Malignant Pleural Mesothelioma Patients Research Articles

OA09.06 Nivolumab in Recurrent Malignant Pleural Mesothelioma: Real-World Data From Expanded Access Program In The Netherlands

Second-line treatment options for patients with recurrent malignant pleural mesothelioma (MPM) after first line chemotherapy are lacking. Nivolumab, an anti-PD-1 monoclonal antibody, showed promising results in phase II trials in pre-treated MPM patients. Data from the PROMISE-meso randomized phase III trial (NCT02991482), however, failed to show superiority of pembrolizumab (anti-PD-1) over chemotherapy in second line treatment. The aim of our study was to describe the clinical outcome of pre-treated MPM patients receiving nivolumab in a real-world setting and potentially identify a subgroup of patients that do benefit from anti-PD-1 treatment through extensive analysis of clinical and peripheral blood parameters.

P24.02 Rick Factors for the Occurence of Postoperative Empyema in Malignant Pleural Mesothelioma Patients Undergoing Macroscopic Complete Resection

P24.02 Rick Factors for the Occurence of Postoperative Empyema in Malignant Pleural Mesothelioma Patients Undergoing Macroscopic Complete Resection

Expression and clinical significance of SETD2 in maligant pleural mesothelioma

Objective: To analyze the gene mutation profile in malignant pleural mesothelioma (MPM) and investigate the expression of high-frequency mutant genes and its relationship with clinicopathological parameters. To screen out key genes and clinicopathologic factors related to the prognosis of MPM patients. Methods: The second generation sequencing data, somatic mutation data and clinical pathological data of 86 MPM cases and gene chip expression data of 89 MPM cases were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) in March 2020. Summarize the gene mutation profile of tissue samples in the TCGA database and analyze the relationship between the expression level of high-frequency mutation genes and the clinicopathological characteristics, asbestos exposure history and prognosis of MPM patients. The genes significantly related to MPM prognosis were screened out for gene set enrichment analysis (GSEA) . Survival analysis and GSEA were performed for the selected key genes and clinicopathological features verification using the microarray expression data from the GEO database. Results: The top 10 genes with highest single nucleotide variations frequencies were BAP1, NF2, TP53, TTN, SETD2, LATS2, CCDC168, FAT4, PTCH1 and ZNF469. The high expression rates of NF2, TP53, SETD2 and CCDC168 genes in wild type were higher than those of mutated type, and the differences were statistically significant (P<0.05) . Cox multivariate analysis of TCGA data showed that MPM patients with epithelial type (HR=0.425, 95%CI: 0.235-0.767, P<0.01) and SETD2 low expression (HR=0.516, 95%CI: 0.307-0.868, P=0.011) had lower risk of death. The survival analysis of GEO data verified that patients with epithelial type MPM had longer survival time, while patients with sarcoma type MPM had shortest survival time (P<0.01) . GSEA showed that SETD2 was involved in G2M checkpoint, E2F targets, MYC signaling pathways, protein secretion, mitotic spindle, MTORC1 pathway, TGF-β pathway, androgen response and uv response. Conclusion: MPM is accompanied with higher frequency of gene mutations represented by BAP1, NF2, TP53, TTN, SETD2, LATS2 and so on. SETD2 expression level and epithelia type of MPM may be influential factors for MPM prognosis.

Impact of CT convolution kernel on robustness of radiomic features for different lung diseases and tissue types.

In this study, we aimed to assess the impact of different CT reconstruction kernels on the stability of radiomic features and the transferability between different diseases and tissue types. Three lung diseases were evaluated, i.e. non-small cell lung cancer (NSCLC), malignant pleural mesothelioma (MPM) and interstitial lung disease related to systemic sclerosis (SSc-ILD) as well as four different tissue types, i.e. primary tumor, largest involved lymph node ipsilateral and contralateral lung. Pre-treatment non-contrast enhanced CT scans from 23 NSCLC, 10 MPM and 12 SSc-ILD patients were collected retrospectively. For each patient, CT scans were reconstructed using smooth and sharp kernel in filtered back projection. The regions of interest (ROIs) were contoured on the smooth kernel-based CT and transferred to the sharp kernel-based CT. The voxels were resized to the largest voxel dimension of each cohort. In total, 1386 features were analyzed. Feature stability was assessed using the intraclass correlation coefficient. Features above the stability threshold >0.9 were considered stable. We observed a strong impact of the reconstruction method on stability of the features (at maximum 26% of the 1386 features were stable). Intensity features were the most stable followed by texture and wavelet features. The wavelet features showed a positive correlation between percentage of stable features and size of the ROI (R2 = 0.79, p = 0.005). Lymph node radiomics showed poorest stability (<10%) and lung radiomics the largest stability (26%). Robustness analysis done on the contralateral lung could to a large extent be transferred to the ipsilateral lung, and the overlap of stable lung features between different lung diseases was more than 50%. However, results of robustness studies cannot be transferred between tissue types, which was investigated in NSCLC and MPM patients; the overlap of stable features for lymph node and lung, as well as for primary tumor and lymph node was very small in both disease types. The robustness of radiomic features is strongly affected by different reconstruction kernels. The effect is largely influenced by the tissue type and less by the disease type. The study presents to our knowledge the most complete analysis on the impact of convolution kernel on the robustness of CT-based radiomics for four relevant tissue types in three different lung diseases. .

Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients.

Simple SummaryRadical hemithoracic radiotherapy represents a promising new advance in the field of radiation oncology and encouraging results have been achieved in the treatment of malignant pleural mesothelioma patients. This study showed that this radiotherapy modality produces significant changes in serum metabolomics profile mainly affecting arginine and polyamine biosynthesis pathways. Interestingly, individual metabolomics alterations were found associated with the clinical overall survival outcome of the radiotherapy treatment. These results highlight metabolomics profile analysis as a powerful prognostic tool useful to better understand the mechanisms underlying the interpatients variability and to identify patients who may receive the best benefit from this specific radiotherapy treatment.Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.

The prognostic value of 18F-fluorodeoxyglucose positron emission tomography/ computed tomography parameters in patients with malignant pleural mesothelioma.

Background In this study, we aimed to investigate the prognostic value of metabolic 18F-fluorodeoxyglucose positron emission tomography/computed tomography parameters in malignant pleural mesothelioma patients. Methods A total of 65 patients with malignant pleural mesothelioma (34 males, 31 females; median age: 60 years; range, 39 to 84 years) who underwent whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography for staging before treatment between March 2008 and January 2018 were included. Relationships between clinicopathological factors and 18F-fluorodeoxyglucose positron emission tomography/computed tomography parameters and overall survival were evaluated using a log-rank test and Cox regression analysis. Results The median follow-up was 13 (range, 4 to 55) months. The Kaplan-Meier analysis revealed a mean survival time of 17±2.6 months. The cumulative two- and five-year survival rates were 34.8% and 7.8%, respectively. Univariate analysis showed that ≥60 age, left hemithorax involvement, a maximum standardized uptake value of ≥9.8, c-T4 status, c-M1 status, and non-surgery were negatively associated with overall survival (p<0.05). Multivariate analysis showed that ≥60 age, left hemithorax involvement, a maximum standardized uptake value of ≥9.8, c-M1 status, and a total lesion glycolysis of ≥180.2 g were negatively associated with overall survival (p<0.05). Conclusion Metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography/computed tomography have the potential to provide prognostic information for malignant pleural mesothelioma patients who are receiving surgery and/or chemotherapy.

Clinical prognostic factors in pleural mesothelioma: best supportive care and anti-tumor treatments in a real-life setting

Background This study aims to investigate patient- and disease characteristics associated with survival in malignant pleural mesothelioma (MPM) patients with anti-tumor treatment or with best supportive care (BSC). Materials and methods Consecutive MPM cases diagnosed in North Denmark Region from 1972 to 2015 were reevaluated and verified by two pathologists using modern immunohistochemical techniques. Danish registries and hospital records were used to gather patient-, asbestos exposure-, and disease information. Results Of the 279 patients, anti-tumor treatment was administered to 184 patients (66.0%). All of those received chemotherapy alone or as part of a multimodal treatment, where pemetrexed was given to 126 (68.5%) patients. Asbestos exposure was documented in 92.5% of all patients. In the treated group, mean age was lower (66 years versus 74 years, p < 0.01), rate of occupational asbestos exposure was higher (74.5 versus 54.7%, p < 0.01), more patients had better performance score (98.4 versus 60%, p < 0.01) and stage was lower (81 versus 63.2%, p < 0.01) compared to the BSC group. Multivariate analysis showed that epithelioid subtype was the only common prognostic factor for OS in both groups. In BSC patients, good PS and female gender was associated with improved OS. Median overall survival (OS) was 17 versus 4 months (p < 0.01), and independently of the histopathological subtype, the median and 2-year survival was higher in the treated versus the BSC group (p < 0.02). Conclusions This retrospective study showed that epithelioid subtype is the only independent positive prognostic factor of survival in treated patients with MPM. For BSC patients, the epithelioid subtype, good PS, and female gender were positive prognostic factors, while age and comorbidities were not significant. This study with long-term follow-up of treated and BSC MPM patients can contribute to the clinical stratification of patients. Further validation is appropriate to verify these findings.

