Prognosis Of Malignant Pleural Mesothelioma Research Articles

Mesothelin-targeted MRI for assessing migration, invasion, and prognosis in malignant pleural mesothelioma

BackgroundMesothelin (MSLN) has been implicated in cancer migration, invasion, and prognosis, making it a potential tumor marker. However, the precise role of MSLN in the migration and invasion of malignant pleural mesothelioma (MPM) remains elusive, and effective noninvasive methods for assessing MSLN status are currently lacking. In this study, we focused on MSLN expression and elucidated the underlying mechanisms by which MSLN regulates migration and invasion in MPM. Building upon this knowledge, we developed an MRI nanoprobe that targets MSLN to assess its status in vitro and in vivo by comparing T2 signal intensity and T2 values on magnetic resonance imaging examinations. This nanoprobe combines the anatomical information obtained from MRI with biological information obtained from MSLN for comprehensive evaluation of MPM.ResultsNotably, we observed that MSLN expression in the epithelial type of MPM was higher and increased continuously with tumor growth than that in other types. In addition, MSLN upregulation promoted N-cadherin, matrix metalloproteinase-7, and MMP9 expression and resulted in higher migration/invasion ability and shorter survival. We synthesized MSLN-targeted nanoprobes (Fe3O4@SiO2-PEG-MSLN, FSPM) to assess MSLN expression by comparing the T2 signal intensity and T2 value of different cell lines and mice after 14, 28, and 42 days of modeling. Remarkably, MSLN-targeted nanoprobes demonstrated excellent targeting capabilities. In vitro studies revealed a pronounced reduction in T2 signal intensity and T2 values of the epithelial type as the probe concentration increased. In addition, in vivo experiments demonstrated a gradual decline in these parameters over time, particularly in the epithelial type as compared to the biphasic type, corresponding to the dynamic expression patterns of MSLN during different growth stages.ConclusionOur comprehensive research succeeded in confirming the regulatory mechanisms by which MSLN influences migration and invasion. Moreover, we introduced a promising method for monitoring MSLN expression that may help in facilitating the early detection, histological subtype identification, and assessment of migration, invasion, and prognosis in MPM.

LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study

BackgroundLymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM.MethodsWe used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan–Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed.ResultsLAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM.ConclusionsLAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM.Trial registrationThis study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022–0048) at Tokyo Women’s Medical University.

Pleural Fluid-to-Blood BNP Ratio May Contribute to Prognosis in Malignant Pleural Mesothelioma.

Brain natriuretic peptide (BNP) seems to be produced from malignant mesothelial cells other than cardiomyocytes. We aimed to evaluate whether an increased pleural fluid-to-blood BNP ratio in patients with malignant pleural mesothelioma (MPM) could facilitate prognosis beyond diagnosis. Patients with MPM were included (observational study). One- and two-year survival and factors affecting it were tested. To evaluate the prognostic significance of the natriuretic peptide precursor B (NPPB) gene expression in MPM, we constructed a survival curve from data derived from The Cancer Genome Atlas. Nineteen consecutive patients with MPM were included (age: 67 (61, 80), male 78.9%). One- and two-year survival were 52.6% and 31.6%, respectively. Age, performance status, and the other variables tested did not differ between survivors and non-survivors. Non-survivors presented higher pleural fluid BNP in two years (699 (210, 5000) vs. 379.5 (5, 567), p = 0.036) and BNP ratios than survivors (1-year: 28.75 (4.05, 150.24) vs. 3.49 (0.3, 26) p = 0.001, 2-years: 22.8 (2.42, 150.24) vs. 3.49 (0.3, 7.76), p = 0.001). One- and two-year survival rates in patients with BNP ratios above/equal to the median value (8.82) were 20% and 0%, and 88.9% and 66.7%, respectively, in patients with BNP ratios below 8.82 (p = 0.006 and p = 0.002, respectively). MPM patients with low NPPB expression presented significantly higher survival rates compared to patients with higher expressions (p = 0.032). A high pleural fluid/blood BNP ratio, an easily performed in everyday practice, costless biomarker seems to predict poorer survival better than the commonly reported prognostic factors in MPM.

