.2 vs. 13.8 months; p = 0.08) and overall survival (76.4 vs. 23.4 months; p = 0.06) but this did not reach statistical significance. Our study suggests that patients who achieve pathological CR after chemotherapy may have improved survival in MPM.

Objectives Pleural invasion has been recognized as an important negative prognostic factor in non-small cell lung cancer (NSCLC), and therefore, accurate evaluation is required. However, when the visceral pleura adheres to the parietal pleura around a tumor and parietal pleural structures are destroyed and unrecognizable as a result of inflammation, it is often difficult to accurately evaluate pleural invasion, and classification of the T stage is unclear. To aid in categorization, we defined this status as pl1-3 and investigated the prognostic impact of the pl1-3 status on NSCLC. Materials and methods We retrospectively examined the clinicopathological characteristics and prognoses of 929 NSCLC patients who underwent curative surgical resection. The pl1-3 status was defined as invasion beyond the elastic layer of the visceral pleura (pl1 or higher) but showing unclear parietal pleural invasion. We compared the prognoses of pl1-3 status NSCLC patients with that of patients with other pleural invasion statuses. Results Thirty-one patients (3%) had a pl1-3 status. The 5-year overall survival rate for pl1-3 patients was 58.9%, and the prognosis was significantly worse than pl1 (p = 0.04). In pN0 cohort, pl1-3 disease had a significantly worse prognosis than pl1 and pl2 diseases (p = 0.01 and 0.04, respectively) and a similar prognosis to pl3 disease. Furthermore, similar relationships were also observed after adjusting for other prognostic factors in multivariate analysis. Among the pl1-3 and pN0 patients, 11 (46%) developed recurrences (9 patients had distant metastasis, one had local recurrence, and one had both). Although the proportion of pl1-3 patients who underwent adjuvant therapy was similar to that of T3 patients, more individuals received oral tegafur-uracil treatment than intravenous chemotherapy. Conclusion These results indicate that pl1-3 patients can be managed in the same manner as patients with T3 and pl3 disease. These results may be informative for treatment decisions during postoperative chemotherapy.

Objectives Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is still challenging. Detection of homozygous deletion (HD) of 9p21 region including p16 INK4A ( p16 ) by fluorescence in situ hybridization (FISH) and immunohistochemical detection of loss of BRCA1 associated protein 1 (BAP1), are reliable markers for MPM diagnosis. However, not all laboratories are equipped to perform 9p21 FISH; immunohistochemistry (IHC) is a more common and feasible technique. Thus, we sought to develop a IHC-based method that could predict the deletion of p16 in MPM in concordance with 9p21 FISH. Materials and methods We examined the expression of the 9p21.3-related proteins (p14, p15, p16, and methylthioadenosine phosphorylase (MTAP)) and BAP1 using IHC in 51 MPM and 25 RMH cases, and assessed their correlation with HD of p16 detected by FISH. The diagnostic usefulness of IHC of the 9p21.3-related proteins and BAP1 and their combinations was assessed using the cut-off values set by receiver operating characteristic (ROC) analysis. Results Among the 9p21.3-related proteins, MTAP IHC findings showed best concordance with 9p21 FISH results (kappa coefficient of 0.69) and a specificity of 100%. We also examined the combinations of MTAP IHC with the other products. The loss of p16 and MTAP had better concordance (kappa coefficient of 0.71), although lower specificity (85%). For differentiating MPM from RMH, only MTAP showed 100% specificity among the 9p21.3-related proteins, as did BAP1 IHC and 9p21 FISH. Among BAP1 combinations, only that of BAP1 with MTAP showed 100% specificity. Its sensitivity was 76.5%, which was lower than BAP1 IHC and 9p21 FISH combination (84.3%), but higher than BAP1 IHC alone (60.8%) or 9p21 FISH alone (60.8%). Conclusions A combination of MTAP or BAP1 loss detected by IHC can likely detect MPM with good sensitivity and 100% specificity, and serve as useful ancillary IHC for discriminating MPM from RMH.

