Malignant Pleural Mesothelioma Patients Research Articles

Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma

Purpose Malignant pleural mesothelioma (MPM) is a rare and deadly malignancy. Current MPM therapies remain inadequate, and outcomes are often disappointing. New meaningful therapeutic approaches are urgently needed. Accumulating evidence indicates that the cAbl pathway promotes various tumor-stimulating processes in MPM. In this study, we sought to determine ponatinib’s potential utility, a clinically approved and potent cAbl inhibitor, in MPM treatment. Material and methods Four MPM lines (MSTO211H, H28, H2452, H2052) were treated with ponatinib in vitro, and their growth was assessed. Scratch wound assay was used to investigate the ponatinib effect on cell migration. The expression levels of pAbl and its downstream effectors pCrkL, pAKT, and pSTAT5 were characterized. The in vivo ponatinib effect was evaluated in human MPM cells derived tumor model. Results In all four MPM lines, significant expression levels of phosphorylated cAbl/Arg and pCrkl were observed. Differentially but strongly, ponatinib inhibited the in vitro cell growth and migration of all four MPM line. Western blot analysis showed that the activation of Abl signaling was blocked in the ponatinib-treated MMP lines. In keeping, the cellular levels of pAbl and its downstream effector pCrkL, pAKT, and pSTAT5 were markedly decrease following ponatinib treatment. Moreover, ponatinib treatment amplified the levels of γH2AX in cells denoting increased double-strand DNA breaks levels. Notably, ponatinib treatment reduced in vivo tumor growth and reduced pCrkl and pSTAT5 levels in tumor samples. Conclusion Ponatinib may offer a new therapeutic strategy for MPM patients based on cAbl signaling pathway inhibition.

A case of malignant pleural mesothelioma with metastasis on the lower gingiva

Malignant Pleural Mesothelioma (MPM) is a representative asbestos-related disease and occurs mesothelium cell covering the pleura inside. MPM patients have a poor prognosis. We describe a 70-year-old man who had two soft masses in the left lower gingiva. On biopsy, the lesion was histopathologically diagnosed as a metastatic tumor from MPM. Positron emission tomography-CT (PET-CT) showed accumulation in the right pleura, the mesentery lymph node, the left gluteus and the lower left gingiva. After consulting the MPM chief physician, we performed tumor resections under general anesthesia. Four months later, there had been no sign of recurrence, and he started using a partial denture. However, his pulmonary lesion grew worse, and he died 8 months after the operation.

Malignant Pleural Mesothelioma in Patients Who Previously Received Radiotherapy for Their First Malignant Tumor

Malignant Pleural Mesothelioma in Patients Who Previously Received Radiotherapy for Their First Malignant Tumor

A Phase II Trial of Nivolumab With Chemotherapy Followed by Maintenance Nivolumab in Patients With Pleural Mesothelioma After Surgery: The NICITA Study Protocol

BackgroundIn selected patients with early-stage malignant pleural mesothelioma (MPM), a multimodal therapy that includes surgical cytoreduction, chemotherapy, and/or radiotherapy is recommended. Several clinical trials have demonstrated the beneficial effects of immune checkpoint inhibitors in pretreated MPM patients with advanced disease. Recent clinical data have suggested that the combination of chemotherapy and checkpoint inhibition might improve efficacy. Trial DesignThe NICITA (nivolumab with chemotherapy in pleural mesothelioma after surgery) trial is a prospective, 1:1 randomized, open-label, multicenter phase II clinical trial (ClinicalTrials.gov identifier, NCT04177953). Ninety-two patients with MPM epithelioid subtype, who had undergone extended pleurectomy and decortication with or without hyperthermic intrathoracic chemoperfusion, will be included to receive adjuvant treatment. All patients will receive ≤ 4 cycles of platinum-based chemotherapy with pemetrexed (arms A and B). Patients in arm B will additionally receive nivolumab, together with the adjuvant chemotherapy, and subsequently for ≤ 12 cycles as maintenance therapy. The primary endpoint of this study is the time-to-next-treatment. The secondary endpoints include progression-free survival, overall survival, proportion of patients with treatment beyond progression, duration of treatment beyond progression in this population, and quality of life. ConclusionThis prospective trial will contribute data to assess the efficacy of standard chemotherapy combined with nivolumab in the context of multimodal management of early-stage MPM. The study is currently enrolling patients.

Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study.

Simple SummaryMalignant pleura Mesothelioma (MPM) is an aggressive cancer arising from the mesothelial cells of the pleura. About 80% of mesothelioma cases are linked to asbestos exposure; the remainder may be related to prior chest radiation, genetic predisposition or spontaneous occurrence. Understanding the genetic alterations that drive MPM is critical for successful development of diagnostics, prognostics and personalized therapeutic modalities. Because MPM is rare, genomic studies are limited and have typically involved a small number of samples. The aim of our study was to understand the mutational landscape of MPM. Our analysis identified significantly mutated genes. This study on a rare tumor type will be important for patients “in real life”.Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer. Data are not available in prospective trials on correlations between genetic alterations and outcomes of therapies. In this study, we assessed the genetic profile of MPM patients (pts) in tissue samples. Patients and Methods: From December 2016 to July 2018 (end of enrolment), 164 pts were enrolled. We evaluated by targeted sequencing the mutational profile of a panel of 34 genes: ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6. Genetic profiling was correlated with clinical and pathological variables. Results: Overall, 110 pts (67%) from both treatment arms had samples available for molecular analysis. Median age was 63 years (45–81), 25.5% (n = 28) were females, and 74.5% (n = 82) were males. Tumor histotype was 81.8% (n = 90) epithelioid and 18.2% (n = 20) non-epithelioid; 28.5% of the tumors (n = 42) were stage IV, 71.5% (n = 68) were stage III. Targeted sequencing of tissue specimens identified 275 functional somatic mutations in the 34 genes analyzed. The number of mutated genes was positively associated with higher stage and metastatic disease (p = 0.025). RDX (42%), MXRA5 (23%), BAP1 (14%), and NF2 (11%) were the most frequently mutated genes. Mutations in RAPGEF6 (p = 0.03) and ACTG1 (p = 0.02) were associated with the non-epithelioid subtype, and mutations in BAP1 (p = 0.04) were related to progression-free survival (PFS) > 6 months. Conclusions: In the Ramucirumab Mesothelioma clinical trial (RAMES), mutation of the gene BAP1 is related to a prolonged PFS for patients treated with platinum/pemetrexed regimens (p = 0.04).

Identification of Potential Hub Genes and Therapeutic Drugs in Malignant Pleural Mesothelioma by Integrated Bioinformatics Analysis

Introduction: Malignant pleural mesothelioma (MPM) is closely linked to asbestos exposure and is an extremely aggressive tumor with poor prognosis. Objective: Our study aimed to elucidate hub genes and potential drugs in MPM by integrated bioinformatics analysis. Methods: GSE42977 was download from the Gene Expression Omnibus (GEO) database; the differentially expressed genes (DEGs) with adj.p value <0.05 and |logFC| ≥2 were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by DAVID database. The STRING database was used to construct a protein-protein interaction network, and modules analysis and hub genes acquisition were performed by Cytoscape. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to assess the impact of hub genes on the prognosis of MPM patients. The Drug-Gene Interaction database (DGIdb) was used to select the related drugs. Results: A total of 169 upregulated and 70 downregulated DEGs were identified. These DEGs are enriched in the pathway of extracellular matrix-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and PPAR signaling pathway. Finally, 10 hub genes (CDC20, CDK1, UBE2C, TOP2A, CCNB2, NUSAP1, KIF20A, AURKA, CEP55, and ASPM) were identified, which are considered to be closely related to the poor prognosis of MPM. In addition, 119 related drugs that may have a therapeutic effect on MPM were filtered out. Conclusion: These discovered genes and small-molecule drugs provide some new ideas for further research on MPM.