An anoikis-based gene signature for predicting prognosis in malignant pleural mesothelioma and revealing immune infiltration.

Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant tumor. Anoikis is a particular type of programmed apoptosis brought on by the separation of cell-cell or extracellular matrix (ECM). Anoikis has been recognized as a crucial element in the development of tumors. However, few studies have comprehensively examined the role of anoikis-related genes (ARGs) in malignant mesothelioma. ARGs were gathered from the GeneCard database and the Harmonizome portals. We obtained differentially expressed genes (DEGs) using the GEO database. Univariate Cox regression analysis, and the least absolute shrinkage and selection operator (LASSO) algorithm were utilized to select ARGs associated with the prognosis of MPM. We then developed a risk model, and time-dependent receiver operating characteristic (ROC) analysis and calibration curves were employed to confirm the ability of the model. The patients were divided into various subgroups using consensus clustering analysis. Based on the median risk score, patients were divided into low- and high-risk groups. Functional analysis and immune cell infiltration analysis were conducted to estimate molecular mechanisms and the immune infiltration landscape of patients. Finally, drug sensitivity analysis and tumor microenvironment landscape were further explored. A novel risk model was constructed based on the six ARGs. The patients were successfully divided into two subgroups by consensus clustering analysis, with a striking difference in the prognosis and landscape of immune infiltration. The Kaplan-Meier survival analysis indicated that the OS rate of the low-risk group was significantly higher than the high-risk group. Functional analysis, immune cell infiltration analysis, and drug sensitivity analysis showed that high- and low-risk groups had different immune statuses and drug sensitivity. In summary, we developed a novel risk model to predict MPM prognosis based on six selected ARGs, which could broaden comprehension of personalized and precise therapy approaches for MPM.

A biomarker predicting unfavorable prognosis in malignant pleural mesothelioma: systemic immune–inflammation index

Aim: Malignant pleural mesothelioma (MPM) is an extremely mortal condition. Only a few prognostic biomarkers have been described for MPM. Our study looked into the association between patient survival and the Systemic Immune Inflammation Index (SII).
 Material and Method: A total of 158 patients who were admitted to our hospital between January 2013 and December 2022, and had a histopathologically confirmed diagnosis of MPM were included in the study. Before treatment, hematological parameters and SII were determined. A Spearman's correlation analysis was performed to analyze the correlation of mean survival with hematological parameters.
 Results: The study involved 158 patients in all. 70 patients had a history of smoking, the median age was 63 years, the mean survival time was 15.3 months, and 57.6% of the participants were men. The epithelioid type (84.2%) was the most prevalent histological subtype, and 29 patients had stage 4 illnesses. Of the participants, 84% had received chemotherapy, and 22% had received radiotherapy before. Among the 39 patients who had surgery, 5 had an extrapleural pneumonectomy. SII mean±sd was (1427.2±1207.3). The patients with stage 4 disease had significantly shorter survival (p=0.001). The patients who had surgery survived significantly longer (p=0.01). Hemoglobin (Hb) (r:0.21, p:0.01) and Hematocrit (Hct) (r:0.18, p:0.03) values showed weak positive correlations with mean survival. It was evident that mean survival got shorter as SII (r:-0.17, p:0.04) and neutrophil-lymphocyte ratio (NLR) (r:-0.19, p:0.02) values got higher. On the other hand, there was a strong positive association between mean survival and the lymphocyte-monocyte ratio (LMR) (r:0.21, p:0.01). When the parameters that had statistically significant differences among the groups were taken as control variables and the statistical analysis was re-performed, it was found that Hgb and Hct values as well as NLR and LMR ratios lost their significant correlations with survival. However, the SII ratio was still negatively correlated with survival (r:-0.16, p:0.04). 
 Conclusion: Pretreatment SII is a noninvasive and easy-to-calculate biomarker that predicts the prognosis of MPM. It is negatively correlated with mean survival regardless of the tumor stage and surgical management.