Objectives Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM. Methods This open-label multicentre phase II trial [NCT01769547] enrolled fit, consenting adult patients with advanced MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Dovitinib was administered orally at 500 mg/day for 5 days on, 2 days off, in 28-day cycles. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. The primary end-point was the proportion of patients progression-free at 3 months (PF3) using a two-stage design. Results 12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1–8). One unconfirmed partial response was observed. PF3 was 50% (95% confidence interval 28.4% to 88.0%); although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population. One of 12 tumour specimens had low amplification of FGFR-1. Conclusions Dovitinib has minimal activity in previously-treated MPM. The role of the FGFR pathway in MPM remains unclear.

Objectives Homozygous deletion (homo-d) of the p16 (CDKN2A) gene, as determined by fluorescence in situ hybridization (FISH), helps differentiate malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH). Heterozygous deletion (hetero-d) has also been identified variably in p16 FISH. This study aimed to investigate the significance of homo-d and hetero-d of p16 in the diagnosis and prognosis of MPM. Materials and methods p16 FISH was performed in 93 MPMs and 47 RMHs. Real-time polymerase chain reaction (PCR) and methylation specific PCR (MSP) were also performed for cases in which DNA was available. Overall survival (OS) was assessed via the Kaplan-Meier method and logrank test. Results Cutoff values for homo-d and hetero-d were set at 10% and 47%, respectively, based on p16 FISH results in RMH. In MPM, 80/93 (86.0%) were homo-d positive, and 15/93 (16.1%) were hetero-d positive. No RMH was homo/hetero-d positive. In nine cases of MPM with the low homo-d ( 47%) pattern, FISH with a shorter probe caused a slight increase (from 20.1% to 26.5%) in the mean percentage of homo-d and a decrease in that of hetero-d (from 59.6% to 55.6%). Four cases in which the low homo-d/high hetero-d pattern was maintained with the shorter probe were further analyzed by real-time PCR, which separated them into a two (n = 2) or one allele deletion group (n = 2). MSP revealed no promoter methylation in the two cases with one allele deletion. The OS was significantly shorter in homo-d positive cases (n = 24) than homo-d negative cases (n = 5, p = 0.0002) in the 29 MPM cases with follow-up data. Also, low homo-d/high hetero-d cases (n = 5) had a significantly better prognosis than high homo-d (≥30%) cases (n = 17, p = 0.011). Conclusions Within p16 homo-d positive MPMs with poorer prognosis, the low homo-d/high hetero-d pattern may belong to a better prognostic subgroup in homo-d positive MPMs.

Introduction Peritoneal metastasis from lung cancer is an uncommon clinical event and there are limited data on what factors predict peritoneal progression. This study retrospectively investigated whether patterns of metastatic spread and oncogene status in patients with advanced non-small cell lung cancer (NSCLC) are associated with peritoneal metastasis. Methods Patients with metastatic non-squamous NSCLC (n = 410) were identified at the University of Colorado Cancer Center. Sites of metastatic disease and baseline oncogene status (EGFR, ALK, KRAS, or triple negative) were documented via a retrospective chart review. In patients with EGFR mutations who developed peritoneal disease, we documented the presence of known resistance mechanisms. Median time to peritoneal metastasis, time from peritoneal disease to death, and overall survival were collected. Results Eight percent (33/410) patients in this study developed peritoneal metastasis. Malignant pleural disease at baseline was significantly associated with subsequent peritoneal spread. There was no association between oncogene status and peritoneal metastasis. Three patients with EGFR mutations who developed peritoneal metastasis had documented resistance to tyrosine kinase inhibitors (TKIs) in the ascitic fluid. Median time from stage IV disease to peritoneal metastasis was 16.5 months (range 0.6–108 months). There were no differences in overall survival between patients who developed peritoneal metastasis and those who did not. Conclusions Malignant pleural disease is highly associated with peritoneal metastasis in patients with advanced NSCLC. The underlying mechanism is not clear. The presence of resistance mutations in ascitic fluid implies that poor drug penetration is unlikely to be the dominant mechanism. Despite being a late clinical finding, there were no differences in overall survival between patients who developed peritoneal metastasis and those who did not. Additional studies exploring treatment related factors in patients with malignant pleural disease that can reduce risk of peritoneal metastasis are warranted.

Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3K pathway and PD-L1 in MPM and its relationship with the patient́s prognosisTwenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3K pathway and PD-L1 RESULTS: Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p 0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3K pathwayThis study shows PTEN/PI3K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3K pathway in MPM.

