Malignant Mesothelioma Of Pleura Research Articles

CUL4B is a Potential Novel Prognostic Biomarker and is Correlated with Immune Infiltrates in Malignant Pleural Mesothelioma.

BackgroundMalignant pleural mesothelioma (MPM) is a particularly fatal cancer with a median survival of less than one year. The value of single-agent checkpoint inhibitors is still obscure in MPM. We aim to reveal CUL4B prognostic role and immune infiltrates in MPM patients.MethodsCUL4B expression profile and clinical information of malignant pleura mesothelioma individuals were collected from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) dataset. Quantitative real-time PCR (qRT-PCR) analysis measured CUL4B mRNA expression in epithelioid, biphasic, sarcomatoid, and normal pleural cell lines.ResultsCUL4B expression elevated in MPM and had a high diagnostic value with AUC = 0.772. Additionally, our results showed that CUL4B high expression significantly correlated with poorer outcomes in MPM. Moreover, GSEA revealed 15 KEGG pathways enriched in the CUL4B high-expression group, and 22 were exhibited in the CUL4B low-expression group. Otherwise, our results showed that CUL4B was relevant to Wnt antagonistic factors (BARX2), Insulin-like growth factor binding protein 3 (IGFBP3), and Phosphatase and tensin homolog (PTEN). In addition, our results revealed that CUL4B expression was positively linked with four types of immune cells, whereas CUL4B expression was negatively linked with three types of immune cells. Additionally, our results showed that CUL4B expression regulates T helper cells, Tcm, and Th2 cells infiltration MPM microenvironment. Finally, our results identified CUL4B high expression in MPM cell line NCI-H2052 (epithelioid), MSTO-211H (biphasic), and NCI-H28 (sarcomatoid).ConclusionCUL4B is a valuable prognostic biomarker and a critical immune cell infiltration regulator in MPM.

Datenquellen zur Häufigkeit des malignen Pleuramesothelioms in der Schweiz seit 2001

Objective: Malignant pleural mesothelioma is a cancer of the membranes of the pulmonary pleurae and is caused predominantly by asbestos. While no exact incidence data are available for Switzerland, the case numbers have been increasing for many years and pleural mesothelioma is a topic of concern. Case numbers can be estimated, however, thanks to a variety of data sources. The purpose of this article is to present and compare these sources and to present corresponding analyses. Methods: We determined the numbers of patients with malignant pleura mesothelioma from 2001 to 2019 by using various datasets, including data from accident insurers, the National Institute for Cancer Epidemiology and Registration (NICER), the causes of death statistics and hospital inpatient data. The analysis of the latter dataset was specifically conducted for this publication. Results: All analyses showed increasing numbers of patients with malignant pleural mesothelioma during the study period. The numbers from the accident insurers and the causes of death statistics converged during the observation period. The numbers from NICER and from inpatient data were considerably higher than those from the other two datasets. Conclusions: This is the first study that describes the incidence of pleural mesothelioma in various data sources in Switzerland. A comparative study of different data sources is shown to provide valuable additional information. The comparison of accident statistics and the causes of death statistics suggest that the recording of malignant pleural mesothelioma as an occupational disease is becoming increasingly thorough. Keywords: malignant pleural mesothelioma – asbestos – routine data – Switzerland

Datenquellen zur Häufigkeit des malignen Pleuramesothelioms in der Schweiz seit 2001

Data sources on the incidence of malignant pleural mesothelioma in Switzerland since 2001 Objective: Malignant pleural mesothelioma is a cancer of the membranes of the pulmonary pleurae and is caused predominantly by asbestos. While no exact incidence data are available for Switzerland, the case numbers have been increasing for many years and pleural mesothelioma is a topic of concern. Case numbers can be estimated, however, thanks to a variety of data sources. The purpose of this article is to present and compare these sources and to present corresponding analyses. Methods: We determined the numbers of patients with malignant pleura mesothelioma from 2001 to 2019 by using various datasets, including data from accident insurers, the National Institute for Cancer Epidemiology and Registration (NICER), the causes of death statistics and hospital inpatient data. The analysis of the latter dataset was specifically conducted for this publication. Results: All analyses showed increasing numbers of patients with malignant pleural mesothelioma during the study period. The numbers from the accident insurers and the causes of death statistics converged during the observation period. The numbers from NICER and from inpatient data were considerably higher than those from the other two datasets. Conclusions: This is the first study that describes the incidence of pleural mesothelioma in various data sources in Switzerland. A comparative study of different data sources is shown to provide valuable additional information. The comparison of accident statistics and the causes of death statistics suggest that the recording of malignant pleural mesothelioma as an occupational disease is becoming increasingly thorough. Keywords: malignant pleural mesothelioma – asbestos – routine data – Switzerland

