Biomarkers For Malignant Pleural Mesothelioma Research Articles

P2.01-034 The Pregnancy Associated Endometrial Protein Glycodelin as a Biomarker for Malignant Pleural Mesothelioma

P2.01-034 The Pregnancy Associated Endometrial Protein Glycodelin as a Biomarker for Malignant Pleural Mesothelioma

MicroRNA Expression in Malignant Pleural Mesothelioma and Asbestosis: A Pilot Study.

Background The identification of diagnostic/prognostic biomarkers for asbestos-related diseases is relevant for early diagnosis and patient survival and may contribute to understanding the molecular mechanisms underlying the disease development and progression. Aims To identify a pattern of miRNAs as possible diagnostic biomarkers for patients with malignant pleural mesothelioma (MPM) and asbestosis (ASB) and as prognostic biomarkers for MPM patients. Methods miRNA-16, miRNA-17, miRNA-126, and miRNA-486 were quantified in plasma and formalin-fixed paraffin-embedded samples to evaluate their diagnostic and prognostic roles compared to patients with other noncancerous pulmonary diseases (controls). Results. The expression of all the miRNAs was significantly lower in patients with MPM and ASB than that in controls. miRNA-16, miRNA-17, and miRNA-486 in plasma and tissue of MPM patients were significantly correlated. Furthermore, the expression of miRNA-16 in plasma and tissue, and miRNA-486 only in tissue, was positively related with cumulative survival in MPM patients. Conclusions All the miRNA levels were decreased in patients with MPM or ASB, supporting the role of circulating miRNAs as a potential tool for diseases associated with exposure to asbestos fibers. miRNA-16 was directly related to MPM patient prognosis, suggesting its possible use as a prognostic marker in MPM patients.

Elevated aspartate aminotransferase and monocyte counts predict unfavorable prognosis in patients with malignant pleural mesothelioma.

Limited biomarkers predicting prognosis of malignant pleural mesothelioma (MPM) have been identified. The present study aims to assess potential laboratory prognostic factors of MPM. We retrospectively reviewed the clinical data of 105 patients with MPM. The overall survival and prognostic factors were assessed by Kaplan-Meier curves and Cox regression analysis. A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off values. The mean age of the 105 patients (62 men, 43 women) was 56.0 years. The major clinical presentations were dyspnea, cough and chest pain. The most common laboratory abnormalities were thrombocytosis and elevated monocyte count. Significant prognostic factors on univariate analysis were performance status (PS), serum albumin, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), monocyte, platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and treatment strategy. Multivariate analysis showed PS, AST, monocyte, and treatment strategy were statistically significant (p<0.05). Higher AST level and monocyte count were both related to the presence of anemia (p=0.001 and 0.010, respectively) and higher ALP level (p=0.049 and 0.001, respectively). A higher AST level was also associated with higher alanine aminotransferase (ALT) and LDH level (p<0.05). A higher monocyte count was also correlated with male patients, higher white blood cell (WBC), platelet, neutrophil counts, lower red blood cell (RBC) and LMR counts (p<0.05). In conclusion, our data show that PS<2, normal AST level, lower monocyte count, and multimodality treatment are independent positive prognostic factors of MPM. The elevated AST and monocyte levels represent unfavorable prognostic biomarkers of MPM.

P3.03-039 Prognostic Biomarkers for Malignant Pleural Mesothelioma Treated with Chemotherapy: Topic: Mesothelioma Clinical

