Prognosis Of Malignant Mesothelioma Research Articles

Comprehensive bioinformatics analysis of the role of VWF in the tumor microenvironment of malignant mesothelioma.

To explore the influence and effect of tumor microenvironment on the development of malignant mesothelioma using machine learning methods. 87 open cases were downloaded from the Cancer Genome Atlas database including transcriptome data, clinical data, and mutation data. The immune, stromal, and estimate scores were calculated for each case by using the ESTIMATE algorithm, and then the cases were grouped according to high and low stromal scores to predict all-cause survival in malignant mesothelioma cases. Their mutation data were analyzed to reveal the differences in mutated genes between the 2 groups, and then the von Willebrand factor (VWF) and FCRL3 genes were identified according to the intersection of DEGs and high-frequency mutated genes. Lastly, the correlation between VWF and the immune checkpoint of 22 kinds of immune cells was analyzed by using the CIBERSORT package of R software. A significant difference was found in the survival time of patients between the high and low stromal score groups. High expression of the VWF gene was negatively correlated with the prognosis of malignant mesothelioma, and the expression of VWF was positively correlated with naive B cells and activated CD4 memory T cells and negatively correlated with NK cells. The results revealed that high expression of VWF may involve in the development of malignant mesothelioma, and the anti-CTLA4 immune checkpoint treatment may have certain efficacy.

High Expression of SMO and GLI1 Genes with Poor Prognosis in Malignant Mesothelioma.

To investigate the value of SMO and GLI1 genes in the hedgehog pathway in malignant mesothelioma specimens. Further study on the expression and prognosis of SMO and GLI1 in malignant mesothelioma tissues and the relationship between the two and the molecular mechanisms of mesothelioma immunity and to further investigate the prognostic value of mesothelioma expression. Immunohistochemistry and RT-qPCR were applied to detect the expression of SMO and GLI1 proteins and mRNA in biopsy specimens and plasma cavity effusion specimens from malignant mesothelioma (n = 130) and benign mesothelial tissues (n = 50) and to analyze the clinicopathological significance and survival risk factors of SMO and GLI1 protein expression in mesothelioma. The mechanisms of mesothelioma cell expression and immune cell infiltration were investigated using bioinformatics methods. SMO and GLI1 in mesothelioma tissues detected high concordance between the diagnostic results of mesothelioma biopsy specimens and plasma cavity effusion specimens. The expression levels of SMO and GLI1 protein and mRNA in mesothelioma tissues were higher than those in benign mesothelioma tissues. The expression levels of SMO and GLI1 protein were correlated with the age, site, and asbestos exposure history of patients with mesothelioma. The expression levels of SMO and GLI1 protein were correlated with the expressions of ki67 and p53 (P < 0.05). SMO and GLI1 gene expression levels were negatively correlated with good prognosis in mesothelioma patients (P < 0.05). Cox proportional risk model indicated that protein expressions of invasion, lymph node metastasis, distant metastasis, staging, and genes were independent prognostic factors of mesothelioma. The GEPIA database showed the overall survival rate and the disease-free survival rate of mesothelioma patients in the high SMO and GLI1 expression groups; the UALCAN database analysis showed lower SMO expression levels in mesothelioma patients with more pronounced TP53 mutations (P = 0.001); GLI1 gene expression levels were strongly correlated with lymph node metastasis in mesothelioma patients (P = 0.009). Timer database analysis showed that the mechanism of immune cell infiltration was closely related to SMO and GLI1 expression. The degree of immune cell infiltration was strongly correlated with the prognosis of mesothelioma patients (P < 0.05). The expression levels of both SMO and GLI1 proteins were higher than those of normal mesothelial tissues, and the mRNA expression levels also changed in the same direction. SMO and GLI1 gene expressions in mesothelioma were negatively correlated with age, site of occurrence, and history of asbestos exposure. Positive expression of SMO and GLI1 was negatively correlated with patient survival. The Cox proportional risk model showed that gender, history of asbestos exposure, site of occurrence, SMO, and GLI1 were independent prognostic factors for mesothelioma. The mechanism of immune cell infiltration in mesothelioma is closely related to the gene expression of both and the survival prognosis of mesothelioma patients.