MALIGNANT PLEURAL MESOTHELIOMA WITH NO ASBESTOS EXPOSURE

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Malignant pleural mesothelioma (MPM) is the primary malignant tumor of the pleura which is highly aggressive with median survival around 12 months. This cancer is linked with asbestos exposure, but in 20% cases, the exposure fails to be found. CASE PRESENTATION: A 73 year- old lifetime non-smoking female presented with sharp, non-radiating, lower right chest pain. Her vital signs were normal and the physical exam was significant only for mild tenderness over her right flank. A CT angiogram of chest showed a soft tissue mass within the right posterior pleura measuring up to 3.4cm with enlarged subcarinal lymph nodes measuring up to 15mm. She denied any direct or indirect asbestos exposure, worked as a homemaker and her husband worked in agriculture. Subsequent PET scan was compatible with a malignant process. Bronchoscopy with biopsy of the subcarinal lymph node showed a poorly differentiated epithelioid neoplasm. A confirmatory CT-guided biopsy showed the same. Tumor cells had a high nuclear-cytoplasmic ratio, hyperchromatic nuclei with irregular contours. The cells showed positive immunostaining with Calretinin, WT-1, GATA-3, D2-40. The above workup was consistent with an atypical presentation of mesothelioma, stage IIIA (cT3N1), not felt to be resectable given subcarinal nodal involvement, and the patient underwent radiation followed by systemic chemotherapy. DISCUSSION: MPM affects men in 80% of cases and it is most frequent around the age of 60 years [1]. The male to female ratio is 4:1 with a predominance of right side over the left. The main etiological factor is previous exposure to asbestos with a typical long latency period of around 20 - 40 years. Few cases of MPM without asbestos exposure have been reported in literature [2,3]. The possibility of association of MPM and exposure to some dust or chemicals (stone cutter, leather factory or textile factory worker, agricultural chemicals) has also been reported. Typical presentation includes progressive dyspnea, cough and chest pain . Weight loss and generalized fatigue are seen at advanced stages and linked with poor outcomes. The most common radiological presentation is a unilateral pleural effusion, which is recurrent, and sometimes exudative and hemorrhagic. Bronchoscopy has a high sensitivity of 95% for diagnosis of MPM. In our case the patient is a lifetime non-smoker without any direct or indirect asbestos exposure. CONCLUSIONS: MPM has a poor prognosis despite advancement in surgery and oncology. Although linked with asbestos exposure, in 20% of the cases this exposure fails to be found. A significant increase in survival among MPM patients can be reached through earlier diagnosis. This case was unusual in that the initial presentation was due to pain, there was no significant pleural effusion identified, and no known exposure to asbestos. Reference #1: Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005; 366:397-408. Reference #2: Batahar SA, Ouradi O, Elidrissi S, Amro L. Pleural Mesothelioma with No Asbestos Exposure: A Case Report. Journal of Clinical and Diagnostic Research : JCDR. 2016 Nov;10(11):OD07-OD08. DOI: 10.7860/JCDR/2016/21066.8849. Reference #3: Kant S, Verma SK, Sanjay. Malignant pleural mesothelioma without asbestos exposure with distant metastasis in a peripheral lymph node: a case report. Lung India. 2008;25(1):31–33. doi:10.4103/0970-2113.44137 DISCLOSURES: No relevant relationships by SYED ABBAS, source=Web Response No relevant relationships by Amarpreet Bhalla, source=Web Response No relevant relationships by Aditi Desai, source=Web Response No relevant relationships by Vivek Murthy, source=Web Response

The role of extrapleural pneumonectomy for malignant pleural mesothelioma: reviewing 20-years of experience

Background: For patients with malignant pleural mesothelioma (MPM), a multimodality treatment concept including neoadjuvant chemotherapy and radical surgery offers improved overall survival. While the lung-sparing extended pleurectomy and decortication (EPD) has become the preferential surgical approach, the more aggressive extrapleural pneumonectomy (EPP) remains reserved for a selected group of patients. Based on our experience from the past two decades, we aim to discuss and assess today’s role of EPP. Methods: Out of 523 MPM patients intended to be treated by induction chemotherapy followed by macroscopic complete resection between January 1999 and December 2019, we identified 151 consecutive patients who underwent EPP at our center. All patients were treated within a multimodality concept including neoadjuvant chemotherapy with platinum-based agents plus gemcitabine or pemetrexed. Clinical data were collected in an online database and analyzed retrospectively. Results: Of all patients, 57.6% were of IMIG stage IA or IB (n=87), 39.0% of all patients IMIG stage IIIA or IIIB (n=59). Mean tumor volume after induction chemotherapy was 294.6±315.0 cm3. Most patients were operated in the first decade between 1999 and 2009 [112 patients (74.2%)]. The overall 30- and 90-day mortality was 4.6% and 10.6%, respectively. The median overall survival was 18.5 months. Major postoperative morbidity was assessed as a composite outcome and occurred in 38.4% of all patients. Conclusions: Although EPD became the procedure of first choice, EPP is a reasonable approach in selected patients with high tumor burden and extensive involvement of the lung parenchyma, where parenchyma-sparing resection is technically not feasible or functionally not rational. All patients should be preoperatively assessed and informed about the eventuality of EPP, depending on intraoperative findings. Keywords: Extrapleural pneumonectomy (EPP); malignant pleural mesothelioma (MPM); surgical treatment; multimodality treatment; macroscopic complete resection

UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma.

Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.

1897P Germline and somatic mutational landscape in a cohort of malignant pleural mesothelioma patients

Germline mutations in BAP1 and in other genes, such as BRCA2, CHEK2, CDKN2A or ATM, have been associated to hereditary predisposition to malignant pleural mesothelioma (MPM). We aim to characterize the genomic landscape in MPM patients at germline and somatic level.

1902P Association of high-intensity statins with clinical outcome in malignant pleural mesothelioma and advanced non-small cell lung cancer patients treated with PD1 inhibitors

1902P Association of high-intensity statins with clinical outcome in malignant pleural mesothelioma and advanced non-small cell lung cancer patients treated with PD1 inhibitors

Double-staining Immunohistochemistry Reveals in Malignant Pleural Mesothelioma the Coexpression of ERCC1 and RRM1 as a Frequent Biological Event Related to Poorer Survival.

Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. To date, standard MPM therapy is still limited to surgery, radiotherapy, and chemotherapy, including pemetrexed and platinum compounds. The main mechanisms of platinum resistance are associated with DNA repair pathways. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) are important components of the DNA repair, considered as prognostic and predictive biomarkers in various cancer types. The main goal of the present study was to investigate the ERCC1 and RRM1 expression and their potential impact on outcome in this tumor. A series of 73 MPM, mainly treated with a platin-based regimen, was collected and the immunohistochemistry tests were performed to assess ERCC1 and RRM1 expression. In addition, a multiplex immunohistochemistry has been validated to detect simultaneously the 2 proteins on the same slide. In our series, 36 of 73 cases showed ERCC1 expression and 55 of 73 showed RRM1 expression. The double immunohistochemical staining showed the coexpression of ERCC1/RRM1 in 34 of 73 cases. A significant association between ERCC1 and RRM1 expression was observed in our series (P<0.05). Patients with ERCC1/RRM1 coexpression experienced shorter median overall survival (6.6 vs. 13.8 mo, log-rank=7688; P=0.006). Our results suggest that the coexpression of ERCC1/RRM1 could define a group of MPM patients with the worst prognosis who should need likely alternative treatment. In conclusion, we propose the putative usefulness of ERCC1/RRM1 coexpression as prognostic biomarkers for overall survival in MPM.

Abstract 4478: Effective prediction of treatment responders with anti-PD-1 antibody in malignant pleural mesothelioma by diversity of peripheral CD8+PD-1+ T cell subpopulation