Genomic analysis in short- and long-term patients with malignant pleura mesothelioma treated with palliative chemotherapy

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive tumour with poor prognosis. The aim of this study was to identify genetic mutations associated with poor or extended survival in patients who received palliative chemotherapy. MethodsA total of 720 patients diagnosed with MPM between 2005 and 2015 were identified. Overall survival (OS) was longer than 30 months from diagnosis for 27 patients. Twelve of 27 (44%) of the pleural biopsies from long-term survivors were retrieved and matched with 12 biopsies from patients who survived less than 12 months; one biopsy was then excluded for poor DNA quality. ResultsA total of 11 patients had a mean OS of 5.5 months, whereas 12 patients lived more than 30 months (mean OS: 55.8 ± 25). Mutational analysis identified 428 alterations; of which, 148, classified as somatic and functional, were considered further. Among these, 85% were missense variants, 8% were variants causing a stop gain and 6% were splice variants. Loss-of-function mutations in UQCRC1 were significantly associated with reduced survival in patients with MPM (p = 0.027), while a higher frequency of mutations in MXRA5 and RAPGEF6 was registered in long-term survivors. ConclusionThis is the first study evaluating the relationship between the mutational profile and outcome in patients with MPM after palliative chemotherapy. UQCRC1 codes for cytochrome b-c1 complex subunit 1 which plays a fundamental role in normal mitochondrial functions and in cell metabolism. Recent studies described UQCRC1 deregulation in other cancers. Our results suggest a possible role for mitochondrial metabolism in the biology of mesothelioma.

WS05.04 Particularities of Lymphadenectomy in Malignant Pleural Mesothelioma

WS05.04 Particularities of Lymphadenectomy in Malignant Pleural Mesothelioma

MA12.05 Genomic Analysis of Long Term Malignant Pleura Mesothelioma Patients Treated with Palliative Chemotherapy

MA12.05 Genomic Analysis of Long Term Malignant Pleura Mesothelioma Patients Treated with Palliative Chemotherapy

Mesothelin as a target for cervical cancer therapy.

The cell surface glycoprotein Mesothelin is overexpressed in several tumor entities and novel immune-based therapies are currently under the early clinical evaluation for the treatment of malignant pleura mesothelioma, ovarian cancer, and pancreatic cancer. Cervical cancer has not been recognized as a suitable target for Mesothelin-directed immune therapies so far. To exploit a possible role of Mesothelin in cervical cancer treatment, we analysed Mesothelin expression in 79 cervical carcinomas and aligned expressions patterns with tumor growth parameters. A novel anti-Mesothelin drug conjugate (Anetumab Ravtansine) was applied for dose-efficiency studies in a Mesothelin positive tumor model for cervical cancer in Scid mice. In more than three-quarters (77%) of cervical adenocarcinomas, Mesothelin was expressed to high levels. Among squamous cell carcinomas of the cervix uteri expression levels were lower and expression patterns were less intense, but still ranged between 50-60% (57%). A significant correlation between Mesothelin expression levels and tumor grade, metastatic behaviour, and lymph- or hemangiosis was not found. The novel anti-Mesothelin-drug conjugate (Anetumab Ravtansine) showed a substantial dose-dependent therapeutic efficiency in a xenotransplant model for cervical cancer in SCID mice (hela cell tumors). Applying the ADC at a dose of 10mg/kg twice weekly induced complete tumor regression in 88% of animals within 6weeks. Mesothelin should be taken into account as a target in cervical cancer therapy and histological determination of Mesothelin expression should be considered in routine diagnostics of cervical carcinomas.

Extrapleural pneumonectomy- perioperative anaesthetic conduct

Malignant mesothelioma is a rare tumour arising from mesothelial lining that mostly occurs in the pleura with survival of around 12 months. 1 Extrapleural pneumonectomy, which is the mainstay of treatment for locally advanced malignant pleural mesothelioma, presents a great challenge to anaesthesiologists as it can be associated with high perioperative morbidity and mortality. We present a case report on anaesthetic management for extrapleural pneumonectomy in a 64-year-old patient with advanced malignant pleura mesothelioma. Our case report highlights: crucial role of anaesthetic management in reducing perioperative complications by better knowledge of physiology and technical aspects of the surgery; issues and challenges related to the anaesthetic management such as invasive monitoring, lung isolation, protective lung ventilation strategy, appropriate fluid management and adequate analgesia to enable extubation post-surgery in the operating room; high vigilance for diagnosing life-threatening complications such as cardiac herniation; team working and collaboration with surgeon to improve patient outcome and post-operative monitoring and management.