Prognosis of Malignant Pleural Mesothelioma (MPM) is poor and median survival is about 12 months. If any associations can be established between biomarkers and MPM, there will be benefit to clinical practice. In this study, the aim is to examine expression levels of the genes selected from relevant literature and utilizing in silico methods in the determination of prognosis of MPM. The study group consisted of 54 MPM patients treated by chemotherapy. The expression of 6 genes; sestrin 1 (SESN1), laminin subunit alpha 4 (LAMA4), midkine (MKN), fibulin-3 (EFFL-3), syndecan-1 (SOC-1) and hyaluronan-2 (HYA-2) were examined by qPCR in the tumor tissues. SESN1 and LAMA4 were identified using an in house R based script “Unsupervised Survival Analysis Tool.” MKN, EFFL-3, SOC1 and HYA-2 were determined according to existing literature. We used two housekeeping genes; glucose-6-phosphate dehydrogenase (G6PD), TATA-box binding protein (TBP) as controls. qPCR Relative quantification of gene expression was based on the geometric mean G6PD, TBP. The relation between gene expression and prognosis was determined by categorizing samples into two groups using all possible cut-off values, analyzed by the Log Rank test (Log-rank test with multiple cut-offs). Cut-offs generating a p value less than 0.05, between %10-90 percentiles were considered significant. Mean age of study group was 62.5± 9.7 years (r:36-82). Of the patients, 43 (79.6%) had epithelioid cell type mesothelioma. The median survival (MS) for all patients was 10 (±1.18 SE) months (CI 95%;7.69 to 12.30). Twenty-five patients (46.3%) survived less than 12 months, 29 (53.7%) more than 12 months, and 4 (7.4%) were still surviving at the end of the study. The clinical factors that was associated with survival were histopathology (p=0.004) and stage (p=0.036). MKN, EFFL-3, SOC1, HYA-2, SESN-1 were found to be associated with survival time by univariate analyses. After the correction with histopathology and stage, MKN (p=0.041), SOC1 (p=0.015), HYA-2 (p=0.003), SESN-1 (p=0.028) were found to be related with survival time. Additionally, in only epithelioid type MPM patients, HYA-2 expression was found to be related with survival time according to multivariate analyses (p=0.016). High MKN expression is potential biomarker of poor prognosis and high SOC1, HYA-2, SESN-1 expressions are potential biomarkers of good prognosis in MPM patients, and should be further investigated. High HYA-2 expression also can be utilized as good prognosis biomarker for epithelioid type MPM. *This study was partly supported by General Directorate of Health Researches, Republic of Turkey, Ministry of Health.

P3.03-024 Malignant Pleural Mesothelioma: Gene Expression Profiling of the Main Histological Subtypes: Topic: Mesothelioma Transitional

Malignant pleural mesothelioma (MPM) is a low-incidence, aggressive, asbestos-related tumor, whose treatment options are currently limited. MPM is a heterogeneous tumor with three main histological subtypes: epithelioid (E), sarcomatoid (S) and biphasic (B). S- and B- MPMs are rarer and have a poorer prognosis than the E-subtype. In the present study we compared the expression profile of 117 genes with a crucial role in cancer between the E- and S/B- subtypes, in order to identify histology-specific molecular markers. Gene expression analysis was performed by Nanostring system directly on RNA from 38 formalin-fixed and paraffin-embedded tissues of MPM patients (25 E-subtype, 13 S/B-subtypes). After data normalization, differences of gene expression levels between the two groups were evaluated by a non-parametric Mann-Whitney U-test (p-value < 0.05). 39 genes were differentially expressed. In particular, 21 genes were statistically up-regulated and 18 down-regulated in E- compared to S/B-subtypes (Table 1). The identification of gene expression profiles specific for each histological subtype could improve the clinical approach to MPM. In this study we found genes differentially expressed between E- and S/B-subtypes. In detail, up-regulated genes in E-MPM encode for proteins involved in epithelial cell differentiation and regulation of apoptosis, whereas down-regulated genes belong to pathways related to extracellular matrix, cell adhesion and angiogenesis. Moreover, some of the deregulated genes have been already described to influence the sensitivity to chemotherapy, such as ASS1, to play an important role in the mesenchymal transition, like MMP9, and others, among which ESR2, have been proposed as potential therapeutic targets. Our results reveal genes activated or inactivated in a histotype-dependent manner as new potential biomarkers for MPM, however, further studies are needed to better understand their clinical value.