Expression of CD24 gene in human malignant pleural mesothelioma and its relationship with prognosis

Objective: To investigate the expression of CD24 gene in human malignant pleural mesothelioma (MPM) cells and tissues, and evaluate its relationship with clinicopathological characteristics and clinical prognosis of MPM patients. Methods: In February 2021, UALCAN database was used to analyze the correlation between CD24 gene expression and clinicopathological characteristics in 87 cases of MPM patients. The TIMER 2.0 platform was used to explore the relationship between the expression of CD24 in MPM and tumor immune infiltrating cells. cBioportal online tool was used to analyze the correlation between CD24 and MPM tumor marker gene expression. RT-qPCR was used to analyze the expressions of CD24 gene in human normal pleural mesothelial cell lines LP9 and MPM cell lines NCI-H28 (epithelial type), NCI-H2052 (sarcoma type), and NCI-H2452 (biphasic mixed type). RT-qPCR was performed to detect the expressions of CD24 gene in 18 cases of MPM tissues and matched normal pleural tissues. The expression difference of CD24 protein in normal mesothelial tissue and MPM tissue was analyzed by immunohistochemistry. A Kaplan-Meier model was constructed to explore the influence of CD24 gene expression on the prognosis of MPM patients, and Cox regression analysis of prognostic factors in MPM patients was performed. Results: The CD24 gene expression without TP53 mutation MPM patients was significantly higher than that of patients in TP53 mutation (P<0.05). The expression of CD24 gene in MPM was positively correlated with B cells (r(s)=0.37, P<0.001). The expression of CD24 gene had a positive correlation with the expressions of thrombospondin 2 (THBS2) (r(s)=0.26, P<0.05), and had a negative correlation with the expression of epidermal growth factor containing fibulin like extracellular matrix protein 1 (EFEMP1), mesothelin (MSLN) and calbindin 2 (CALB2) (r(s)=-0.31, -0.52, -0.43, P<0.05). RT-qPCR showed that the expression level of CD24 gene in MPM cells (NCI-H28, NCI-H2052 and NCI-H2452) was significantly higher than that in normal pleural mesothelial LP9 cells. The expression level of CD24 gene in MPM tissues was significantly higher than that in matched normal pleural tissues (P<0.05). Immunohistochemistry showed that the expressions of CD24 protein in epithelial and sarcoma MPM tissues were higher than those of matched normal pleural tissues. Compared with low expression of CD24 gene, MPM patients with high expression of CD24 gene had lower overall survival (HR=2.100, 95%CI: 1.336-3.424, P<0.05) and disease-free survival (HR=1.800, 95%CI: 1.026-2.625, P<0.05). Cox multivariate analysis showed that compared with the biphasic mixed type, the epithelial type was a protective factor for the prognosis of MPM patients (HR=0.321, 95%CI: 0.172-0.623, P<0.001). Compared with low expression of CD24 gene, high expression of CD24 gene was an independent risk factor for the prognosis of MPM patients (HR=2.412, 95%CI: 1.291-4.492, P=0.006) . Conclusion: CD24 gene and protein are highly expressed in MPM tissues, and the high expression of CD24 gene suggests poor prognosis in MPM patients.

