Search

Background: Epithelial cell adhesion molecule (EpCAM) is frequently used to distinguish carcinoma from background mesothelial cells during cytologic examination of body cavity fluids. Previously, the authors identified one malignant mesothelioma case with strong and diffuse membranous EpCAM staining, making it indistinguishable from carcinoma. Methods: In this study, the authors evaluated all available effusion specimens from patients with malignant mesothelioma, including the above‐mentioned index case, obtained at Stanford Health Care, from 2011 to 2021 (N = 17) as well as control cases (N = 5). Analyses included an immunohistochemistry (IHC) assay for EpCAM and claudin‐4, a multiplexed immunofluorescent (IF) assay for EpCAM, and an RNA in situ hybridization assay targeting EpCAM. Results: The authors detected EpCAM positivity of variable intensity and percentage in four malignant mesothelioma cases (23.5%; although only two showed positivity for the epithelial‐specific IHC marker MOC31 in ≥40% of cells) and claudin‐4 negativity in all cases, with two cases displaying focal and weak claudin‐4 staining in <1% of cells. Multiplexed IF staining on the cases with EpCAM IHC positivity showed strong, membranous EpCAM staining in one of four cases. RNA in situ hybridization also was used to assess the correlation between EpCAM positivity by IHC/IF and RNA expression levels. Strong EpCAM RNA expression was detected in the three malignant mesothelioma cases. Conclusions: The current findings revealed that a subset of epithelioid malignant mesothelioma cases mimic or exhibit the immunophenotypic features of carcinoma when evaluating for EpCAM only. Additional biomarker testing, such as claudin‐4, may help avoid this potential pitfall to yield accurate diagnoses. The authors examined epithelial biomarkers in effusion specimens of 17 malignant mesothelioma cases and five benign cases. By combining immunohistochemistry for epithelial cell adhesion molecule (EpCAM) and claudin‐4, a multiplexed immunofluorescent assay for EpCAM, and RNA in situ hybridization targeting EpCAM, this study revealed that a subset of epithelioid malignant mesothelioma cases mimic or exhibit features of carcinoma when evaluating for EpCAM only. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma (MPM) is a rare, aggressive, and fatal neoplasm of the abdominal mesothelium with a very abysmal survival if left untreated. MPM with EWSR1-ATF1 fusion is an uncommon entity recently recognized by molecular studies. We report the first case of MPM with EWSR1-ATF1 fusion and aberrant CK20 expression. The patient was a 38-year-old man who presented to our institution with three months history of abdominal pain and distention, a significant weight loss (>30 lb), and failure to thrive. He was working in a construction company with 20 year-history of questionable asbestos exposure. Imaging studies demonstrated radiographic patterns suggestive of extensive peritoneal carcinomatosis. However, serum tumor markers were within the normal limit (CA 19–9, CEA, AFP, and βHCG). Subsequently, he underwent a biopsy of the peritoneal nodules. Biopsy showed a proliferation of epithelioid/round cells with ample cytoplasm and occasional vacuoles, displaying papillary architecture. Immunohistochemistry showed tumor cells were strongly and diffusely positive for WT1, AE1/3, CK7, CK20, desmin, and CD99, focally positive for calretinin, D2-40, and CK5/6, while negative for BerEp4, MOC-31, trypsin, TTF-1, P40, GATA3, CDX2, and PAX8. P16 and BAP1 were retained. Fluorescence in situ hybridization studies showed EWSR1 rearrangement, and the NGS fusion panel revealed EWSR1-ATF1 fusion. A diagnosis of MPM with EWSR1-ATF1 fusion was rendered. Unfortunately, the patient passed away within a month of diagnosis. Pathologists should be aware of this entity, especially when faced with tumors displaying mesothelioma morphology but showing atypical immunoprofile (co-expression of mesothelial markers with strong CK20).

Synchronous malignant mesothelioma (MM) and lung carcinoma are extremely rare in patients without a history of asbestos exposure and poses tremendous difficulties in clinical management. We report a patient without asbestos exposure diagnosed with MM during EGFR-TKI treatment of lung adenocarcinoma (LUAD), who responded to first-line chemotherapy with pemetrexed plus carboplatin and failed to subsequent systemic therapy. Clinicians should be careful about the possibility of MM comorbidity in LUAD patients whose lesions respond differently to EGFR-TKI, even in those without a history of asbestos exposure.