Glycodelin is a potential novel follow-up biomarker for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a short survival time arising from the mesothelial cells of the pleura. Soluble mesothelin-related peptide (SMRP), osteopontin or EFEMP1 (Fibulin-3) are well described biomarkers for malignant mesothelioma with moderate sensitivity and specificity. In this study, we characterized the expression of glycodelin, a marker for risk pregnancy, in MPM by RNA and protein analyses and investigated its potential as a MPM biomarker. We were able to detect glycodelin in the serum of MPM patients. Compared to benign lung diseases, the serum levels were significant increased. Patients with high glycodelin serum levels revealed a worse overall survival. The glycodelin serum levels correlated with the tumor response to treatment. A comparison of SMRP and glycodelin serum measurement in a large patient cohort demonstrated that the detection of both soluble factors can increase the reliable diagnostic of MPM. Glycodelin was highly expressed in MPM tumors. Analyses of a tissue micro array indicated that the immunomodulatory form glycodelin A was expressed in MPM and correlated with the survival of the patients. Altogether, glycodelin seems to be a new potential biomarker for the aggressive malignant pleural mesothelioma.

Circulating microRNAs found dysregulated in ex-exposed asbestos workers and pleural mesothelioma patients as potential new biomarkers.

Malignant pleural mesothelioma (MPM), a fatal cancer, is an occupational disease mostly affecting workers ex-exposed to asbestos fibers. The asbestos, a cancerogenic mineral of different chemical composition, was widely employed in western Countries in industrial manufactures of different types. MPM may arise after a long latency period, up to five decades. MPM is resistant to conventional chemo- and radio-therapies. Altogether, these data indicate that the identification of new and specific markers are of a paramount importance for an early diagnosis and treatment of MPM. In recent years, microRNAs expression was found dysregulated in patients, both in cancer cells and sera, affected by tumors of different histotypes, including MPM. Cell and circulanting microRNAs, found to be dysregulated in this neoplasia, were proposed as new biomarkers. It has been reported that circulating microRNAs are stable in biological fluids and could be employed as potential MPM biomarkers. In this investigation, circulating microRNAs (miR) from serum samples of MPM patients and workers ex-exposed to asbestos fibers (WEA) and healthy subjects (HS) were comparatively analyzed by microarray and RT-qPCR technologies. Our results allowed (i) to select MiR-3665, an endogenous stable microRNA, as the internal control to quantify in our analyses circulating miRNAs; to detect (ii) miR-197-3p, miR-1281 and miR 32-3p up-regulated in MPM compared to HS; (iii) miR-197-3p and miR-32-3p up-regulated in MPM compared to WEA; (iv) miR-1281 up-regulated in both MPM and WEA compared to HS. In conclusion, three circulating up-regulated microRNAs, i.e. miR-197-3p, miR-1281 and miR-32-3p are proposed as potential new MPM biomarkers.

Prognostic and Therapeutic Implications of MicroRNA in Malignant Pleural Mesothelioma.

Malignant Pleural Mesothelioma (MPM) is an aggressive disease characterized by a dismal prognosis, mainly due to late diagnosis. To date, there are very few treatment options available and the refractoriness to the majority of therapeutic strategies, leading to consider MPM a relevant problem in public health. Therefore, the identification of novel prognostic markers and alternative therapeutic strategies remain a top priority. Several efforts have been made in this direction and to date a number of studies have investigated the role of microRNA as biomarkers in MPM, identifying the potential prognostic role of miR-29c* and miR-31. Very recently, the first microRNA signature able to discriminate poor or and good prognosis of MPM patients underwent surgery has been published. Very interestingly, several microRNA such as miR-1, miR-16, and miR-34b/c have been identified as potential therapeutic agents. Indeed, the forced expression of these microRNA resulted in anti-tumor effects both in vitro and in vivo. Besides, the introduction of microRNA mimic, some agents such as EphrinA1 and Onconase, seemed to exert anti-tumor effects through specific microRNA. Moreover, microRNA have also been reported to play a role in chemoresistance enhancing the sensitivity to specific drug such as pemetrexed. In this review the most relevant and updated data about the role of microRNA as prognostic markers and therapeutic agents in MPM will be presented, opening new avenues towards improved management of this aggressive disease.