Clinical, Laboratory, Histological, Radiological, and Metabolic Features and Prognosis of Malignant Pleural Mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is an aggressive and rare malignant pleural tumor. Methods: MPM patients diagnosed in Beijing Chaoyang Hospital and Beijing Tongren Hospital were the focus of this study. We collected and analyzed the histological, radiological, and metabolic features of MPM patients. At the same time, Cox univariable and multivariable analyses were used to explore the laboratory risk factors affecting the prognosis of MPM patients. Results: A total of 129 MPM patients were included in this study. MPM includes three main histological subtypes: epithelioid, sarcomatoid and biphasic. Among them, epithelial subtypes accounted for the highest proportion. Calretinin, Wilms' tumor gene (WT1), cytokeratin 5/6 (CK5/6), and D2-40 were the most useful mesothelial markers to support a MPM diagnosis. The imaging features of MPM patients are pleural thickening and pleural effusion. In PET-CT, the affected pleura showed obvious high uptake of tracer, and the degree was related to the specific subtype. The median follow-up time was 55.0 (30.0, 94.0) months. A total of 92 (71.3%) patients died during follow-up. The median survival time of patients was 21.0 (9.0, 48.0) months. The Cox multivariable analysis showed that age [hazard ratio (HR), 1.824; 95% confidence interval (CI) 1.159-2.872; p = 0.009; uncorrected], ESR (HR, 2.197; 95% CI 1.318-3.664; p = 0.003; with Bonferroni correction), lymphocytes (HR, 0.436; 95% CI 0.258-0.737; p = 0.002; with Bonferroni correction), platelets (HR, 1.802; 95% CI 1.084-2.997; p = 0.023; uncorrected) and total protein (HR, 0.625; 95% CI 0.394-0.990; p = 0.045; uncorrected) were independent risk factors for prognosis, after adjusting for confounding factors. Conclusions: Age, ESR, lymphocytes, platelets and total protein may be related to the prognosis of MPM patients. Summarizing the histological, radiological, and metabolic features of MPM patients in the two centers can increase clinicians' understanding of this rare tumor.

Diagnostic and Therapeutic Challenges of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma is a rare cancer characterized by a very poor prognosis. Exposure to asbestos is the leading cause of malignant pleural mesothelioma. The preinvasive lesions, the mesothelial hyperplasia and its possible evolution are the focus of the majority of the studies aiming to identify the treatable phase of the disease. The role of BAP-1 and MTAP in the diagnosis of mesothelioma in situ and in the prognosis of malignant pleural mesothelioma is the main topic of recent studies. The management of preinvasive lesions in mesothelioma is still unclear and many aspects are the subject of debate. The diagnosis, the disease staging and the accurate, comprehensive assessment of patients are three key instants for an appropriate management of patients/the disease.

Identification of glycolysis genes signature for predicting prognosis in malignant pleural mesothelioma by bioinformatics and machine learning.

Glycolysis-related genes as prognostic markers in malignant pleural mesothelioma (MPM) is still unclear. We hope to explore the relationship between glycolytic pathway genes and MPM prognosis by constructing prognostic risk models through bioinformatics and machine learning. The authors screened the dataset GSE51024 from the GEO database for Gene set enrichment analysis (GSEA), and performed differentially expressed genes (DEGs) of glycolytic pathway gene sets. Then, Cox regression analysis was used to identify prognosis-associated glycolytic genes and establish a risk model. Further, the validity of the risk model was evaluated using the dataset GSE67487 in GEO database, and finally, a specimen classification model was constructed by support vector machine (SVM) and random forest (RF) to further screen prognostic genes. By DEGs, five glycolysis-related pathway gene sets (17 glycolytic genes) were identified to be highly expressed in MPM tumor tissues. Also 11 genes associated with MPM prognosis were identified in TCGA-MPM patients, and 6 (COL5A1, ALDH2, KIF20A, ADH1B, SDC1, VCAN) of them were included by Multi-factor COX analysis to construct a prognostic risk model for MPM patients, with Area under the ROC curve (AUC) was 0.830. Further, dataset GSE67487 also confirmed the validity of the risk model, with a significant difference in overall survival (OS) between the low-risk and high-risk groups (P < 0.05). The final machine learning screened the five prognostic genes with the highest risk of MPM, in order of importance, were ALDH2, KIF20A, COL5A1, ADH1B and SDC1. A risk model based on six glycolytic genes (ALDH2, KIF20A, COL5A1, ADH1B, SDC1, VCAN) can effectively predict the prognosis of MPM patients.