Oral metastasis of pleural sarcomatoid mesothelioma, a rare aggressive variant of mesothelioma and a diagnostic challenge

<h3>Introduction</h3> Malignant mesothelioma is a rare neoplasm that most commonly develops after exposure to asbestos and arises from the serosal cells of the pleura or rarely peritoneum. Various histological subtypes have been recog- nized: epithelioid, sarcomatoid, biphasic-epithelioid, and biphasic-sarcomatoid, with the sarcomatoid variant being a less common, but more aggressive variant. Numerous genetic alterations have been identified in the development and progression of malignant mesothelioma, most notably mutations in tumor suppressor genes, <i>neurofibromatosis type 2 (NF2), BRCA1-associated protein-1 (BAP1),</i>and <i>cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF)</i>. Mesothelioma metastasis to the oral cavity is infrequent, with only nineteen cases reported in the literature. Soft tissue involvement of the oral cavity has been reported in the tongue, followed by the mandibu- lar gingiva, and alveolar mucosa. Prognosis for malignant mesothelioma is poor as it is typically unresponsive to conventional chemotherapeutic agents. New targeted therapies are currently in ongoing clinical trials. <h3>Case Findings</h3> An 81-year-old male, undergoing treatment for malignant pleural mesothelioma and with a history of asbestos exposure, presented for evaluation of a raised, necrotic mass on the left posterior mandibular buccal and lingual gingiva. Panoramic radiograph revealed extensive bone loss. The histopathology was that of a sarco- matoid neoplasm. Immunohistochemistry demonstrated positive staining for WT1, cyclin D1, and P53, supporting the diagnosis of metastatic malignant mesothelioma, sarcomatoid variant. Other stains that help to define mesothe- lioma such as CK5/6, calretinin, and D2-40 were negative. Despite equivocal immunostaining results, the diagnosis was further supported by comprehensive genomic analysis with identification of mutated <i>NF2</i>and <i>BAP1</i>tumor sup- pressor genes. <h3>Conclusion</h3> The diagnosis of malignant pleural mesothelioma relies on morphology supplemented with immuno- histochemistry. The diagnosis is challenging, especially so for the sarcomatoid variant, with immunohistochemical staining profiles often being inconsistent. The current case demonstrates the utility of comprehensive genomic analysis in firmly establishing the diagnosis.

A panel of emerging EMT genes identified in malignant mesothelioma

Malignant mesothelioma (MESO) is a highly aggressive cancer with poor prognosis. Epithelial–mesenchymal transition (EMT) is a critical process in malignancies involved in tumor angiogenesis, progression, invasion and metastasis, immunosuppressive microenvironment and therapy resistance. However, there is a lack of specific biomarkers to identify EMT in MESO. Biphasic MESO with dual phenotypes could be an optimal model to study EMT process. Using a powerful EMTome to investigate EMT gene signature, we identified a panel of EMT genes COL5A2, ITGAV, SPARC and ACTA2 in MESO. In combination with TCGA database, Timer2.0 and other resources, we observed that overexpression of these emerging genes is positively correlated with immunosuppressive infiltration, and an unfavorable factor to patient survival in MESO. The expression of these genes was confirmed in our patients and human cell lines. Our findings suggest that these genes may be novel targets for therapeutics and prognosis in MESO and other types of cancers.

Workshop summary: Potential usefulness and feasibility of a US National Mesothelioma Registry.