Circulating activin A is a novel prognostic biomarker in malignant pleural mesothelioma – A multi-institutional study

IntroductionThe deregulation of activin expression is often observed in various malignancies. Previous studies indicate that activin A plays a protumourigenic role in malignant pleural mesothelioma (MPM). The aim of the study was to evaluate circulating activin A level as a biomarker in MPM. MethodsPlasma samples were collected from 129 MPM patients in four institutions at the time of diagnosis or before surgical resection. Samples from 45 healthy individuals and from 16 patients with non-malignant pleural diseases served as controls. Circulating activin A was measured by enzyme-linked immunosorbent assay and correlated to clinicopathological variables. ResultsPlasma activin A level was significantly elevated in MPM patients (862 ± 83 pg/ml) when compared to healthy controls (391 ± 21 pg/ml; P < 0.0001). Patients with pleuritis or fibrosis only showed a modest increase (versus controls; 625 ± 95 pg/ml; P = 0.0067). Sarcomatoid (n = 10, 1629 ± 202 pg/ml, P = 0.0019) and biphasic (n = 23, 1164 ± 233 pg/ml, P = 0.0188) morphology were associated with high activin A levels when compared to epithelioid histology (n = 94, 712 ± 75 pg/ml). The tumour volume showed a positive correlation with increased circulating activin A levels. MPM patients with below median activin A levels had a significantly longer overall survival when compared to those with high activin A levels (median survival 735 versus 365 d, P < 0.0001). Importantly, circulating activin A levels were exclusively prognostic in epithelioid MPM. ConclusionsOur findings suggest that the measurement of circulating activin A may support the histological classification of MPM and at the same time help to identify epithelioid MPM patients with poor prognosis.

A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma.

Background:We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM).Methods:Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts.Results:Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC.Conclusions:Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.

MicroRNAs as potential biomarkers in malignant pleural mesothelioma

MicroRNAs as potential biomarkers in malignant pleural mesothelioma Eric Santoni-Rugiu, Morten Andersen, Morten Grauslund Laboratory of Molecular Pathology, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Abstract: Malignant pleural mesothelioma (MPM), a highly lethal cancer strictly related to asbestos exposure, is usually characterized by delayed diagnosis, resistance to current therapies, and dismal prognosis. MPM is difficult to distinguish histologically from nonmalignant reactive mesothelial proliferations (RMPs) as there are no clinically validated immunohistochemical markers yet and the main diagnostic criterion remains deep invasion into the pleura and underlying fat tissue, which is often not appreciable in small pleural biopsies. In this regard, microRNAs (miRNAs), given their size and stability, are particularly attractive biomarkers in formalin-fixed paraffin-embedded tissue specimens for routine pathology. Moreover, circulating miRNAs appear to be promising biomarkers for early detection and monitoring of patients with MPM. Here, we review the studies mostly performed by miRNA arrays and reverse transcription-quantitative polymerase chain reaction in formalin-fixed paraffin-embedded or frozen tissue samples, MPM cell lines, and blood/plasma/serum samples that have highlighted the potential of miRNAs as biomarkers in MPM. Certain studies have pointed to the ability of miRNAs to distinguish the different histological MPM subtypes or separate MPM from lung adenocarcinoma, and other investigations have revealed that miRNAs can aid in differentiating MPM from RMP or have prognostic value in predicting the patient outcome. Mechanistic aspects of the involvement of miRNAs in mesothelioma genesis and possible use of miRNAs as future therapeutic targets in MPM are also emphasized. Finally, limitations of the data currently obtained due to the drawbacks of reverse transcription-quantitative polymerase chain reaction, heterogeneity of MPM tissue samples, and differences in methodological platforms as well as in types of specimens utilized in different studies are discussed. Because of these inherent weaknesses of collected data, further studies assessing the expression and distribution of miRNAs by in situ hybridization in combination with the codetection of their respective targets by immunohistochemistry and further validation of miRNAs&rsquo; targets in vitro are warranted to fully reveal the potential clinical utility of miRNAs in MPM. Keywords: malignant pleural mesothelioma, miRNAs, cancer biomarkers, diagnosis, prognosis, future therapy

Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis.