Malignant mesothelioma (MM) is an aggressive asbestos-related cancer, against which no curative modalities exist. Oncolytic virotherapy is a promising therapeutic approach, for which MM is an ideal candidate; indeed, the pleural location provides direct access for the intra-tumoral injection of oncolytic viruses (OVs). Some non-human OVs offer advantages over human OVs, including the non-pathogenicity in humans and the absence of pre-existing immunity. We previously showed that caprine herpesvirus 1 (CpHV-1), a non-pathogenic virus for humans, can kill different human cancer cell lines. Here, we assessed CpHV-1 effects on MM (NCI-H28, MSTO, NCI-H2052) and non-tumor mesothelial (MET-5A) cells. We found that CpHV-1 reduced cell viability and clonogenic potential in all MM cell lines without affecting non-tumor cells, in which, indeed, we did not detect intracellular viral DNA after treatment. In particular, CpHV-1 induced MM cell apoptosis and accumulation in G0/G1 or S cell cycle phases. Moreover, CpHV-1 strongly synergized with cisplatin, the drug currently used in MM chemotherapy, and this agent combination did not affect normal mesothelial cells. Although further studies are required to elucidate the mechanisms underlying the selective CpHV-1 action on MM cells, our data suggest that the CpHV-1-cisplatin combination could be a feasible strategy against MM.

The thermal behavior of a woolly erionite-K sample (Lander County, NV, USA), chemical formula (Ca2.03Na0.73K2.52 Mg0.26)[Al8.22Si27.78O71.80]·35.94H2O, was investigated in the 303-1173 K thermal range by in situ X-ray powder diffraction. Present data suggest a general thermally-induced volume contraction whose magnitude increases as Si/ Si+Al ratio becomes smaller. An inverse correlation between Si/ Si+Al ratio and Tdehydr is observed because higher Si/ Si+Al ratio values are associated to lower dehydration temperatures. A positive dependence exists between Si/ Si+Al ratio and Tbreak. A higher Si content results in a greater thermal stability, in agreement with the general trend observed in zeolites. On the contrary, no correlation has been found between Tbreak and weighted ionic potential (Z/r)wt as suggested by reference data. Heating produces a general depletion of the Ca1, Ca2, Ca3, and K1 sites, which is counterbalanced by an increase of the K2 site scattering, even though the latter is not populated at RT. No "internal ion exchange" mechanism was apparently acting in the present sample differently from other erionite samples analysed in the past. At 303 K approximately 20 e- allocated at the OW H2O sites might be assigned to (extra-framework) EF cations. Such fraction increases due to their migration from the extra-framework cation sites following the same mechanism reported in reference data. [ABSTRACT FROM AUTHOR]

Background: Malignant mesothelioma (MM) is an aggressive, fatal tumor. Current therapeutic options only marginally improve survival. Programmed cell death ligand 1 (PD-L1) is a dominant mediator of immunosuppression, binding to programmed cell death 1 (PD-1). PD-L1 is up-regulated in cancer cells, and the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion, thus providing a target for antitumor therapy. Further, a correlation between PD-L1 expression and prognosis has been reported. Studies performed on histological material have revealed expression of PD-L1 in MM, but no study has been performed on MM effusions thus far.Methods: PD-L1 expression was determined by a commercially available antibody (clone 28-8) in 74 formalin-fixed, paraffin-embedded cell blocks from body effusions obtained at diagnosis from patients with MM. The presence of MM cells was confirmed with CK5/6, calretinin, and EMA and the admixture of macrophages was assessed with CD68. Only cases containing more than 100 tumor cells were assessed. Membranous staining in tumor cells was considered positive. Survival time was calculated from the appearance of the first malignant effusion until death.Results: Reactivity was observed in 23 of 61 (38%) of cases and was classified as ≥1%-5% (n = 9 cases), >5%-10% (n = 4 cases), >10%-50% (n = 4 cases), and >50% (n = 6 cases) positive cells. Survival times did not differ significantly between patients with PD-L1-positive and PD-L1-negative tumors.Conclusion: MM effusions are suitable for immune-cytochemical assessment of PD-L1 expression in malignant cells and the results are similar to those reported for histological specimens. Cancer Cytopathol 2017;125:908-17. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Inhalation of erionite has been proven to be the cause of the extended epidemic of malignant mesothelioma occurring in Central Anatolia, Turkey, and of cases of lung diseases in the U.S.A. Its carcinogenicity is three orders of magnitude greater than that of regulated asbestos. Here we report the results of the investigation of the structural and crystal chemical modifications occurring in erionite leached with artificial lysosomal fluid (ALF) and Gamble's solution. ALF leaching produces a migration of Na+ ions from Ca1 to Ca2 extraframework cationic site, without the occurrence of any significant modification of the chemical composition of the fibers. In contrast, leaching with Gamble's solution induces a complex ionic-exchange process resulting in a temporary partial replacement of Na+ by Ca2+, coming from the fluid, which is fixed at a third Ca3 cationic site. Subsequently, the exchange process reverses. In fact, Ca2+ is removed from Ca3 and Na+ migrates back to Ca1, the structure being indistinguishable from the starting, unleached material. Such processes seem to be accompanied by a progressive amorphization of fibers. Present data could provide valuable background for a more detailed comprehension of the morphostructural/biological activity relationships inducing pathogenicity. [ABSTRACT FROM AUTHOR]