Hyperthermic intrathoracic chemotherapy after extended pleurectomy and decortication for malignant pleura mesothelioma: an observational study on outcome and microcirculatory changes.

In the treatment of malignant pleural mesothelioma the Hyperthermic Intra THOracic Chemotherapy (HITHOC) can improve the efficacy of pleurectomy and decortication with a local cytotoxic effect. However its biological impact in patient's hemodynamic and microcirculatory changes were rarely investigated. Aim of this study is to describe our experience with HITHOC after pleurectomy and decortication evaluating the role of sublingual video-microscopy in assessing the microcirculatory changes in the perioperative period. This is a prospective and observational study concerning 10 consecutive patients undergoing extended P/D followed by HITHOC. These patients underwent sublingual microcirculatory monitoring, which was adopted as a routine procedure since 2012. Haemodynamic parameters were collected at eight consecutive times: the day before surgery (T1), induction of anaesthesia (T2), surgical phase before HITHOC beginning (T3), 5 and 30 minutes after HITHOC start (T4 and T5, respectively), 5 minutes from HITHOC end (T6), after the admission in ICU (T7), at discharge from the ICU (T8). Cardiac output (CO) was calculated with MostCare. Systemic vascular resistance (SVR), oxygen delivery (DO2), and oxygen extraction rate (O2ER) were calculated using standard formulas. Arterial blood pressure and central venous pressure (CVP) were obtained with standard arterial and venous catheters. At the same times we assessed the sublingual microcirculation with Sidestream Dark Field technique. Hemodynamic and microcirculatory data were collected in 10 patients, 8 male and 2 females (mean age 68.6±9.0, and body surface area of 1.9±0.1 m2). All patients had arterial hypertension, and one patient had diabetes. The mean arterial pressure significantly decreased at T2, with respect to T1 (P=0.05). CO, CVP, DO2, O2ER, and ScvO2, did not change significantly over the time. All patients needed infusion of noradrenalin from T4 to T6. TVD significantly decreased from T1 to T3, T5, and T8. Similarly, PVD significantly decreased from T1 to T3 and T8, and MFI from T1 to T6 and T8. PPV and HI did not change over the study period. No correlation was found between hemodynamic parameters (MAP, CO, CVP, DO2, O2ER, ScvO2) and microcirculatory data (TVD, PVD, PPV, MFI, HI), at any time of the study. In patients who receive HITHOC the fluid load can reduce the microvascular impairment restoring the normal tissue perfusion. This process takes days but is most evident in the first 72 h. The use of colloid and blood transfusion is much more effective in restoring microcirculation and reducing tissue damaging.

Cytological profile of a case of malignant mesothelioma of pleura with supraclavicular lymph node metastasis

Malignant mesothelioma of pleura is a locally aggressive rare neoplasm of mesothelial cells, which produces distant metastasis in advanced stages of its course. It is exceptional for patients to present with metastasis prior to the detection of primary tumor in the pleura. Here, we report a case of malignant mesothelioma of pleura in a 65-year-old quarry worker where the initial diagnosis was offered by fine needle aspiration of an enlarged supraclavicular lymph node. Subsequent pleural fine needle aspiration cytology (FNAC), tumor biopsy, and immunohistochemical analysis confirmed the diagnosis.

Airways microbiota: Hidden Trojan horses in asbestos exposed individuals?

Malignant pleura mesothelioma (MPM) is a rare type of cancer with devastating prognosis, which develops in the pleural cavity from transformed mesothelium. MPM has been directly associated with asbestos exposure however there are aspects of the pathophysiology involved in the translocation of asbestos fibers in the pleura that remain unclear. Here, we propose and discuss that certain proteins secreted by airways symbiotic microbiota create membrane pores to the airway epithelial cells, through which asbestos fibers can penetrate the lung parenchyma and reach the sub-pleural areas. We evaluate this hypothesis using data from the published literature regarding the airways microbiota toxins such as cholesterol-dependent cytolysins (CDCs).

Identification of circulating miRNAs profiles that distinguish malignant pleural mesothelioma from lung adenocarcinoma.