Background:Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies.Methods:ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan–Meier method, respectively.Results:FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1–76.4) and 56% (95% CI: 41.5–71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14–45.93)).Conclusions:These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients.

BAP1 facilitates diagnostic objectivity, classification, and prognostication in malignant pleural mesothelioma

BRCA-associated protein 1 (BAP1) has emerged as a promising biomarker for malignant pleural mesothelioma (MPM). Loss of BAP1 expression can occur by a variety of mechanisms, but reports on incidence are variable and the clinical significance is unclear. In order to investigate the diagnostic and prognostic significance of BAP1, we constructed a tissue microarray consisting of 111 MPM cases and performed BAP1 immunohistochemistry. BAP1 was lost in 77% of epithelioid cases (n=58) but was retained in all sarcomatoid cases (n=10); 49% of biphasic cases showed loss (n=43), and BAP1-negative cases demonstrated loss of staining in both the epithelioid and sarcomatoid components. All non-neoplastic mesothelial tissues (n=20) retained BAP1, resulting in a sensitivity, specificity, positive predictive value, and negative predictive value of 61%, 100%, 100%, and 32%, respectively. Moreover, BAP1 expression in spindled mesothelium enabled discrimination of reactive and malignant cells, thus providing a more objective means of distinguishing epithelioid from biphasic morphology compared to histology alone. Nonetheless, BAP1 staining was patchy in some benign mesothelial neoplasms, which raises concern for using BAP1 in small biopsies. Kaplan-Meier analysis demonstrated a significant improvement in overall survival with BAP1 loss, but this did not reach significance in multivariate analysis accounting for histologic subtype. When only epithelioid cases were analyzed there was a trend toward increased survival, but it did not reach significance. We conclude that BAP1 loss is frequent in epithelioid MPM, which is in turn associated with improved survival, and that it can have additional clinical significance by facilitating histologic classification.

The Pregnancy Associated Endometrial Protein Glycodelin and its Potential as a Biomarker for Malignant Pleural Mesothelioma

The Pregnancy Associated Endometrial Protein Glycodelin and its Potential as a Biomarker for Malignant Pleural Mesothelioma

The established and future biomarkers of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with a median survival of 12months. The MPM incidence is 1-6/100,000 and is increasing as a result of historic asbestos exposure in industrialized countries and continued use of asbestos in developing countries. Lack of accurate biomarkers makes diagnosis, prognostication and treatment prediction of MPM challenging. The aim of this review is to identify the front line of MPM biomarkers with current or potential clinical impact. Literature search using the PubMed and PLoS One databases, the related-articles function of PubMed and the reference lists of associated publications until April 26th 2015 revealed a plethora of candidate biomarkers. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in the epithelioid and biphasic type, but sarcomatous type do not have specific markers, making diagnosis more difficult. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic with high specificity but low sensitivity. Circulating proteomic and microRNA signatures, fibulin-3, tumor cell gene-ratio test, transcriptomic, lncRNA, glycopeptides, pleural fluid FISH assay, hyaluronate/N-ERC mesothelin and deformability cytometry may be important future markers. Putative predictive markers for pemetrexed-platinum are tumor TS and TYMS, for vinorelbine the ERCC1, beta-tubuline class III and BRCA1. Mutations of the BAP1 gene are potential markers of MPM susceptibility. In conclusion, the current status of MPM biomarkers is not satisfactory but encouraging as more sensitive and specific non-invasive markers are emerging. However, prospective validation is needed before clinical application.