Marital status as an independent prognostic factor for patients of malignant pleural mesothelioma.

The prognostic impact of marital status on malignant pleural mesothelioma (MPM) is not investigated. This paper probes into the relationship between the prognosis of MPM and marital status. The Surveillance, Epidemiology, and End Results (SEER) database of American had been applied to choose eligible patients over the 2004-2015 periods. Moreover, cancer-specific survival (CSS) and overall survival (OS) of unmarried and married groups were compared. A total of 3,997 patients in total had been identified, including 2,735 (68.43%) married patients. In comparison to unmarried patients, married ones tended to be younger, male, white, and received active treatment (surgery, chemotherapy, or radiotherapy). In addition, the 1, 3, and 5-year CSS rates were 44.40, 12.09, and 6.88% in married patients, while 35.75, 12.12, and 6.37% in unmarried group (p = 0.0014). At the same time, the 1, 3, and 5-year OS rates were 41.84, 10.56, and 5.91% in married patients, while 33.67, 10.44, and 4.93%, respectively, in the unmarried group (p < 0.0001). As revealed by the multivariate analysis results, the marital status was an independent favorable prognostic factor, in which the married groups showed better CSS [hazard ratio (HR): 0.870; 95% confidence interval (CI): 0.808-0.938; p < 0.001] as well as OS (HR: 0.871; 95% CI: 0.810-0.936; p < 0.001). According to the results of subgroup analysis, the CSS and OS survival of married groups were better than the unmarried groups in almost all the subgroups. Marital status is an independent favorable prognostic indicator of MPM. Poor prognosis in unmarried patients is likely to be related to insufficient treatments and socioeconomic and psychosocial factors.

EP07.01-011 Integrating PD-L1 Expression to the CALGB Prognostic Scoring System in Malignant Pleural Mesothelioma

Programmed death ligand-1 (PD-L1) expression is a predictive biomarker guiding treatment decisions with immunotherapy in lung cancer patients, but its role in malignant pleural mesothelioma (MPM) is unclear. However, evidence suggests that higher PDL-1 expression correlates with worse survival outcomes. The Cancer and Leukemia Group B (CALGB) prognostic scoring system is widely used to define prognosis in MPM. This study aims to assess the prognostic value of PDL-1 expression integrating it into the CALGB scoring system.

Prognostic risk assessment model for alternative splicing events and splicing factors in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and highly malignant thoracic tumor. Although alternative splicing (AS) is associated with tumor prognosis, the prognostic significance of AS in MPM is unknown. Transcriptomic data, clinical information, and splicing percentage values for MPM were obtained from The Cancer Genome Atlas (TCGA) and TCGA SpliceSeq databases. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox analyses were performed to establish a model affecting the prognosis of MPM. Survival and ROC analyses were used to test the effects of the prognostic model. LASSO/multivariate Cox analysis was used to construct the MPM prognostic splicing factor (SF) model. The SF-AS interaction network was analyzed using Spearman correlation and visualized using Cytoscape. The association between the MPM prognostic SF model and drug sensitivity to chemotherapeutic agents such as cisplatin was analyzed using pRRophetic.R. The LASSO/multivariate Cox analysis identified 41 AS events and 2 SFs that were mostly associated with survival. Nine prognostic prediction models (i.e., seven types of AS model, total AS model, and SF model) were developed. An MPM prognostic SF-AS regulatory network was subsequently constructed with decreased drug sensitivity in the SF model high-risk group (p=0.025). This study provides the first comprehensive analysis of the prognostic value of AS events and SFs in MPM. The SF-AS regulatory network established in this study and our drug sensitivity analysis using the SF model may provide novel targets for pharmacological studies of MPM.