Introduction: Pleural mesothelioma has a dismal prognosis and is refractory to local treatment. Combination chemotherapy can increase median survival by several months and was gradually introduced in the period 2003-2006. Elderly patients may be unfit for chemotherapy but little is known about age-related treatment practice. To determine treatment patterns and current survival outcome, three large population-based registries were queried in a uniform manner. Methods: Data from the Belgian Cancer Registry, the Netherlands Cancer Registry and the UK National Lung Cancer Audit were analyzed for patients diagnosed with pleural mesothelioma since 2007. Treatment patterns and survival rates were compared between countries and age-groups. Results: The study included 900, 2306 and 5808 patients from Belgium, the Netherlands and England, respectively. Fifty-nine percent of patients were 70 years or older and 84% were men. Chemotherapy use decreased with advancing age and was used more often in Belgium (60%) than in the Netherlands (41%) and England (37%). For patients aged 70-79 years, chemotherapy use was 55%, 36% and 34% in the respective countries. Median survival was 10.7 months in Belgium versus 9.2 months for the Netherlands and 9.5 months for England. Survival rates decreased with advancing age. On average, median survival was 5.6 months longer for patients treated with chemotherapy, irrespective of age. Conclusions: Combined analysis of data from three countries with high mesothelioma rates demonstrates that chemotherapy has become standard treatment for younger patients. Elderly patients currently account for more than half of all cases and less toxic treatment options will be required to improve their prospects. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Introduction and methods Malignant pleural mesothelioma (MPM) is an uncommon cancer with poor survival. We have used data collected for the UK National Lung Cancer Audit to assess current practice and to highlight regional variation in the management of mesothelioma patients, as well as to describe survival patterns in subgroups. Results Our data on 8740 cases seen in hospitals in England and Wales is the largest cohort of MPM in the literature and represents approximately 80% of the total incident cases. 83% are male and median age is 73 years. Performance status is recorded in 81% and of these approximately 70% are PS 0–2. Stage is poorly recorded and unreliable in this dataset. The patient pathway is similar to lung cancer with approximately one-fifth having a non-elective referral to secondary care. A histo-cytological diagnosis is made in 87% and varies across organisations. Only 67% have anti-cancer treatment, and this also varies across organisations, but there has been an annual increase in the proportion receiving chemotherapy. Overall median survival was 9.5 months, with a 1YS of 41.4% and 3YS of 12.0%, but was strongly linked to performance status and histological subtype. Median survival also varied by cancer network from 209 days to 349 days, but appeared to increase from of 9.2 months in 2008 to 10.5 months in 2012. Conclusion Our data provide a large scale, detailed assessment of MPM epidemiology, treatment choices and outcomes. Incidence is increasing in line with predictions and uptake of treatments has generally mirrored publication of key MPM treatment trials, in particular increasing use of chemotherapy but low uptake of radical surgery. However, there is significant variation in care patterns and outcomes that may reflect limited expertise in area with low incidence. Initiatives to improve outcomes should include improved recording of clinical stage.

Pleuropulmonary angiosarcomas are very rare, with less than fifty cases reported in the literature. In most cases, the etiology is unknown but the presence of a chronic tuberculous pyothorax has been reported in several Asian case reports as a possible risk factor. We report the case of a Caucasian 68-year old man who presented with a pleuropulmonary angiosarcoma that arose from a chronic tuberculous pyothorax and which involved the ribs and the vertebrae, the psoas muscle, and the jejunum. The patient received adapted anti-tuberculosis treatment, embolization of the mass in the small bowel, palliative external beam radiotherapy on the spine and systemic chemotherapy with liposomal non-pegylated doxorubicin and ifosfamide. With this multidisciplinary approach the patient‘s symptoms were well controlled and he achieved a complete metabolic response after six cycles of chemotherapy. Unfortunately, the patient died after eight months from the beginning of chemotherapy due to an acute lung injury secondary to extensive bilateral interstitial infiltrates. Opportunistic pathogens or drug-induced lung toxicity were the most probable causes. Treatment with liposomal non-pegylated doxorubicin and ifosfamide could be a reasonable option in pleuropulmonary angiosarcoma but it should be validated in clinical trials. Chronic pyothorax seems to be a predisposing factor for the development of pleural angiosarcoma but further investigations are required to assess a causal association.