The burden and prognosis of malignant mesothelioma in the United States have remained largely unchanged for decades, with approximately 3200 new cases and 2400 deaths reported annually. To address care and research gaps contributing to poor outcomes, in March of 2019 the Mesothelioma Applied Research Foundation convened a workshop on the potential usefulness and feasibility of a national mesothelioma registry. The workshop included formal presentations by subject matter experts and a moderated group discussion. Workshop participants identified top priorities for a registry to be (a) connecting patients with high-quality care and clinical trials soon after diagnosis, and (b) making useful data and biospecimens available to researchers in a timely manner. Existing databases that capture mesothelioma cases are limited by factors such as delays in reporting, deidentification, and lack of exposure information critical to understanding as yet unrecognized causes of disease. National disease registries for amyotrophic lateral sclerosis (ALS) in the United States and for mesothelioma in other countries, provide examples of how a registry could be structured to meet the needs of patients and the scientific community. Small-scale pilot initiatives should be undertaken to validate methods for rapid case identification, develop procedures to facilitate patient access to guidelines-based standard care and investigational therapies, and explore approaches to data sharing with researchers. Ultimately, federal coordination and funding will be critical to the success of a National Mesothelioma Registry in improving mesothelioma outcomes and preventing future cases of this devastating disease.

Abstract 3800: Inhibition of Polycomb Repressive Complex 2 EZH2 lysine methyltransferase improves tumoricidal activity of macrophages towards mesothelioma cells

Abstract Rationale: Clinical evidence indicates that tumor infiltration by tumor associated macrophages (TAMs) correlates with poor prognosis in malignant mesothelioma (MM). By attenuating the immune response, TAMs indeed promote survival of MM cells. TAMs share properties with alternative macrophages (M2) that are activated by anti-inflammatory (e.g. IL-10) or Th2-associated (i.e. IL-4, IL-13) cytokines. Objectives: We hypothesized that macrophage activation is mediated by a transcriptional program tightly regulated by epigenetic modifications. We focused on the Polycomb Repressive Complex 2 (PRC2) EZH2 lysine methyltransferase responsible for trimethylation of histone H3 at lysine 27 (H3K27me3). We investigated the effect of a selective EZH2 inhibitor (EPZ005687) on tumoricidal activity of primary human monocyte-derived macrophages. Results: Our data show that inhibition of EZH2 reduces CD206 expression and phagocytic activity of macrophages conditioned in MM pleural effusions (PE-macrophages). Moreover, EZH2 inhibition enhances the cytotoxic potential of PE-macrophages towards MM cells. Inhibition of EZH2 also increases the ability of macrophages to support proliferation of autologous T-cells. Conclusion: Induction of cytotoxic activity of PE-macrophages via PRC2 EZH2 lysine methyltransferase could be of therapeutic value in MM. Citation Format: Malik Hamaidia, Clotilde Hoyos, Luc L. Willems. Inhibition of Polycomb Repressive Complex 2 EZH2 lysine methyltransferase improves tumoricidal activity of macrophages towards mesothelioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3800.

Immunohistochemical expression and distribution of VEGFR‐3 in malignant mesothelioma