Abstract: Background: Mitochondria, essential to the cell homeostasis maintenance, are central to the intrinsic apoptotic pathway and their dysfunction is associated with multiple diseases. Recent research documents that microRNAs (miRNAs) regulate important signalling pathways in mitochondria, and many of these miRNAs are deregulated in various diseases including cancers. Scope of review: In this review, we summarise the role of miRNAs in the regulation of the mitochondrial bioenergetics/function, and discuss the role of miRNAs modulating the various metabolic pathways resulting in tumour suppression and their possible therapeutic applications. Major conclusions: MiRNAs have recently emerged as key regulators of metabolism and can affect mitochondria by modulating mitochondrial proteins coded by nuclear genes. They were also found in mitochondria. Reprogramming of the energy metabolism has been postulated as a major feature of cancer. Modulation of miRNAs levels may provide a new therapeutic approach for the treatment of mitochondria-related pathologies, including neoplastic diseases. General significance: The elucidation of the role of miRNAs in the regulation of mitochondrial activity/bioenergetics will deepen our understanding of the molecular aspects of various aspects of cell biology associated with the genesis and progression of neoplastic diseases. Eventually, this knowledge may promote the development of innovative pharmacological interventions. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. [Copyright &y& Elsevier]

Highlights: [•] Resveratrol and clofarabine enhances a strong cytotoxicity with increased p53 activity. [•] Combination treatment of resveratrol and clofarabine enhances p53 transactivation. [•] The combined effect of resveratrol and clofarabine on apoptosis is synergistic. [•] Resveratrol could be useful to increase the efficacy of existing chemotherapy in the treatment of MM. [ABSTRACT FROM AUTHOR]

Summary: DNA methylation markers provide a powerful tool to make diagnoses based on genetic material obtained directly from tumors or from “remote” locations such as sputum, pleural fluid, or serum. In particular when limited cell numbers are available, amplifyable DNA markers can provide a very sensitive tool for cancer detection and classification. Malignant mesothelioma (MM), an aggressive cancer strongly associated with asbestos exposure, can be difficult to distinguish from adenocarcinoma of the lung when limited material is available. In an attempt to identify molecular markers for MM and adenocarcinoma, we examined the DNA methylation status of 14 loci. Analysis of methylation levels in 10 MM and 8 adenocarcinoma cell lines showed that methylation of APC was significantly elevated in adenocarcinoma compared to MM cell lines (P=0.0003), while methylation of CDH1 was higher in MM (P<0.02). Subsequent examination of the methylation status of the 14 loci in 6 MM and 7 adenocarcinoma primary tumors, which yielded similar methylation profiles, supported these observations. Comparison of methylation in MM cell lines and tumors versus non-tumor lung tissue indicated that APC exhibits less methylation in MM (P=0.003) while RASSF1, PGR1, ESR1, and CDH1 show more methylation in MM, the latter two showing the most significant difference between the two tissue types (P≤0.0001). Comparison of methylation in adenocarcinoma cell lines and tumors versus non-tumor lung tissue showed methylation of ESR1, PGR1 and RASSF1 to be significantly elevated in adenocarcinoma, with RASSF1 being most significant (P=0.0002). Thus, with the examination of 14 loci, we have identified 5 candidates that show potential for distinguishing between MM, adenocarcinoma and/or non-cancer lung. Our observations support the strong potential of methylation markers as tools for accurate diagnosis of neoplasms in and around the lung. [Copyright &y& Elsevier]

Malignant pleural mesothelioma (MPM) is an aggressive serosal tumor, strongly associated with former exposure to asbestos fibers and for which there is currently no effective treatment available. In human, MPM is characterized by a high local invasiveness, poor prognosis and therapeutic outcomes. In order to assess molecular changes that specify this phenotype, we performed a global gene expression profiling of human MPM. Using a 10,000-element microarray, we analyzed mRNA relative gene expression levels by comparing a mesothelioma cell line to either a pleural cell line or tumor specimens. To analyze these gene expression data, we used various bioinformatics softwares. Hierarchical clustering methods were used to group genes and samples with similar expression in an unsupervised mode. Genes of known function were further sorted by enzyme, function and pathway clusters using a supervised software (IncyteGenomics). Taken together, these data defined a molecular fingerprint of human MPM with more than 700 up- or down-regulated genes related to several traits of the malignant phenotype, specially associated with MPM invasiveness, protection and resistance to anticancer defenses. This portrait is meaningful in disease classification and management, and relevant in finding new specific markers of MPM. These molecular markers should improve the accuracy of mesothelioma diagnosis, prognosis and therapy. [Copyright &y& Elsevier]