A combination of intrinsic and extrinsic features improves prognostic prediction in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a lung pleural cancer with very poor disease outcome. With limited curative MPM treatment available, it is vital to study prognostic biomarkers to categorise different patient risk groups. We defined gene signatures to separately characterise intrinsic and extrinsic features, and investigated their interactions in MPM tumour samples. Specifically, we calculated gene signature scores to capture the downstream pathways of major mutated driver genes (BAP1, NF2, SETD2 and TP53) as tumour-intrinsic features. Similarly, we inferred the infiltration levels for major immune cells in the tumour microenvironment to characterise tumour-extrinsic features. Lastly, we integrated these features with clinical factors to predict prognosis in MPM. The gene signature scores were more prognostic than the corresponding genomic mutations, mRNA and protein expression. High immune infiltration levels were associated with prolonged survival. The integrative model indicated that tumour features provided independent prognostic values than clinical factors and were complementary with each other in survival prediction. By using an integrative model that combines intrinsic and extrinsic features, we can more correctly predict the clinical outcomes of patients with MPM.

Prognostic value of 18F-FDG PET/CT in malignant pleural mesothelioma: a meta-analysis.

Several FDG PET/CT parameters have been utilized to evaluate the prognosis in malignant pleural mesothelioma (MPM). However, there are still controversial results due to the low incidence of MPM. To assess the prognostic value of 18F-FDG PET/CT in MPM. A systematic literature search was performed in PubMed, Embase, Medline, and The Cochrane Library to identify eligible studies from inception to 12 February 2020. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) of several variables, such as maximum standardized uptake value (SUVmax), the reduction of SUVmax after treatment (ΔSUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and the reduction of TLG after treatment (ΔTLG), were calculated. Meta-regression with subsequent subgroup analyses were conducted to determine the heterogeneity of cutoff values, treatment regimen, study design, uptake time, and scanners across various studies. In total, 19 eligible studies including 1819 patients were enrolled in the meta-analysis. The univariate analysis showed that the pooled HRs (95% CI) of SUVmax, ΔSUVmax, MTV, TLG, and ΔTLG were 1.29 (1.16-1.42), 1.12 (1.05-1.19), 1.15 (1.00-1.33), 1.47 (1.23-1.76), and 1.27 (1.12-1.45), respectively. The multivariate analysis showed that the pooled HRs (95% CI) of SUVmax, ΔSUVmax, MTV, and TLG for overall survival (OS) were 1.20 (1.08-1.33), 1.10 (1.02-1.19), 0.95 (0.81-1.11), and 1.13 (1.08-1.18), respectively. SUVmax, ΔSUVmax, TLG, and ΔTLG are significant prognostic indicators for OS, while more clinical studies are needed to confirm the prognostic value of MTV in MPM.

Prognostic impact of inflammation in malignant pleural mesothelioma: A large-scale analysis of consecutive patients

BackgroundPrediction of prognosis is a key step of malignant pleural mesothelioma (MPM) management and treatment assignment. Aim of this study was to identify simple prognostic factors, focusing on inflammation-related parameters. MethodsBaseline clinical and laboratory data were extracted from a single-center 20-year cohort of consecutive patients exhibiting a proven MPM. Inflammation-related ratios and composite scores were evaluated as prognostic indicators. Results468 patients were identified. Mean age and BMI were 73.0 years and 25.1 kg/m2. The histologic subtype was epithelioid, sarcomatoid, or biphasic in 80.3%, 6.2%, and 13.5% of cases, respectively. Mean Neutrophil to Lymphocyte Ratio (NLR), systemic Inflammation Index (SII) and Advanced Lung cancer inflammation Index (ALI) were 5.8, 1,836.6, and 29.6. Median survival was 13.0 months. Univariate analyses revealed that age > 70 years, persistent asthenia, hemoglobin < 13 g/dL, and non-epithelioid histologic type were associated with poorer survival, as well as the following high-inflammation-related criteria: CRP > 25 mg/L, white blood cell count (WBC) > 109/dL, NLR > 5, SII > 1,270, and ALI < 18. Multivariate regression showed that age, histology, hemoglobin, and WBC were independent predictors of survival. Also, the inflammation-related factors ALI and NLR were independently associated with survival. Interestingly, hemoglobin was statistically significant predictor of survival in all multivariate models. We found higher proportion of survival > 18 months (66th percentile) in patients exhibiting SII < 2,000 and NLR < 5. ConclusionThe prognosis of MPM is strongly influenced by systemic inflammation and patients exhibiting higher NLR, SII and lower ALI have shorter survival, which strengthens the level of evidence about the major role played by inflammation in MPM.