160P - Pretreatment Serum Albumin Level is an Independent Prognostic Biomarker in Malignant Pleural Mesothelioma

160P - Pretreatment Serum Albumin Level is an Independent Prognostic Biomarker in Malignant Pleural Mesothelioma

Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery

Survival and response to platinum-based induction chemotherapy are heterogeneous among patients with malignant pleural mesothelioma. The aim of the present study was to assess the prognostic role of DNA repair markers, such as excision repair cross-complementation group 1 and ribonucleotide reductase M1, in multimodally treated patients with malignant pleural mesothelioma. Tumor tissue of a malignant pleural mesothelioma cohort (n = 107) treated with platinum/gemcitabine (n = 46) or platinum/pemetrexed (n = 61) induction chemotherapy followed by extrapleural pneumonectomy was assembled on a tissue microarray. Immunohistochemical expression of excision repair cross-complementation group 1 (nuclear) and ribonucleotide reductase M1 (nuclear and cytoplasmic) was assessed for its prognostic impact (association with overall survival or freedom from recurrence). Patients with high nuclear ribonucleotide reductase M1 expression before chemotherapy showed significantly longer freedom from recurrence (P = .03). When specifically analyzed in the subgroup of patients receiving platinum/gemcitabine followed by extrapleural pneumonectomy, high nuclear ribonucleotide reductase M1 was associated with prolonged freedom from recurrence (P = .03) and overall survival (P = .02). Low excision repair cross-complementation group 1 expression in prechemotherapy tumor tissues was associated with significantly longer freedom from recurrence (P = .04). Nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 were independent prognosticators of freedom from recurrence in addition to pT stage in multivariate analysis. In the present study, nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 expression were identified as independent prognosticators for freedom from recurrence of malignant pleural mesothelioma in patients undergoing induction chemotherapy followed by extrapleural pneumonectomy.

MDM2 is an important prognostic and predictive factor for platin-pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53.

Background:Malignant pleural mesothelioma (MPM) is a highly aggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed. Until now, predictive and prognostic biomarkers are lacking, making it a non-tailored therapy regimen with unknown outcome. P53 is frequently inactivated in MPM, but mutations are extremely rare. MDM2 and P14/ARF are upstream regulators of P53 that may contribute to P53 inactivation.Methods:A total of 72 MPM patients were investigated. MDM2 immunoexpression was assessed in 65 patients. MDM2 and P14/ARF mRNA expression was analysed in 48 patients of the overall collective. The expression results were correlated to overall survival (OS) and progression-free survival (PFS).Results:OS and PFS correlated highly significantly with MDM2 mRNA and protein expression, showing a dismal prognosis for patients with elevated MDM2 expression (for OS: Score (logrank) test: P⩽0.002, and for PFS: Score (logrank) test; P<0.007). MDM2 was identified as robust prognostic and predictive biomarker for MPM on the mRNA and protein level. P14/ARF mRNA expression reached no statistical significance, but Kaplan–Meier curves distinguished patients with low P14/ARF expression and hence shorter survival from patients with higher expression and prolonged survival.Conclusions:MDM2 is a prognostic and predictive marker for a platin–pemetrexed therapy of patients with MPMs. Downregulation of P14/ARF expression seems to contribute to MDM2-overexpression-mediated P53 inactivation in MPM patients.

A critical update on prognostic and predictive biomarkers in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a devastating and treatment-resistant disease. Currently, well-established prognostic and predictive biomarkers are rare in clinical practice, whereas there is a whole body of various MPM biomarker studies published in medical literature in the past decades. Besides well-established pathological parameters, including histological subtype, disease stage, or level of lymph node involvement, blood parameters and circulating proteins related to a proinflammatory phenotype are emerging as prognostic biomarkers. Here we provide an overview about the current status of prognostic and predictive biomarkers in MPM, with a strong emphasis on their applicability in clinical practice.

Biomolecular and clinical practice in malignant pleural mesothelioma and lung cancer: what thoracic surgeons should know

Today, molecular-profile-directed therapy is a guiding principle of modern thoracic oncology. The knowledge of new biomolecular technology applied to the diagnosis, prognosis, and treatment of lung cancer and mesothelioma should be part of the 21st century thoracic surgeons' professional competence. The European Society of Thoracic Surgeons (ESTS) Biology Club aims at providing a comprehensive insight into the basic biology of the diseases we are treating. During the 2013 ESTS Annual Meeting, different experts of the field presented the current knowledge about diagnostic and prognostic biomarkers in malignant pleural mesothelioma including new perspectives as well as the role and potential application of microRNA and genomic sequencing for lung cancer, which are summarized in the present article.