Accurate diagnosis of malignant pleura mesothelioma (MPM) is challenging. Differential diagnosis of MPM versus lung adenocarcinoma (AD) is particularly difficult, yet clinically important since the two neoplasias call for different treatment approaches. Circulating miRNA-profiling to identify miRNAs that can be used to distinguish MPM from AD has not been reported. We conducted a wide screening study of miRNA profiles in serum pools of MPM patients (N = 11), AD patients (N = 36), and healthy subjects (N = 45) to identify non-invasive biomarkers for differential diagnosis of MPM and AD, using deep sequencing. Sequencing detected up to 300 known miRNAs and up to 25 novel miRNAs species in the serum samples. Among known miRNAs, 7 were upregulated in MPM and 12 were upregulated in AD compared to healthy controls. Of these, eight were distinctive for AD and three were unique for MPM. Direct comparison of the miRNA profiles for MPM and AD revealed differences in miRNA levels that could be useful for differential diagnosis. No differentially expressed novel miRNAs were found. Further bioinformatics analysis indicated that three upregulated miRNAs in MPM are associated with the p38 pathway. There are unique alterations in serum miRNAs in MPM and AD compared to healthy controls, as well as differences between MPM and AD profiles. Differing miRNA levels between MPM and AD may be useful for differential diagnosis. A potential association to p38 pathway of three upregulated miRNAs in MPM was revealed.

English

Malignant mesothelioma is an asbestos-induced, highly aggressive tumor. Malignant mesothelioma is a tumor of the serosal cavities most commonly involving the pleura and tends to present at relatively advanced stages. We describe a case of (epithelial) type of malignant mesothelioma of pleura in an elderly lady from a rural background with no history of exposure to asbestos, presented with left encysted hemothorax initially suspected to be due to trauma which later turned out to be due to malignant mesothelioma.

DICOM-RT Plan Complexity Verification for Volumetric Modulated Arc Therapy

The purpose of this study was to investigate the relationship between plan parameters verified with DICOM-RT and dosimetric results for volumetric modulated arc therapy (VMAT). We investigated three treatment locations: prostate cancer (ten cases), maxillary sinus cancer (four cases), and malignant pleura mesothelioma (four cases) with treatment plans generated by a MonacoTM treatment planning system (TPS), and delivered with an Elekta SynergyTM linear accelerator. We calculated plan parameters, including gantry and multileaf collimator (MLC) positions, Monitor Units (MU), and millimeters of MLC motion per degree of gantry rotation (mm/degree), and performed quality assurance (QA) with a DICOM-RT plan verification system. We measured the VMAT dose with a two-dimensional diode array detector. The average gamma passing rate with percent dose acceptance criteria and distance to agreement criteria of 2 mm and 2% (2 mm/2%) were 97.4%, 97.8% and 92.0% for prostate cancer, maxillary sinus cancer, and malignant pleural mesothelioma, respectively. The mean 95th percentile value for DICOM-calculated mm/degree was 4.0, 5.2, and 11.1 for prostate cancer, maxillary sinus cancer, and malignant pleural mesothelioma, respectively. The gamma passing rate showed a correlation with calculated mm/degree, with a coefficient of determination (R2) of 0.60. Higher calculated mm/degree values led to increased dosimetric errors. We conclude that dose distribution calculated by a TPS is more reliable at smaller mm/degree.

Expression of carbonic anhydrase IX (CAIX) in malignant mesothelioma. An immunohistochemical and immunocytochemical study

Malignant mesothelioma is an aggressive tumor with a poor prognosis. Carbonic anhydrase IX (CAIX) is a membranously located metalloenzyme involved in pH homeostasis with influence on regulation of cell proliferation, oncogenesis and tumor progression. Much attention has been paid recently to carboanhydrases and their inhibitors as they offer an opportunity for both developing novel anticancer drugs, as well as diagnostic and prognostic tools. This study was designed to assess the expression of CAIX in malignant pleural and peritoneal mesotheliomas, their benign counterparts, and in pleural effusions from patients with malignant mesothelioma, metastatic carcinoma or a benign disease. Tissue blocks from 51 malignant mesotheliomas of pleura (47 cases; 41 epithelioid, 2 biphasic, 4 sarcomatoid) and peritoneum (4 cases; all epithelioid), 14 cases with normal or reactive pleural tissue, and 19 cell blocks were analyzed. CAIX expression was determined using immunohistochemistry and its membranous immunoreactivity was semiquantitatively evaluated. Specimens were divided into five subgroups according to the staining pattern and intensity.Overall, 92.2% (47/51) of mesotheliomas expressed CAIX. All epithelioid mesotheliomas showed CAIX positivity, which was predominantly strong and diffuse (73.3%, 33/45). Sarcomatoid mesotheliomas and sarcomatoid areas in biphasic mesotheliomas were negative. A strong diffuse staining was observed in all cases of normal mesothelia. In pleural effusions, CAIX expression was observed in malignant cells as well as in benign mesothelial cells. In conclusion, CAIX is expressed virtually in all mesotheliomas except for sarcomatoid subtype, and in benign mesothelia. There are probably more mechanisms of CAIX overexpression than hypoxia-induced in malignant mesothelioma, with the influence of other tissue specific transcription or growth factors depending on the type of the cell lineage. CAIX immunoreactivity is not a reliable diagnostic marker for distinguishing malignant cells from benign mesothelia in pleural effusions. Nevertheless, our data support the potential use of therapeutics targeting CAIX in patients with advanced mesothelioma.

Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients

We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1–2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients.

Short interfering RNA- mediated suppression of specific tumor proteins results in a reduced viability of malignant pleuramesothelioma cell lines

Objectives: The incidence of the malignant pleural mesothelioma (MPM) remains to continue despite the well known risk factors and the worldwide launched prophylaxis. It remains to be an unique aggressive and bad treatable malignoma with only limited surgical and chemotherapeutic options despite an extended demand. Our study follows a new approach by siRNA mediated silencing of survival necessary proteins. In different cell lines of MPM the potency of siRNA application was evaluated under the question of supporting or revising existing therapeutic protocols in order to enhance the limited prognosis. siRNA provides by its highly sensitive features the possibility to knock out specific targets. Proteins which are involved in the replication of the cells and tumor specific survival proteins are promising therapeutic targets.

Epidemiologie und arbeitsmedizinische Aspekte des Pleuramesothelioms

Malignant mesothelioma of the pleura represents a signal tumour for (occupational) exposure to asbestos. Almost 20 years after the ban of asbestos in Germany, incident cases are still occurring due to the long latency period between the initial exposure to asbestos and the onset of the tumour. Of particular interest is the development of mesothelioma epidemiology. In Germany, it is extensively discussed whether the incidence of malignant pleura mesothelioma continues to rise, has already reached a plateau or is expected to decline in the next few years. The development is predominantly caused by the total asbestos use, its application and the gradual substitution of asbestos. The prevention of asbestos-related diseases due to former exposures, but also due to existing asbestos contaminations and their restoration is still a hot topic in occupational medicine. It is thus of major importance to ensure an adequate occupational safety and to care for asbestos-exposed workers - even after cessation of their exposure - with effective and efficient measures of early detection. New technologies, such as nanotechnology with carbon nanotubes, represent new potential health hazards.

Malignant Mesothelioma of Pleura : A Report of 2 Cases

Malignant Mesothelioma of Pleura is a rare tumor, which presents with chest pain & pleural effusion. It needs to be distinguished from pulmonary adenocarcinoma, which may be very difficult or even impossible task at the routine cytology & H&E level. Therefore a panel of immunohistochemical markers is required to reach the correct diagnosis.

Human malignant pleura mesothelioma ‐ a three‐dimensional (3D) tumor model

Human malignant pleura mesothelioma (MPM) is an extremely aggressive tumor of the mesothelium lining pleural cavity. Once diagnosed, it is uniformly fatal, with a median survival ranging from 4 to 12 month. The aim of our study is to design a 3D MPM model, to get knowledge of the biologic processes, which promote and maintain the uncontrolled proliferation of MPM cells, because the use of monolayer (2D) cultures does not accurately reflect the behaviour of cells in vivo. Human anchorage-depended MPM cells were seeded with macroporous gelatine microcarriers in the NASA-developed Rotary Cell Culture System™ (RCCS™). By simulating weightlessness (10−2 g) cells are maintained in a dynamic fluid suspension. Cells were examined at the state of viability, growth, morphology, differentiation and protein level in comparison to 2D controls. Different tumor marker were evaluated by immunohistochemistry, and the secretion of mucoglycoproteins by Alcian Blue staining. In addition, a comparative proteomic profile was established by 2D gel elektrophoreses and MALDI-TOF MS. Morphology, cell-cell junctional complexes and the well-developed formation of microvilli was shown by electron microscopy. The resulting morphological and functional differentiated tumor spheroids (5 mm in average) displayed a distinct protein pattern, than the control. Interestingly, the MPM marker Calretinin and Vimentin are expressed in a different manner. The organized 3D arrangement of mesothelioma cells with different phenotypes such as proliferating, non-proliferating, necrotic cells and extracellular matrix-interactions, represents the histological complexity of MPM tissue in-vivo. In conclusion, we find that this 3D in vitro culture is a credible and reliable preclinical tumor model.