Metformin Induces Apoptosis and Inhibits Notch1 in Malignant Pleural Mesothelioma Cells.

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related cancer arising from the mesothelial cells lining the pleural cavity. MPM is characterized by a silent clinical progression and a highly resistance to conventional chemo/radio-therapies. MPM patients die in a few months/years from diagnosis. Notch signaling is a well-conserved cell communication system, which regulates many biological processes. In humans, the dysregulation of Notch pathway potentially contributes to cancer onset/progression, including MPM. Metformin is the first-line drug used to treat type 2 diabetes mellitus. Metformin is proven to be an effective antitumor drug in preclinical models of different types of cancer. To date, clinical efficacy is being studied in many clinical trials. In this study, the anti-proliferative effect of metformin on MPM cells and the putative involvement of Notch1 as a mediator of metformin activities, were investigated. MPM cells showed high levels of Notch1 activation compared to normal pleural mesothelial cells. Furthermore, metformin treatment hampered MPM cell proliferation and enhanced the apoptotic process, accompanied by decreased Notch1 activation.

Relationship between Pretreatment Serum Albumin Levels with the Risk of Malignant Pleural Mesothelioma

Background: Malignant Pleural Mesothelioma (MPM) is a very rare and aggressive form of cancer. Recently it was found that pretreatment Serum Albumin (SA), the main circulating protein in blood is a significant prognostic factor for MPM patients. The objective of this present article is to show the relationship between pretreatment Serum albumin (SA) levels with the risk of MPM. Methods: Generalized additive model (GAM), an advanced regression analysis method has been introduced here to find this mathematical relationship between the response variable (SA) and the cofactors. Results: The main determinates of SA are identified - asbestos exposure, hemoglobin, disease diagnosis status (patients having MPM) are the factors having significant association with SA, whereas duration of asbestos exposure, duration of disease symptoms, total protein (TP), Pleural lactic dehydrogenise (PLD), pleural protein (PP), pleural glucose (PG) and C-reactive protein (CRP) are the significant continuous variables for SA. The non-parametric estimation part of this model shows Lactate dehydrogenase (LDH) and Glucose level are the significant smoothing terms. Additionally it is also found that, second and third order interactions between cofactors are highly significant for SA. Conclusions: The findings of this present work can conclude that - serum albumin may play the role of a very significant prognostic factor for MPM disease and it has been established here through mathematical modeling. Few of the findings are already been exist in MPM research literature whereas some of the findings are completely new in the literature.

A review of malignant pleural mesothelioma in a large North East UK pleural centre.

ObjectivesThe National Mesothelioma Audit 2020 showed Northumbria to have low rates of histopathological confirmation, treatment and one-year survival rates for malignant pleural mesothelioma (MPM). We hypothesized that an internal analysis over a 10-year period provides valuable insights into presentation, diagnosis, treatment and outcomes.MethodsA single-centre retrospective case series of all confirmed MPM patients between 1 January 2009 and 31 December 2019 was performed. Demographics, clinical, radiological and histopathological characteristics and outcomes were collected. Statistical analysis was performed using SPSS V26.0.ResultsA total of 247 patients had MPM. About 86% were male, mean age 75.7 years. Dyspnoea (77.4%) and chest pain (38.5%) were commonest symptoms. 64.9 and 71.4% had pleural thickening and effusion, respectively. About 86.8% had at least one attempt to obtain a tissue biopsy, but histopathological confirmation in only 108 (43.7%). About 66.3% with PS 0 and 1 (62.7% of total cohort) had at least one anti-cancer therapy. Death within 12 months was associated with disease progression within 6 months (p≤0.001). Chemotherapy (p≤0.001) and epithelioid histological subtype (p=0.01) were protective.ConclusionsThis study confirms known epidemiology of MPM, demonstrates variability in practices and highlights how some NMA recommendations are not met. This provides the incentive for a regional mesothelioma multi-disciplinary meeting.

Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients

Simple SummaryMalignant pleural mesothelioma (MPM) is a rare tumor with unfavorable prognosis for which new therapeutic interventions are urgently needed. The aim of our study was to develop a preclinical model representative of the different histotypes found in human tumors that can be used as models for the discovery of new treatments and combinations. We successfully generated patient-derived xenografts (PDXs) from MPM, which strongly resembled the tumors of origin in terms of morphology and immunohistochemistry. These tumors, when growing in mice, poorly respond to cisplatin, a finding that aligned with the clinical results. From one of the PDXs, we generated 2D and 3D cultures maintaining the phenotypical characteristics of human tumors and PDXs. Altogether, these preclinical models represent a useful tool for the discovery of new targets and drug combinations.Background: Malignant pleural mesothelioma (MPM) is a very aggressive tumor originating from mesothelial cells. Although several etiological factors were reported to contribute to MPM onset, environmental exposure to asbestos is certainly a major risk factor. The latency between asbestos (or asbestos-like fibers) exposure and MPM onset is very long. MPM continues to be a tumor with poor prognosis despite the introduction of new therapies including immunotherapy. One of the major problems is the low number of preclinical models able to recapitulate the features of human tumors. This impacts the possible discovery of new treatments and combinations. Methods: In this work, we aimed to generate patient-derived xenografts (PDXs) from MPM patients covering the three major histotypes (epithelioid, sarcomatoid, and mixed) occurring in the clinic. To do this, we obtained fresh tumors from biopsies or pleurectomies, and samples were subcutaneously implanted in immunodeficient mice within 24 h. Results: We successfully isolated different PDXs and particularly concentrated our efforts on three covering the three histotypes. The tumors that grew in mice compared well histologically with the tumors of origin, and showed stable growth in mice and a low response to cisplatin, as was observed in the clinic. Conclusions: These models are helpful in testing new drugs and combinations that, if successful, could rapidly translate to the clinical setting.

High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients.

In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients treated with PD-1 inhibitors. A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated. Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P=.02), PFS (median 6.7 versus 2.9 months, hazard ratio [HR] 0.57, 95% CI 0.39-0.83, P<.01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45-1.00, P=.05). In the control MPM cohort treated with chemotherapy (n=77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P=.05), PFS (median 6.7 versus 2.4 months, P<.01), and OS (median not reached versus 6.0 months, P=.01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P=.04) and PFS (median 7.8 versus 3.6 months, P=.03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P=.30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P=.02 and P=.59, respectively). Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner.

Programmed cell death 1 ligand 1 (PD-L1) expression is associated with poor prognosis of malignant pleural mesothelioma patients with good performance status

Malignant pleural mesothelioma (MPM) is often associated with a poor prognosis and options for the treatment of this disease are few. To date, the important role of the immune microenvironment in modifying the disease natural history is well established. The programmed cell death pathway (PD-1/PD-L1) limits the T lymphocyte activation in peripheral tissues when an inflammatory response occurs, and controls the tumour immune escape. PD-L1 is broadly expressed in several malignant tumours and associated with poor clinical outcomes. Thus, the aim of our study is to investigate the potential role of PD-L1 expression in MPM prognosis. Biopsy samples from 198 patients diagnosed with MPM were examined by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) to evaluate PD-L1 protein and gene expression. For PD-L1 protein expression we consider at least 5% membranous staining as positive. Gene expression levels were calculated with ΔΔCt method. Positive expression of PD-L1 by IHC was correlated with worse overall survival (OS; p=0.0225) in MPM patients. PD-L1 positive status was correlated with worse OS in the subgroup of patients with ECOG score <2 (p=0.0004, n=129) and these data were confirmed by multivariate analysis. No significant correlation was found between PD-L1 gene expression and OS. Our results show that PD-L1 evaluated by IHC assay may be a prognostic biomarker for MPM patients with good performance status.

CT for detection of malignant posterior intercostal lymph nodes in patients undergoing pre-operative staging for malignant pleural mesothelioma