Butein-instigated miR-186-5p-dependent modulation of TWIST1 affects resistance to cisplatin and bioenergetics of Malignant Pleural Mesothelioma cells.

Aim: Malignant pleural mesothelioma is a chemoresistant tumor, and biphasic and sarcomatoid histologies portend the worst prognosis for malignant pleural mesothelioma (MPM) patients. We obtained the microRNA expression profile of three biphasic-sarcomatoid MPM cell lines to identify commonly expressed microRNAs and evaluate the effect of butein, a chemo-sensitizing compound, on this microRNA subset. Methods: Nanostring-based microRNA profiling and analysis through the ROSALIND platform were employed to identify the commonly modulated microRNAs and their targets. MicroRNA-mimic transfection, Luciferase assay, and Western blotting were employed to show specific perturbation of TWIST1 levels by miR-186-5p. Sphere-forming assays, invasion assay, and metabolic profiling were used to assess the biological consequences of the butein-instigated miR-186-5p-mediated perturbation of TWIST1 levels. TGCA analysis was used to search for the correlation between TWIST1 and miR-186-5p levels in biphasic and epithelioid MPM specimens. Results: We identified a set of perturbed microRNAs, common to three biphasic/sarcomatoid MPM cell lines, after butein treatment. When focusing on miR-186-5p, we unraveled a butein-ignited and miR-186-5p-mediated modulation of TWIST1 levels which affected the 3D anchorage-independent growth, cisplatin resistance, invasion, and bioenergetics of the MPM cell lines tested. We showed that miR-186-5p and TWIST1 levels are anti-correlated in biphasic MPM specimens from TCGA. Conclusion: We unraveled a novel mechanism of action of butein, which attenuated the pro-tumorigenic features of MPM at least through a miR-186-5p-TWIST1 axis. We suggest that those activities converge into the chemo-sensitizing effect of this compound and may be of translational relevance.

The Association Between Pleural Fluid Exposure and Survival in Pleural Mesothelioma

Most patients with malignant pleural mesothelioma (MPM) seek treatment with malignant pleural effusion (MPE). Invitro evidence suggests that MPE may not be a simple bystander of malignancy, but rather potentially has biological properties that improve cancer cell survival and promote cancer progression. If this is the case, MPE management may need to shift from current symptomatic strategies to aggressive fluid removal to impact survival. Is there an association between pleural fluid exposure and survival in MPM? Data from 761 patients who received a diagnosis of MPM between 2008 and 2018 were collected from patient medical records in three UK pleural units. Data included factors previously identified as influencing prognosis in MPM. Medical imaging was reviewed for presence, size, and duration of pleural effusion. Time-dependent covariate analysis of pleural fluid exposure and survival (model included weight loss, serum albumin, hemoglobin, MPM subtype, performance status, chemotherapy, and age) and multivariate Cox regression analysis of pleurodesis and survival were conducted. Median overall survival was 278days (interquartile range, 127-505days; 95%CI, 253-301days). Pleural fluid exposure duration showed no association with survival (hazard ratio, 1.0; 95%CI, 1.0-1.0). Median survival was 473, 378, and 258days with complete, partial, and no pleurodesis (P= .008). Pleurodesis success seems to be associated with improved survival; however, it is unclear whether duration of MPM exposure to pleural fluid is associated with survival within the limitations of this retrospective study. Future prospective studies are required to assess this potentially important mechanism.