Background Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood. Patients and methods Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR , KRAS , BRAF , PIK3CA , NRAS , MEK1 , AKT1 , PTEN , and HER2 and amplifications in EGFR , MET , PIK3CA , FGFR1 , and FGFR2 . In addition, 21 patients' samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes. Results Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients' samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc. ) by deep sequencing. Conclusions Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance.

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. EMX2 is a homeobox transcription factor that may regulate key developmental pathways known to promote tumorigenesis. In this study, we evaluated the prognostic and predictive significance of EMX2 expression in MPM.Fifty surgically resected MPM specimens were studied. Quantitative real-time RT-PCR was used to analyze EMX2 mRNA expression. Association of EMX2 levels with clinical outcomes was evaluated with using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model.EMX2 expression was significantly associated with IMIG stage (p0.001) and smoking history (p=0.006). Cox hazard regression modeling identified low-EMX2 expression as a negative prognostic factor in progression-free survival by both univariate (p=0.002) and multivariate analysis (p=0.002). Kaplan-Meier analysis revealed significant differences in progression-free survival between low- and high-EMX expressing groups in all patients (p=0.001), and also when grouped by early (I/II) stage disease (p0.001), patients undergoing pleurectomy (p0.001) and patients with an epitheliod subtype (p0.004). Furthermore, EMX2 expression predicted response to neoadjuvant chemotherapy. High-EMX2 expression was associated with decreased progression-free survival after neoadjuvant therapy, suggesting that induction therapy should be avoided in these patients.EMX2 expression is downregulated in advanced cases of malignant pleural mesothelioma and may serve as an important prognostic and predictive molecular biomarker of progression-free survival.

Background Malignant pleural mesothelioma (MPM) is a locally aggressive disease with a poor prognosis. After failure of first line platinum-based chemotherapy, there is no widely approved salvage regimen. New strategies for treatment are needed and phase 1 trials appear as a rationale alternative. Materials and methods MPM patients were enrolled in 20 different phase 1 trials between March 2005 and January 2012, and their data analyzed retrospectively. The primary endpoint was response rate and secondary endpoints were toxicity profile, overall survival (OS) and progression free survival (PFS). OS and PFS were estimated using Kaplan–Meier and their association with baseline characteristics was investigated through a log-rank test. The drugs described were divided into 5 groups based on their mechanism of action. Results Forty-five patients were analyzed with a median follow up of 20.5 months. The best tumor response was as follows: 4% of patients had a RECIST partial response, 60% had stable disease, 24% had progressive disease and 11% were not evaluable. Grade ≥3 toxicities were observed in 19 (42%) patients. Median OS and PFS were estimated to 6 months (95% CI = [4.2–10.5]) and 2 months (95% CI = [1.3–2.7]), respectively. The cellular motility inhibitors group appeared as the most promising class to be developed in a phase 2 setting. Conclusion Including MPM patients in phase I trials beyond first line of treatment can result in modest clinical benefits with an acceptable toxicity profile. Several molecular pathways involved in MPM have been identified and further novel biologic therapies need to be tested.

Pemetrexed-cisplatin is the only FDA-approved regimen for malignant pleural mesothelioma (MPM), and the impact on survival is modest. No drugs have been shown to improve survival as second-line therapy, yet vinorelbine and gemcitabine are prescribed based on the results of small phase II trials. To augment the existing limited data, we examined our institutional experience with vinorelbine and gemcitabine in patients with previously treated MPM.We reviewed charts of patients with MPM treated with vinorelbine and/or gemcitabine as second- or third-line therapy between 2003 and 2010. Toxicity was graded according to the Common Terminology Criteria for Adverse Events Version 4.0. CT scans were reviewed with a reference radiologist according to modified RECIST criteria.Sixty patients were identified: 33 treated with vinorelbine, 15 gemcitabine, and 12 both agents. Eighty-three percent initially received pemetrexed-platinum. Toxicity was substantial: 46% experienced at least one episode of grade 3-4 toxicity. Of 56 patients evaluable radiologically, there was 1 partial response (gemcitabine) giving a response rate of 2% (95% CI: 0-10%). Forty-six percent had stable disease. Median progression free survival was 1.7 months for vinorelbine and 1.6 months for gemcitabine. Median overall survival was 5.4 and 4.9 months, respectively.Response to second- or third-line vinorelbine or gemcitabine is rare. The high rate of stable disease warrants the continued use of these agents in this setting, though the impact on survival is questionable. These data justify the choice of placebo control arms in randomized trials of novel agents in previously treated patients.