IntroductionRecent evidence suggests that patients with malignant pleural mesothelioma (MPM)undergoing extended pleurectomy/decortication (eP/D) with metastasis to the posterior intercostal lymph nodes (PILN) have a worse prognosis. In this study, we determine if MPM PILN metastasis can be reliably detected on computed tomography (CT). Materials and MethodsPreoperative staging CT exams were reviewed for the presence of PILN in MPM patients undergoing eP/D between 2007–2013 with surgical sampling of their PILN. CT images were reviewed by two thoracic radiologists blinded to clinical records, including operative pathology reports. The number and short axis size of PILN were recorded and correlated with surgical pathology. Statistical analysis examined the value of preoperative CT to detect metastatic PILN. ResultsOf 36 patients that underwent eP/D with PILN sampling had preoperative CT images for review. At surgery, 22 of these patients had metastatic PILN and 14 had benign PILN. The positive and negative predictive values for one or more nodes seen on preoperative CT were 60 % and 38 % respectively. The number of PILN on preoperative CT did not predict metastasis (p = 0.40) with an average of 2 PILN seen, regardless of PILN pathology. The average nodal short axis size was 4.6 mm and 4.8 mm for benign and malignant PILN, respectively, and PILN short axis size did not predict metastasis (p = 0.39). There was little inter-observer variability between the size and number of nodes detected by each radiologist. ConclusionsCT does not reliably identify metastatic PILN on preoperative CT for patients with MPM undergoing extended pleurectomy/decortication.

Prognostic Role of Programmed Cell Death 1 Ligand 1 in Resectable Pleural Mesothelioma

The prognostic role of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) is incompletely understood. Our objectives were to evaluate the evidence for tumor PD-L1 as a prognostic biomarker in MPM through meta-analysis and to determine whether tumor PD-L1 expression is associated with survival in MPM patients undergoing macroscopic complete resection. Meta-analysis was performed to determine the association of PD-L1 with overall survival in MPM (n= 1655) from 14 studies containing overall survival and tumor PD-L1 expression. Univariable and multivariable analyses tested the relationship of tumor PD-L1 with overall survival and recurrence-free survival in an institutional cohort of MPM patients treated by macroscopic complete resection (n= 75). To validate the association of PD-L1 with overall survival, we utilized two independent MPM cohorts (n= 284). Meta-analysis demonstrated that high tumor PD-L1 expression was associated with poor overall survival. Among 75 patients undergoing macroscopic complete resection, 49 tumors (65%) expressed PD-L1 (1% or more), and high PD-L1 (50% or greater) was more commonly expressed on nonepithelial (29%) compared with epithelial tumors (14%). High tumor PD-L1 expression was independently associated with poor overall survival (P < .001, hazard ratio 5.67) and recurrence-free survival (P= .003, hazard ratio 3.28). The association of PD-L1 overexpression with unfavorable survival was more significant in epithelial MPMs than nonepithelial MPMs. These findings were validated in RNA sequencing analyses in two independent cohorts. Exploratory transcriptome analysis revealed that MPM tumors with PD-L1 overexpression displayed coexpression of other immune regulatory molecules, programmed cell death 1 ligand 2 and T-cell immunoglobulin mucin receptor3. Tumor PD-L1 expression is a prognostic biomarker in patients undergoing surgical resection for MPM and may be useful in perioperative decision making.

DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma.

Simple SummaryOur study is the first one to investigate DNA methylation changes in white blood cells (WBCs) from easily accessible peripheral blood as malignant pleural mesothelioma (MPM) survival biomarker. The Cox proportional hazards regression model highlighted that the methylation status of the CpG dinucleotide cg03546163 is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Biological validation and replication showed that epigenetic changes at the FKBP5 gene were robustly associated with overall survival (OS) in MPM cases. The identification of simple and valuable prognostic markers for MPM will enable clinicians to select patients who are most likely to benefit from aggressive therapies and avoid subjecting non-responder patients to ineffective treatment.Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.

Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis.

Programmed death-ligand 1 (PD-L1) protein plays a central role in the antitumor immune response, and appears to be a predictor of prognosis and efficacy for PD-L1 and programmed death 1 (PD-1) blockade therapy. The immunoregulatory role and prognostic impact of PD-L1 soluble form (sPD-L1) have been investigated in biological fluids of patients with different tumors. In malignant pleural mesothelioma (MPM), circulating sPD-L1 has been recently reported in patients' sera, but no data are available in pleural effusions (PE). In our study, we evaluated the baseline expression levels of sPD-L1 in PE from 84 MPM patients and correlated them with PD-L1-status in matched tumors and patients' overall survival (OS). sPD-L1 in PE was determined by ELISA and tumor PD-L1 by immunohistochemistry. Association of sPD-L1 with OS was estimated using the Cox regression model. We observed that sPD-L1 was variably expressed in all the PE and tended to be higher (by 30%) in patients with PD-L1-positive tumors (cut-off ≥ 1% stained cells) as compared to patients with PD-L1-negative tumors (geometric mean ratio = 1.28, P value = 0.288). sPD-L1 levels were significantly higher than those of sPD-1 (P value = 0.001) regardless of the MPM histotypes and they were positively correlated (r = 0.50, P value < 0.001). Moreover, high PE sPD-L1 concentrations were associated with a trend towards increased OS (hazard ratio 0.79, 95% CL 0.62-1.01, P value = 0.062). Our study documents the presence of sPD-L1 in PE of MPM patients, and suggests its possible biological and prognostic role in MPM.

Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma

Simple SummaryMalignant pleural mesothelioma (MPM) is an incurable and aggressive malignancy mainly caused by exposure to asbestos fibers. Survival outcomes following the standard of care treatment, including chemotherapy and surgery, remain dismal. Targeted treatments are shortcomings for MPM, as this tumor is driven primarily by a loss of tumor suppressor genes. In this study, we explored the importance of proteins that have been shown to be dysregulated in MPM as a consequence of tumor suppressor gene loss, CUL4A and CUL4B. We assessed their expression levels and identified their correlation with clinical outcomes of MPM. We also aimed to test the efficacy and mechanisms of the available treatments that target these proteins, pevonedistat using in vitro and in vivo models. Our data suggested that CUL4B might serve as a treatment target for MPM and revealed novel mechanism of pevonedistat in the MPM tumor microenvironment. This data may be useful for understanding its efficacy in patients from clinical trials. Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.

Identification of CD24 as a potential diagnostic and therapeutic target for malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is currently incurable due to the lack of an effective early diagnostic method and specific medication. The CDKN2A (p16) and NF2 genes are both frequently mutated in MPM. To understand how these mutations contribute to MPM tumor growth, we generated NF2/p16 double-knockout (DKO) cell clones using human MeT-5A and HOMC-B1 mesothelial cell lines. Cell growth and migration activities were significantly increased in DKO compared with parental cells. cDNA microarray analysis revealed differences in global gene expression profiles between DKO and parental cells. Quantitative PCR and western blot analyses showed upregulation of CD24 concomitant with increased phosphorylation of AKT, p70S6K, and c-Jun in DKO clones. This upregulation was abrogated by exogenous expression of NF2 and p16. CD24 knockdown in DKO cells significantly decreased TGF-β1 expression and increased expression of E-cadherin, an epithelial–mesenchymal transition marker. CD24 was highly expressed in human mesothelioma tissues (28/45 cases, 62%) and associated with the loss of NF2 and p16. Public data analysis revealed a significantly shorter survival time in MPM patients with high CD24 gene expression levels. These results strongly indicate the potential use of CD24 as a prognostic marker as well as a novel diagnostic and therapeutic target for MPM.

The Impact on Outcome by Adding Bevacizumab to Standard Induction Chemotherapy Prior to Mesothelioma Surgery: A Retrospective Single Center Analysis.

ObjectivesAdding bevacizumab, an anti-Vascular Endothelial Growth Factor (VEGF), to platinum-based chemotherapy/pemetrexed in 1st line treatment of advanced malignant pleural mesothelioma (MPM), significantly improved overall survival. However, increased high grade bleeding after operation was reported in patients with colorectal cancer who previously received bevacizumab. In the present analysis, we assessed for the first time the impact of adding bevacizumab to induction chemotherapy prior to surgery for mesothelioma patients.MethodsTwo hundred twenty-seven MPM patients, intended to be treated with induction chemotherapy followed by surgery at the University Hospital of Zurich between 2002 and December 2018, were included in the present analysis. After propensity score matching for gender, histology and age (1:3 ratio), data from 88 patients were analyzed. Sixty-six patients underwent induction chemotherapy (with cis-/carboplatin and pemetrexed: control group) alone and 22 patients underwent induction chemotherapy with the addition of bevacizumab (bevacizumab group) prior macroscopic complete resection (MCR). Perioperative and long-term outcome variables were analyzed.ResultsPatients undergoing combination treatment with bevacizumab had a significantly better response than with chemotherapy alone as assessed by modified RECIST (p=0.046). Intraoperative complications in the bevacizumab group (one patient), or in the control group (three patients) were not related to intraoperative bleeding. Postoperative transfusion of blood products occurred in a larger amount in the control group than in the bevacizumab group (p=0.047). Overall survival was not statistically different between both groups.ConclusionThese initial data demonstrate that MCR can be performed safely after triple induction chemotherapy with bevacizumab without increased intra- and postoperative bleeding complications. Response rates were significantly improved by the addition of bevacizumab.