A narrative review of the health disparities associated with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a cancer of the mesothelial lining of the pleura that has traditionally been associated with asbestos exposure in an industrial setting. Asbestos usage has fortunately been banned or phased out in most industrialized countries resulting in its decline in countries such as the United States. Despite this, MPM continues to place significant burden on its affected patients resulting in overall poor prognosis and survival. Questions arise as to what factors, especially what health disparities, contribute to the disease’s dismal prognosis. This article will present a narrative review of recent literature that identifies the impact age, sex, race, access to medical centers, and economics have on the diagnosis, treatment, and prognosis of MPM. As will be discussed, research has shown that factors including younger age, female sex, non-white race, private insurance, Medicare, and higher income have been associated with better survival in MPM. Whereas older age, male sex, white race, lack of insurance, and lower income are associated with worse survival. The identification of these and other health disparities related to MPM may allow for future research, clinical guidelines, and policies to be implemented to decrease the burden health disparities create in the diagnosis, treatment, and prognosis of patients with MPM.

Combined Analysis of RNA Sequence and Microarray Data Reveals a Competing Endogenous RNA Network as Novel Prognostic Markers in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with short survival time. Unbalanced competing endogenous RNAs (ceRNAs) have been shown to participate in the tumor pathogenesis and served as biomarkers for the clinical prognosis. However, the comprehensive analyses of the ceRNA network in the prognosis of MPM are still rarely reported. In this study, we obtained the transcriptome data of the MPM and the normal samples from TCGA, EGA, and GEO databases and identified the differentially expressed (DE) mRNAs, lncRNAs, and miRNAs. The functions of the prognostic genes and the overlapped DEmRNAs were further annotated by the multiple enrichment analyses. Then, the targeting relationships among lncRNA–miRNA and miRNA–mRNA were predicted and calculated, and a prognostic ceRNA regulatory network was established. We included the prognostic 73 mRNAs and 13 miRNAs and 26 lncRNAs into the ceRNA network. Moreover, 33 mRNAs, three miRNAs, and seven lncRNAs were finally associated with prognosis, and a model including seven mRNAs, two lincRNAs, and some clinical factors was finally established and validated by two independent cohorts, where CDK6 and SGMS1-AS1 were significant to be independent prognostic factors. In addition, the identified co-expressed modules associated with the prognosis were overrepresented in the ceRNA network. Multiple enrichment analyses showed the important roles of the extracellular matrix components and cell division dysfunction in the invasion of MPM potentially. In summary, the prognostic ceRNA network of MPM was established and analyzed for the first time and these findings shed light on the function of ceRNAs and revealed the potential prognostic and therapeutic biomarkers of MPM.

Transcriptomic alterations in malignant pleural mesothelioma cells in response to long‑term treatment with bullfrog sialic acid‑binding lectin.

Malignant pleural mesothelioma (MPM) is a universally lethal type of cancer that is increasing in incidence worldwide; therefore, the development of new drugs for MPM is an urgent task. Bullfrog sialic acid-binding lectin (cSBL) is a multifunctional protein that has carbohydrate-binding and ribonuclease activities. cSBL exerts marked antitumor activity against numerous types of cancer cells, with low toxicity to normal cells. Although in vitro and in vivo studies revealed that cSBL was effective against MPM, the mechanism by which cSBL exerts antitumor effects is not fully understood. To further understand the mechanism of action of cSBL, the present study aimed to identify the key molecules whose expression was affected by cSBL. The present study established cSBL-resistant MPM cells. Microarray analyses revealed that there were significant pleiotropic changes in the expression profiles of several genes, including multiple genes involved in metabolic pathways in cSBL-resistant cells. Furthermore, the expression of some members of the aldo-keto reductase family was revealed to be markedly downregulated in these cells. Among these, it was particularly interesting that cSBL action reduced the level of AKR1B10, which has been reported as a biomarker candidate for MPM prognosis. These findings revealed novel aspects of the effect of cSBL, which may contribute to the development of new therapeutic strategies for MPM.