Radiotherapy is commonly used to treat pain in malignant pleural mesothelioma (MPM). The purpose of this systematic review is to examine the evidence for this practice. Medline (1946-2013), Embase (1974-2013) and Central (The Cochrane Library Issue 9, 2012) databases were searched. Eligible studies met the following criteria: MPM (histological or radiological diagnosis), radiotherapy given with the intent of improving pain, response rates to radiotherapy reported, dose and fractionation reported and the relationship between radiotherapy and pain response explored. All studies had independent review and were graded according to evidence level. Eight studies met the eligibility criteria. Two studies were prospective single arm phase II studies while the remainder were retrospective case series. All were graded as either Level 2 or Level 3 evidence. Due to marked heterogeneity among studies, quantitative synthesis of results was not possible. No high quality evidence currently exists to support radiotherapy in treating pain in MPM. Studies focusing on clear pain endpoints and improving target delineation are needed. Such studies should also use modern radiotherapy techniques and concentrate on dose escalation.

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP). Materials and methods: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined. Results: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 degrees C which was the mean 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P = 0.03) or HVs (P < 0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77. Conclusions: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM.

Objective 23% of mesothelioma tumor specimens have a mutation in the BRCA1-associated protein 1 (BAP1) gene and germline BAP1 mutations predispose to malignant pleural mesothelioma (MPM). Our aim was to investigate germline BAP1 mutations in sporadic MPM patients. Materials and methods Exonic DNA from peripheral blood leucocytes of 78 MPM patients was screened for germline BAP1 mutation. Results One out of 78 patients showed a germline synonymous mutation in exon 11. In all other patients wild-type sequence without any single-nucleotide polymorphisms was detected. Conclusions Taking into account previous similar screenings, the prevalence of germline BAP1 mutations in sporadic MPM patients can be estimated around 1–2%, suggesting a minor role of germline BAP1 mutation in the pathogenesis of sporadic MPM.

Imaging of malignant pleural mesothelioma (MPM) is essential to the diagnosis, assessment, and monitoring of this disease. The complex morphology and growth pattern of MPM, however, create unique challenges for image acquisition and interpretation. These challenges have captured the attention of investigators around the world, some of whom presented their work at the 2012 International Conference of the International Mesothelioma Interest Group (iMig 2012) in Boston, Massachusetts, USA, September 2012. The measurement of tumor thickness on computed tomography (CT) scans is the current standard of care in the assessment of MPM tumor response to therapy; in this context, variability among observers in the measurement task and in the tumor response classification categories derived from such measurements was reported. Alternate CT-based tumor response criteria, specifically direct measurement of tumor volume change and change in lung volume as a surrogate for tumor response, were presented. Dynamic contrast-enhanced CT has a role in other settings, but investigation into its potential use for imaging mesothelioma tumor perfusion only recently has been initiated. Magnetic resonance imaging (MRI) and positron-emission tomography (PET) are important imaging modalities in MPM and complement the information provided by CT. The pointillism sign in diffusion-weighted MRI was reported as a potential parameter for the classification of pleural lesions as benign or malignant, and PET parameters that measure tumor activity and functional tumor volume were presented as indicators of patient prognosis. Also reported was the use of PET/CT in the management of patients who undergo high-dose radiation therapy. Imaging for MPM impacts everything from initial patient diagnosis to the outcomes of clinical trials; iMig 2012 captured this broad range of imaging applications as investigators exploit technology and implement multidisciplinary approaches toward the benefit of MPM patients.