Homogeneity of mesothelial and lymphatic endothelial cells, express some markers that are presumed to be exclusive of the endothelium was recently reported. This similarity is important to improve the diagnosis and prognosis of malignant mesothelioma (MM). Additionally, some of these markers provide the rationale for specific molecular-targeted novel therapies aimed at MM, an aggressive malignant neoplasm, with an usually dismal prognosis. The goal of our study was to determine the prevalence and expression pattern of VEGF receptor-3 (VEGFR-3) immunoreactivity in MM and whether this immunoreactivity occurs in different phenotypes of this neoplasm. Formalin-fixed and paraffin-embedded samples from 29 MM cases and 5 metastatic carcinomas were immuno-stained for VEGFR-3 according to the streptavidin-biotin-peroxidase complex technique using a primary antibody (Zymed Laboratories, CA, USA) diluted at 1:200. Lymphatic vessels (LV) were outlined mainly in the peripheral area surrounding the neoplasms. Blood vessels were only rarely positive for VEGFR-3 in a pattern easily distinguishable from LV. In 25 out of 29 cases (86.2%) LV were strongly positive for VEGFR-3: 14 cases (48.2%) exhibited positive VEGFR-3 reactivity in malignant cells. Epitheliod MM showed a moderate to intense VEGFR-3 positive reaction in LV from 8 out of 19 cases. Among the other histological subtypes, a positive VEGFR-3 reaction was noted in malignant cells from two cases of transitional and one case of pleomorphic MM. Malignant cells from two out of three biphasic and one out of three sarcomatoid MM were also positive for VEGFR-3. Interestingly, one case of the multicystic subtype was negative for VEGFR-3 in malignant cells and faintly positive in an occasional LV. All cases of metastatic carcinoma were negative for VEGFR-3 in the neoplastic cells. In conclusion, VEGFR-3 was expressed in malignant cells from different subtypes of MM, reinforcing the putative role of this marker as a potential therapeutic target in this group of neoplasia.

Tumor Necrosis Correlates With Angiogenesis and Is a Predictor of Poor Prognosis in Malignant Mesothelioma

Malignant mesothelioma (MM) is a fatal tumor of increasing incidence related to asbestos exposure. Microscopic tumor necrosis (TN) is a poor prognostic factor in solid tumors, but it has not been characterized in MM. We wished to evaluate the incidence of TN in MM and its correlations with clinicopathologic factors, angiogenesis, and survival. TN was graded in 171 routine formalin-fixed, paraffin-embedded hematoxylin-eosin-stained tumor sections by two independent observers. Angiogenesis was assessed by the microvessel count (MVC) of CD34 immunostained sections. TN was correlated with survival by Kaplan-Meier and log-rank analysis, and stepwise, multivariate Cox models were used to compare TN with angiogenesis and established prognostic factors and prognostic scoring systems. TN was identified in 39 cases (22.8%) and correlated with low hemoglobin (p = 0.01), thrombocytosis (p = 0.04), and high MVC (p = 0.02). TN was a poor prognostic factor in univariate analysis (p = 0.008). Patients with TN had a median survival of 5.3 months vs 8.3 months in negative cases. Independent indicators of poor prognosis in multivariate analysis were nonepithelioid cell type (p = 0.0001), performance status > 0 (p = 0.007), and increasing MVC (p = 0.004) but not TN. TN contributed independently to the European Organisation for Research and Treatment of Cancer (EORTC) [p = 0.03] and to the Cancer and Leukemia Group B (CALGB) [p = 0.03] prognostic groups in respective multivariate Cox analyses. TN correlates with angiogenesis and is a poor prognostic factor in MM. TN contributes to the EORTC and CALGB prognostic scoring systems.

Value of morphometry, texture analysis, densitometry, and histometry in the differential diagnosis and prognosis of malignant mesothelioma.

Malignant mesothelioma is a tumour with increasing incidence due to widespread use of its causative agent, asbestos, in the past decades. The poor survival necessitates a correct differentiation from other lesions at the same site, such as hyperplastic mesothelium and carcinomas metastatic to pleura or peritoneum. Since genetic and immunohistochemical markers are not absolutely differentiating, the diagnosis is based on the histology complemented with (immuno)histochemistry. However, as the tumour presents itself in numerous heterogeneous histological forms, visual evaluation is extremely difficult. In order to evaluate the prognostic and diagnostic performance of syntactic structure analysis (SSA), chromatin texture analysis, densitometry, and morphometry, an automated KNN-classification system has been used to compare Feulgen-stained tissue sections of hyperplastic mesothelium, malignant mesothelioma, and pulmonary adenocarcinoma. In addition, we also studied most discriminative aspects in the differentiation, typing, and prediction of survival. The results indicate that for the diagnosis of malignant mesothelioma, chromatin texture parameters outperform SSA, densitometry, and morphometry (recognition score=96.8 per cent). Most discriminative parameters highlight spatial patterns of the chromatin distribution that are hard to appraise visually and directly show the benefits of a quantitative approach. Typing of the tumour is best described by SSA parameters, relating to the spatial arrangement of the cells in the tissue (recognition score=94.9 per cent). In survival time classifications, chromatin texture yields the highest recognition score (82.9 per cent), although accurate estimations are unreliable due to a large degree of misclassification.