Malignant mesothelioma (MM) is an aggressive asbestos-related cancer, against which no curative modalities exist. Oncolytic virotherapy is a promising therapeutic approach, for which MM is an ideal candidate; indeed, the pleural location provides direct access for the intra-tumoral injection of oncolytic viruses (OVs). Some non-human OVs offer advantages over human OVs, including the non-pathogenicity in humans and the absence of pre-existing immunity. We previously showed that caprine herpesvirus 1 (CpHV-1), a non-pathogenic virus for humans, can kill different human cancer cell lines. Here, we assessed CpHV-1 effects on MM (NCI-H28, MSTO, NCI-H2052) and non-tumor mesothelial (MET-5A) cells. We found that CpHV-1 reduced cell viability and clonogenic potential in all MM cell lines without affecting non-tumor cells, in which, indeed, we did not detect intracellular viral DNA after treatment. In particular, CpHV-1 induced MM cell apoptosis and accumulation in G0/G1 or S cell cycle phases. Moreover, CpHV-1 strongly synergized with cisplatin, the drug currently used in MM chemotherapy, and this agent combination did not affect normal mesothelial cells. Although further studies are required to elucidate the mechanisms underlying the selective CpHV-1 action on MM cells, our data suggest that the CpHV-1-cisplatin combination could be a feasible strategy against MM. [ABSTRACT FROM AUTHOR]

The global incidence of malignant mesothelioma (MM) causes considerable disease burden, suffering and health care costs. Beside preventive measures and ban the use of asbestos, early diagnosis would largely improve the chance of curative treatment. Current histologic criteria, however, requiring presence of invasion in the surrounding fatty tissue fail to identify MM in sufficiently early stage. Unilateral accumulation of pleural effusion is one of the earliest clinical manifestations of MM that occurs in approximately 90% of the patients. Therapeutic thoracocenthesis is necessary to remove the fluid and to relieve patients' symptoms. This effusion is easily accessible and offers early and minimally invasive diagnosis by combining cytology with immunologic, molecular- and biomarker analyses. Typically, the fluid is rich in malignant cells and cell groups, but incipient stages of the disease may be difficult to recognize as the malignant cells can be masked by presence of inflammatory or reactive mesothelial cells. Recurrent, hemorrhagic and cell rich effusion should always be suspicious for MM and adequately prepared and analyzed to provide necessary information for subsequent therapy. Importantly, early detection of MM by integrating cytology and molecular approaches has high sensitivity and positive predictive value and has a major impact on patient survival. Thus, a conclusive positive MM cytology should lead to treatment without delay. This review summarizes molecular and diagnostic criteria of MM diagnosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at available at http://dx.doi.org/10.21037/tlcr-2019-pps-10). The series “Selected Highlights of the 2019 Pulmonary Pathology Society Biennial Meeting” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Malignant mesothelioma (MM) is uncommon, but very aggressive tumor arising from the mesothelial cells of pleura, pericardium, peritoneum, and tunica vaginalis. Despite multimodality treatments 5-year survival is only 5% after the diagnosis. Histology and TNM staging system are still the best prognostic factors. Furthermore, histologic subtype of MM determines the clinical management of the patients. According to the 2015 WHO classification, MM is divided into diffuse, localized and well differentiated papillary mesothelioma. Major histologic subtypes of diffuse MM, namely epithelioid, biphasic and sarcomatoid, have different prognosis. However, in the last decade it has become evident that more detailed subclassification and histologic/cytological characterization of MM have prognostic and perhaps predictive implications. In this review, major histologic subtypes and cytological features of MM are presented and their relation with prognosis and predictive biomarkers is discussed., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr.2020.03.38). The series “Selected Highlights of the 2019 Pulmonary Pathology Society Biennial Meeting” was commissioned by the editorial office without any sponsorship or funding. LB reports grants, personal fees and non-financial support from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees and non-financial support from MSD, personal fees from Takeda, personal fees and non-financial support from Roche, personal fees and non-financial support from Pfizer, personal fees from Eli Lilly, outside the submitted work. IK has no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Malignant mesothelioma (MM) still remains a dismal disease with a median overall survival between 9-12 months. During the past decade since the introduction of the multi-folate antagonist, pemetrexed, there have been no significant advances in its systemic treatment, particularly with novel therapeutics that have exhibited varying degrees of success in other solid tumours. In recent years, the pleiotropic proinflammatory cytokine, interleukin-6 (IL-6) has emerged as a mediator of pivotal processes such as cell proliferation and chemoresistance within the mesothelioma tumour microenvironment in addition to clinical symptoms commonly witnessed in this disease. This manuscript provides a brief summary on the pathophysiology and clinical management of MM, followed by the role of IL-6 in its tumourigenesis and the rationale for utilising anti-IL-6 therapeutics alongside standard chemotherapy and targeted agents in an attempt to prolong survival.