Abstract Background: Programmed death 1 (PD-1) blockade with Nivolumab are effective in patients with malignant pleural mesothelioma (MPM), however; successful predictive biomarker has not been available. Unlike invasive test with tumor biopsy, peripheral blood is safe and easily obtainable source of biomarkers. We have previously reported that T cell receptor (TCR) diversity of CD8+PD-1+ T cells were effective to predict response to anti-PD-1 antibody treatment in non-small cell lung cancer (NSCLC) patients (AACR2019: Abstract nr 2230). In this study, Next generation sequence(NGS)-based TCR α and β repertoires were examined with peripheral CD8+PD-1+ T cells isolated from 11 patients with MPM and treatment responses were evaluated 2 months after anti-PD-1 antibody treatment. Methods: Peripheral blood mononuclear cells were collected from 11 MPM patients enrolled in this study before administration of anti-PD-1 antibody (Nivolumab). NGS-based TCR α and β repertoire analysis were performed with CD8+PD-1+ T cells isolated with FACS sorting by Repertoire Genesis Inc. TCR diversity was statistically evaluated by Shannon, Simpson and Diversity Evenness 50 (DE50) indices. CT scan was performed during week 8 of treatment and used to determine response to nivolumab. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Three of 11 (27.3%) MPM patients responded to anti-PD-1 treatment. There were good correlation of all diversity indices between TCRα and TCRβ. TCRβ diversity was significantly higher among responders than non-responders based on DE50 (0.0019 ± 0.00032 vs 0.0011 ± 0.00042, P &amp;lt; 0.05). Also, responders exhibited a clear trend to have higher TCR diversity of CD8+PD-1+ T cells in terms of Shannon, normalized Shannon and Simpson indices. Conclusion: Like NSCLC patients, PD-1 blockade was more effective in MPM patients who had higher levels of TCR diversity in peripheral CD8+PD-1+ T cells. This result suggested the TCR diversity of peripheral CD8+PD-1+ T cells has potential to predict response to immune checkpoint inhibitors in various tumor patient. Further clinical study would be needed to verify effectiveness of this biomarker. Citation Format: Seiji Matsumoto, Takaji Matsutani, Yoshiko Fujita, Ryo Takahashi, Takashi Yokoi, Hiroshi Kodama, Yoshie Inao, Kazutaka Kitaura, Tohoru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Aki Kobayashi, Masaki Hashimoto, Nobuyuki Kondo, Ryuji Suzuki, Koichiro Yamakado, Takashi Kijima, Seiki Hasegawa. Effective prediction of treatment responders with anti-PD-1 antibody in malignant pleural mesothelioma by diversity of peripheral CD8+PD-1+ T cell subpopulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4478.

Abstract LB-291: Budget impact analysis of ttfields + platinum-based therapy for first-line malignant pleural mesothelioma

Abstract Objective: To estimate the financial and survival impact of introducing TTFields in combination with pemetrexed and a platinum agent to the formulary of a large U.S. health plan for first-line treatment of malignant pleural mesothelioma (MPM). Methods: An open-cohort health economic model was constructed to compare pre-TTFields approval and post-TTFields approval scenarios to estimate the incremental costs and survival outcomes for MPM patients treated with first-line therapy. A theoretical U.S. health plan covering 45 million lives was utilized. The pre-approval scenario considered first-line treatments of pemetrexed + cisplatin, pemetrexed + cisplatin/carboplatin + bevacizumab, pemetrexed monotherapy, gemcitabine + cisplatin, gemcitabine monotherapy, and vinorelbine monotherapy. Post-approval included all of the previous treatments as well as TTFields + pemetrexed + cisplatin/carboplatin. The model assumed 70% of incident MPM patients were treated with first-line therapy and 30% of eligible patients were treated with subsequent therapy. Subsequent therapy included pemetrexed, gemcitabine, and vinorelbine monotherapies as well as nivolumab + ipilimumab. The market share of TTFields + pemetrexed + cisplatin/carboplatin rose linearly from 9% to 22.5% over the five year time horizon in the post-approval scenario. Overall survival and adverse event rates for all regimens were sourced from clinical trial data, and dosing assumptions were from trial data, NCCN guidelines, and package inserts. Drug/device, administration, adverse event, and subsequent therapy (30% of eligible patients) costs were considered in the model and sourced from Medicare and Novocure. All costs are presented in 2019 USD and discounted at 3%. Results: There were 155 incident MPM patients treated with first-line therapy annually in the model. When compared to the pre-approval scenario the post-approval scenario resulted in 0.9 additional (1.07% increase) patients surviving at the end of year one and 13.8 additional (7.10% increase) patients at the end of year five. The forecasted budget impact ranged from $570,875 in year one to $2,770,856 in year five, for a total budget impact of $8,417,333 over the five-year time horizon. The budget impact was driven by an increase in drug and device costs of $8,338,341 and subsequent therapy costs of $1,242,548, which were slightly reduced by lower drug administration costs ($104,415), and adverse event costs ($1,059,141). The total per member per month (PMPM) cost increased by $0.003 over the five-year time horizon. Conclusion: The increase in the budget of a large U.S. health plan due to the introduction of TTFields as a first-line MPM treatment was relatively small on a PMPM basis and provided a notable survival benefit over the five year time horizon. Citation Format: Bruce C. Wang, Wesley Furnback, Christina Proescholdt, Gordon Chavez. Budget impact analysis of ttfields + platinum-based therapy for first-line malignant pleural mesothelioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-291.