The type of surgery (radical pleurectomy (RP) vs. extrapleural pneumonectomy (EPP)) remains controversial for malignant pleural mesothelioma (MPM). Macroscopic complete resection (MCR) is a key prognostic factor. It is unclear, if patients undergoing incomplete RP within a standardized multimodality treatment protocols have any advantage in terms of survival and if EPP could theoretically have avoided incomplete resections (R2).Eighty-eight patients underwent RP followed by chemoradiation from 2002 to 2011 within a prospective multimodality treatment study at a single institution. MCR were compared to R2 within this patient cohort retrospectively. EPP eligibility was assessed retrospectively based on preoperative cardiopulmonary testing and theoretical feasibility to achieve MCR. Kaplan-Meier analyses, log-rank test and Cox regression analyses were used to estimate survival and to determine predictors of survival.For the complete patient cohort, median survival (MS) was 26.3 months (mo). MCR could be achieved in 64.8% (57/88). Compared to MCR patients, R2-patients (n = 31, 35.2%) had an inferior overall survival (MS 13 vs. 33 mo, P.0001), shorter progression-free-survival (MS 9 vs. 16 mo, P.0001) and inferior survival after disease progression (MS 4 vs. 11 mo; P.0001), respectively. R2 was associated with advanced p-T-Status (P.0001), p-N-Status (P = 0.046) and p-IMIG stage (P.0001). No difference could be observed with regard to age, histology, laterality, surgical morbidity and mortality, respectively. Only 3 out of 88 patients (3.4%) would have been eligible for EPP to achieve MCR. Not resectable T4-disease and impaired cardiopulmonary reserves were the main reasons for ineligibility for EPP in 35.5% (11/31) and 48.4% (15/31), respectively.R2 in patients undergoing RP is associated with inferior outcomes. Only very selected cases would have qualified for EPP to achieve MCR. EPP might be an important surgical extension in selected patients to achieve MCR. There is a need for further investigation of effective intrapleural additive treatment options for patients undergoing R2.

Malignant pleural mesothelioma (MPM) is resistant to conventional treatments. Novel, targeted treatments are hampered by the relative lack of MPM-associated tumour antigens. The aim of this study was to evaluate the level of expression and the relevance of 5T4 as a tumour-associated antigen in MPM. 5T4 expression was assessed by Western blotting, flow cytometry, immuno-cytochemistry and -histochemistry in 11 mesothelioma cell lines, 21 tumour biopsies, and ex vivo tumour cells obtained from the pleural fluid (PF) of 10 patients. 5T4 antibody levels were also determined in the plasma of patients and healthy donors. The susceptibility of MPM cells to 5T4-specific T-cell-mediated killing was determined using an HLA-A2(+), CD8(+) T-cell line, developed against the 5T4(17-25) peptide. We report here that cell surface 5T4 expression was detected in all mesothelioma cell lines and PF cell samples. Mesothelin and CD200, a suggested mesothelioma marker, were co-expressed with 5T4 on tumour cells in PF. Immunohistochemistry confirmed overexpression of 5T4, similar to mesothelin, on tumour cells but not on reactive stroma in all tissue sections tested. Median 5T4 antibody levels were 46% higher in patient than in healthy donor plasma, indicating immune recognition. Importantly, 5T4-specific CD8(+) T-cells were able to kill four out of six HLA-A2(+) MPM cell lines but not an HLA-A2(-) cell line, demonstrating immune recognition of MPM-associated 5T4 antigen at the effector T-cell level. We conclude that 5T4 is a potential new antigen for targeted therapies such as immunotherapy in MPM, as it is overexpressed on mesothelioma cells and recognised by 5T4-specific cytotoxic T-cells. Our findings have been translated into a Phase II clinical trial applying 5T4-targeted therapies in MPM patients.

Background Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM. Patients and methods Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil–lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis. Results Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p =0.04) and overall survival (OS: 23.4 vs 5.6 months; p =0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p =0.004). In multivariate analysis, histology and NLR were independent prognostic factors ( p =0.02 and p =0.04 respectively), but pS6 only showed a trend ( p =0.8). Conclusions This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.

Two patients with rare sites of metastatic pleural mesothelioma are presented and the literature on similar cases is examined. One patient developed colonic metastases from a sarcomatoid mesothelioma. Another patient with epithelioid mesothelioma developed perineal metastases.