Prognosis in malignant mesothelioma related to MIB 1 proliferation index and histological subtype

The aims of this study were to evaluate the use of the proliferation marker MIB 1 and histological subtype as indicators of prognosis in malignant mesothelioma. Sections from 41 cases of malignant mesothelioma were histologically subtyped on hematoxylin and eosin sections and stained immunohistochemically for the proliferation marker MIB 1. A proliferation index was derived and the results compared with patient survival data. A statistically significant difference was found between the survival of patients having a low and high MIB 1 index ( P < .001). Patients with tumors having a low MIB 1 index lived significantly longer than those with a high MIB 1 index. Patients with the spindle cell histological subtype of malignant mesothelioma had significantly shorter survival times than those with the epithelioid or mixed tumors ( P < .01). The MIB 1 proliferation index and histological tumor subtype are useful markers of prognosis in malignant mesothelioma.

Mesothelial and related neoplasms in children and adolescents: a clinicopathologic and immunohistochemical analysis of eight cases.

Mesothelioma is a neoplasm that occurs infrequently in childhood; only an estimated 2-5% of all cases present in the first two decades of life. The diagnosis may be perplexing because of its rarity and its pathologic similarities to other papillary or spindle cell neoplasms in the pediatric age group. We have studied eight cases of mesothelial or submesothelial-derived neoplasms of pleural (four cases) and peritoneal (four cases) origin in patients 4 to 17 years of age at diagnosis. Microscopically, six were epithelial, with papillary, tubuloglandular, and solid patterns. Two tumors were predominantly fibrous appearing, one a localized pleural fibroma and the other a diffuse pleural sarcomatoid mesothelioma. All of the tumors were immunoreactive for vimentin, and all except the pleural fibroma stained for either cytokeratin, epithelial membrane antigen, or both. None reacted with antibodies to carcinoembryonic antigen, placental alkaline phosphatase, or Leu-M1. At last follow-up, three patients were dead of tumor, three were alive and well, and two had been recently diagnosed and were undergoing treatment. These results indicate that the immunohistochemical profile delineated for mesothelioma in adults is equally applicable to mesothelial neoplasms in younger patients and is useful in establishing a diagnosis. The prognosis for malignant mesothelioma in childhood appears to be as unfavorable as the adult counterpart, with the possible exceptions of certain clinicopathologic subtypes.

Surgical treatment of pleural mesothelioma

From 1939 through 1981, 170 patients were seen and treated for pleural mesothelioma. Twenty-one tumors were benign, 47 were fibrosarcomatous, and 102 were epithelioma. Resection was the main mode of treatment in benign and fibrosarcomatous mesothelioma. Treatment of diffuse epithelial mesothelioma presented the greatest challenge. Surgical therapy, radiation therapy, and chemotherapy were used in combination in these patients. The review of our patients treated prior to 1972 had shown no benefit from including pulmonary resection in the surgical treatment of these tumors. Since then, all patients with diffuse mesothelioma were treated by pleurectomy without pulmonary resection. Both internal and external radiation therapy were also used to enhance local control. Forty-nine percent of patients with epithelial mesothelioma lived 1 year. The median survival in patients whose disease was controlled by these methods was 21 months. Despite the poor prognosis in malignant mesothelioma, better controlled by these methods was 21 months. Despite the poor prognosis in malignant mesothelioma, better survival was achieved when the treatment included operation combined with radiation and chemotherapy.