Identification of a Five-Gene Signature for Predicting Survival in Malignant Pleural Mesothelioma Patients.

Malignant pleural mesothelioma (MPM), predominantly caused by asbestos exposure, is a highly aggressive cancer with poor prognosis. The staging systems currently used in clinics is inadequate in evaluating the prognosis of MPM. In this study, a five-gene signature was developed and enrolled into a prognostic risk score model by LASSO Cox regression analysis based on two expression profiling datasets (GSE2549 and GSE51024) from Gene Expression Omnibus (GEO). The five-gene signature was further validated using the Cancer Genome Atlas (TCGA) MPM dataset. Univariate and multivariate Cox analyses proved that the five-gene signature was an independent prognostic factor for MPM. The signature remained statistically significant upon stratification by Brigham stage, AJCC stage, gender, tumor size, and lymph node status. Time-dependent receiver operating characteristic (ROC) curve indicated good performance of our model in predicting 1- and 2-years overall survival in MPM patients. The C-index was 0.784 for GSE2549 and 0.753 for the TCGA dataset showing moderate predictive accuracy of our model. Furthermore, Gene Set Enrichment Analysis suggested that the five-gene signature was related to pathways resulting in MPM tumor progression. Together, we have established a five-gene signature significantly associated with prognosis in MPM patients. Hence, the five-genes signature may serve as a potentially useful prognostic tool for MPM patients.

Does size matter? -a population-based analysis of malignant pleural mesothelioma.

BackgroundThe 8th edition staging system for malignant pleural mesothelioma (MPM) has been proposed. The size of tumor is not taken into consideration. We intend to elucidate the prognostic value of the size of MPM and evaluate the current staging system via the data of SEER database.MethodsAll cases of primary MPM were identified and extracted from the SEER database during the period of 2004–2016. The endpoints were overall survival (OS) and cancer-specific survival (CSS) which were analyzed using Kaplan-Meier method. Log-rank test and Cox regression were utilized to identify the prognostic factors.ResultsA total of 2,138 patients were included in the primary cohort. The 1-, 3- and 5-year survival rates of MPM were 39.4%, 11.8% and 3.8%. Older, male and advanced stage patients accounted for larger proportion of the cohort. Besides tumor extension, lymph node involvement and metastatic status, tumor size, pathological type and differentiation grade were significant prognostic factors. In the stratified analysis of tumor extension, size is a significant prognostic factor in T2 patients and indicates inferior survival outcomes. Surgery, chemotherapy and radiation can increase both OS and CSS in MPM patients. Triple combination treatments showed a superiority to other treatments.ConclusionsTumor size matters in the prognosis of MPM especially in the early stage of MPM patients. The adjusted TNM staging system incorporating tumor size has better accuracy than the 8th edition IMIG system. However, some stages had not been fully identified. More cases of early stages are warranted for essential revision.

Nivolumab in pre-treated malignant pleural mesothelioma: real-world data from the Dutch expanded access program.

BackgroundRandomized phase III trials are ongoing to investigate the efficacy of nivolumab in malignant pleural mesothelioma (MPM), but real-world data are still scarce. In this real-world study, we investigated the clinical outcomes of nivolumab treatment in pre-treated MPM patients.MethodsData from 107 nivolumab treated MPM patients within the Dutch expanded access program were retrospectively analyzed. Treatment was independent of programmed death ligand 1 (PD-L1) expression on tumor samples. Univariable and multivariable analyses were performed to evaluate the relationship between clinically important factors, baseline peripheral blood parameters and survival. The landmark method was used to compare the outcome of patients according to their radiological response.ResultsIn the full cohort, the median progression-free survival (mPFS) was 2.3 months (95% CI: 1.6–2.9) and the median overall survival (mOS) was 6.7 months (95% CI: 6.2–10.0). After 12 weeks, the disease control rate (DCR) was 37% and the objective response rate (ORR) was 10%. PD-L1 status was determined in 33 patients (30%) and PD-L1 positivity (≥1%) was associated with an improved ORR (36% vs. 9%, P value 0.05), but not with PFS or OS. Low albumin was associated with worse OS (P value 0.002). Median OS was significantly longer for patients who had partial response to treatment (P value 0.0002).ConclusionsIn this real-world analysis, ORR and mOS were lower compared to those obtained in phase II trials. However, exceptional survival rates were observed in patients who had a radiological response. Although we cannot determine whether prognostic or predictive, PD-L1 expression and albumin were associated with greater response rate and may represent useful biomarkers for nivolumab treatment in MPM.