Background Pemetrexed in combination with cisplatin (Pem/Cis) is the only approved chemotherapeutic regimen for malignant pleural mesothelioma (MPM). At the time of launch, limited safety information was available. The purpose of this postmarketing all-case registry study was to investigate the safety and effectiveness of pemetrexed in patients with MPM. Methods From January 2007 to May 2008, MPM patients to be treated with pemetrexed in Japan were registered to this study to monitor its safety and effectiveness. Supply of pemetrexed was restricted to institutions with experienced medical oncologists based on predetermined criteria. Results Of 953 patients registered, data from 903 patients were eligible for analysis. Most patients were male, with median age of 65 years and 68.5% had a history of asbestos exposure. More than 90% of patients received the first cycle of Pem/Cis treatment; median number of treatment cycles was 4.0. Treatment-associated death was reported in 0.8% of patients. The incidence of Interstitial lung disease (ILD) associated with Pem/Cis during the observation period was 0.9%. The frequency of ILD in patients with pre-existing asbestosis was higher than that in patients without it. For tumor response, the overall response rate was 25.0% (95% confidence interval (CI): 22.2–28.0%). The six-month survival rate estimated by the Kaplan–Meier method was 75.9%. Conclusions This large scale all case registry study appeared to have enrolled a major portion of Japanese MPM patients. Treatment with pemetrexed was generally well tolerated and showed safety and effectiveness comparable to prior clinical trials.

Identification of new markers for malignant pleural mesothelioma (MPM) is a challenging clinical need. Here, we propose a quantitative proteomics primary screen of the cell surface exposed MPM N-glycoproteins, which provides the basis for the development of new protein-based diagnostic assays. Using the antibody-independent mass-spectrometry based cell surface capturing (CSC) technology, we specifically investigated the N-glycosylated surfaceome of MPM towards the identification of protein-marker candidates discriminatory between MPM and lung adenocarcinoma (ADCA). Relative quantitative CSC analysis of MPM cell line ZL55 in comparison with ADCA cell line Calu-3 revealed a bird's eye view of their respective surfaceomes. In a secondary screen of fifteen MPM and six ADCA, we used high throughput low density microarrays (LDAs) to verify specificity and sensitivity of nineteen N-glycoproteins overregulated in the surfaceome of MPM. This proteo-transcriptomic approach revealed thy-1/CD90 (THY1) and teneurin-2 (ODZ2) as protein-marker candidates for the discrimination of MPM from ADCA. Thy-1/CD90 was further validated by immunohistochemistry on frozen tissue sections of MPM and ADCA samples. Together, we present a combined proteomic and transcriptomic approach enabling the relative quantitative identification and pre-clinical selection of new MPM marker candidates.

Introduction The National Institute for Health and Clinical Excellence (NICE) has previously recommended pemetrexed plus cisplatin for the treatment of patients with advanced malignant pleural mesothelioma (MPM) and WHO performance status 0–1. Subsequent to this appraisal, randomised controlled trial (RCT) data for raltitrexed plus cisplatin and comparing chemotherapy to active symptom control (ASC) has become available, allowing a more complete analysis of the comparative efficacy and cost-effectiveness of first-line chemotherapy in MPM. Methods An adjusted indirect comparison is used to estimate the relative efficacy of raltitrexed plus cisplatin and pemetrexed plus cisplatin. A cost-effectiveness model is used to assess the lifetime costs and health outcomes associated with these comparators and ASC. Patient level data from the EORTC 08983 trial are used to estimate baseline progression and survival rates. Relative treatment effects are taken from RCTs; cost and utility data from the literature. Results Raltitrexed plus cisplatin and pemetrexed plus cisplatin were not found to be statistically significantly different with respect to overall response, progression free survival or overall survival. The cost-effectiveness analysis found raltitrexed plus cisplatin to be cost-effective at a cost per quality adjusted life year of £13,454 compared to cisplatin and £27,360 compared to ASC. Pemetrexed plus cisplatin is dominated by raltitrexed plus cisplatin as the raltitrexed combination offers marginally higher quality adjusted life years (QALYs) and life years (LYs) at a substantially lower total cost. Conclusion Raltitrexed plus cisplatin is a cost-effective first-line treatment for MPM. This conclusion was maintained across a number of sensitivity analyses.