Multiplex Soluble Biomarker Analysis from Pleural Effusion.

Malignant pleural mesothelioma (MPM) is a highly aggressive and therapy resistant pleural malignancy that is caused by asbestos exposure. MPM is associated with poor prognosis and a short patient survival. The survival time is strongly influenced by the subtype of the tumor. Dyspnea and accumulation of pleural effusion in the pleural cavity are common symptoms of MPM. The diagnostic distinction from other malignancies and reactive conditions is done using histopathology or cytopathology, always supported by immunohistochemistry, and sometimes also by analyses of soluble biomarkers in effusion supernatant. We evaluated the soluble angiogenesis related molecules as possible prognostic and diagnostic biomarkers for MPM by Luminex multiplex assay. Pleural effusion from 42 patients with malignant pleural mesothelioma (MPM), 36 patients with adenocarcinoma (AD) and 40 benign (BE) effusions were analyzed for 10 different analytes that, in previous studies, were associated with angiogenesis, consisting of Angiopoietin-1, HGF, MMP-7, Osteopontin, TIMP-1, Galectin, Mesothelin, NRG1-b1, Syndecan-1 (SDC-1) and VEGF by a Human Premixed Multi-Analyte Luminex kit. We found that shed SDC-1 and MMP-7 levels were significantly lower, whereas Mesothelin and Galectin-1 levels were significantly higher in malignant mesothelioma effusions, compared to adenocarcinoma. Galectin-1, HGF, Mesothelin, MMP-7, Osteopontin, shed SDC-1, NRG1-β1, VEGF and TIMP-1 were significantly higher in malignant pleural mesothelioma effusions compared to benign samples. Moreover, there is a negative correlation between Mesothelin and shed SDC-1 and positive correlation between VEGF, Angiopoietin-1 and shed SDC-1 level in the pleural effusion from malignant cases. Shed SDC-1 and VEGF have a prognostic value in malignant mesothelioma patients. Collectively, our data suggest that MMP-7, shed SDC-1, Mesothelin and Galectin-1 can be diagnostic and VEGF and SDC-1 prognostic markers in MPM patients. Additionally, Galectin-1, HGF, Mesothelin, MMP-7, Osteopontin, shed SDC-1 and TIMP-1 can be diagnostic for malignant cases.

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

FDG PET versus CT radiomics to predict outcome in malignant pleural mesothelioma patients

BackgroundCareful selection of malignant pleural mesothelioma (MPM) patients for curative treatment is of highest importance, as the multimodal treatment regimen is challenging for patients and harbors a high risk of substantial toxicity. Radiomics—a quantitative method for image analysis—has shown its prognostic ability in different tumor entities and could therefore play an important role in optimizing patient selection for radical cancer treatment. So far, radiomics as a prognostic tool in MPM was not investigated.Materials and methodsThis study is based on 72 MPM patients treated with surgery in a curative intent at our institution between 2009 and 2017. Pre-treatment Fluorine-18 fluorodeoxyglucose (FDG) PET and CT scans were used for radiomics outcome modeling. After extraction of 1404 CT and 1410 FDG PET features from each image, a preselection by principal component analysis was performed to include only robust, non-redundant features for the cox regression to predict the progression-free survival (PFS) and the overall survival (OS). Results were validated on a separate cohort. Additionally, SUVmax and SUVmean, and volume were tested for their prognostic ability for PFS and OS.ResultsFor the PFS a concordance index (c-index) of 0.67 (95% CI 0.52–0.82) and 0.66 (95% CI 0.57–0.78) for the training cohort (n = 36) and internal validation cohort (n = 36), respectively, were obtained for the PET radiomics model. The PFS advantage of the low-risk group translated also into an OS advantage. On CT images, no radiomics model could be trained. SUV max and SUV mean were also not prognostic in terms of PFS and OS.ConclusionWe were able to build a successful FDG PET radiomics model for the prediction of PFS in MPM. Radiomics could serve as a tool to aid clinical decision support systems for treatment of MPM in future.