Serum diagnostic markers for malignant pleural mesothelioma: a narrative review
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ABSTRACT: Background and Objective
The prognosis of patients with malignant pleural mesothelioma (MPM) is poor, and early diagnosis is key to improving the prognosis. Pleural biopsy is the gold reference for diagnosing MPM, but it is an invasive method that can cause operation-related complications such as bleeding and infection. Serum biomarkers, with the advantages of mini-invasiveness, short turnaround time and objectiveness, represent a promising diagnostic tool for MPM. Methods
We searched the PubMed database to identify clinical studies published between 1990 to July 2022 that investigated the diagnostic accuracy of serum biomarkers for MPM. The major findings of the verified studies were summarized. Key Content and Findings
Currently, there are many available serum markers for MPM, including mesothelin, soluble mesothelin-related peptides, osteopontin, fibulin-3, high mobility group box 1, and microRNA. Systematic review and meta-analysis evidence indicates that the sensitivity and specificity of these serum markers are less than 0.90. In addition, a large portion of previous studies have limitations, especially the representativeness of the study cohort. Conclusions
The diagnostic accuracy of currently available serum biomarkers is unsatisfactory, and further studies are needed to investigate novel serum biomarkers.
SUBMITTER: Wang J
PROVIDER: S-EPMC9834602 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:The malignant pleural mesothelioma is a very aggressive tumor which is arising from mesothelial cells and is associated with asbestos exposure. It is a heterogeneous cancer that shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic abnormalities. The malignant pleural mesothelioma is characterized by a silent and slow clinical progression with an average period of 20-40 years from the asbestos exposure phase to the start of the symptoms. Unfortunately, to date, the therapeutic options are very limited, especially if the tumor is detected late. This narrative review provides an extended overview of the present evidence in the literature regarding the epidemiology, diagnostic pathways and treatment approaches of the malignant pleural mesothelioma. The treatment of mesothelioma has evolved slowly over the last 20 years not only from a surgical point of view but also radiotherapy, chemotherapy and immunotherapy play nowadays a key role. Several surgical strategies are available ranging from extrapleural pneumonectomy to cytoreductive surgery but a multidisciplinary approach seems to be mandatory because a single approach has not proved to date to be resolutive. New non-surgical treatment options appear to be promising but the results have to be taken in account with caution because clear evidence with high-quality studies is still lacking.
| S-EPMC8107529 | biostudies-literature
Project description:Diagnosis of malignant pleural mesothelioma (MPM) is difficult, the most common differential diagnosis being benign pleural diseases and metastatic adenocarcinomas. In order to identify novel markers able to improve diagnostic accuracy, we performed a genome-wide gene expression analysis on tumor cells lines established from pleural effusions (13 MPM and 4 lung adenocarcinoma). Our microarray analysis led to the identification of genes encoding novel cellular and soluble markers whose expression was validated by RT-qPCR. Immunohistochemical staining of tumor biopsies with anti-type-III collagen antibodies were positive in mesothelioma cells but not in adenocarcinoma cells. Using ELISA, we showed that the C-C motif chemokine 2 (CCL2) concentration was significantly higher in pleural effusions from patients with mesothelioma (n = 61) than in subjects with adenocarcinoma (n = 25) or with benign pleural effusions (n = 15): median (interquartile range) = 2.99 ng/mL (1.76-6.01) versus 0.99 ng/mL (0.51-1.83) and 1.47 ng/mL (0.80-1.56), respectively, P < 0.0001. Conversely, the galectin-3 concentration was lower in mesothelioma: 11.50 ng/mL (6.73-23.53) versus 24.74 ng/mL (20.42-70.35) and 17.64 ng/mL (14.81-24.68), respectively, P < 0.0001. The AUC for CCL2 were 0.8030 and 0.7716 for differentiating mesothelioma from adenocarcinoma or benign effusions, respectively. Similarly, the AUC obtained for galectin-3 were 0.7980 and 0.6923, respectively. In conclusion, type-III collagen, CCL2 and galectin-3 are promising new diagnostic markers for mesothelioma.
2009-07-25 | GSE17310 | GEO
Project description:Malignant mesothelioma is a cancer with a poor survival rate. It is difficult to diagnose mesotheliomas because they show a variety of histological patterns similar to those of various other cancers. However, since currently used positive markers for mesotheliomas may show false positives or false negatives, a novel mesothelial positive marker is required. In the present study, we screened 25 claudins and found that claudin-15 is expressed in the mesothelial cells. We made new rat anti-human claudin-15 (CLDN15) monoclonal antibodies that selectively recognize CLDN15, and investigated whether CLDN15 is a good positive marker for malignant pleural mesotheliomas (MPMs) using MPM tissue samples by immunohistochemistry and semi-quantification of the expression level using an immunoreactive score (IRS) method. Of 42 MPM samples, 83% were positive for CLDN15. The positive ratio was equal to or greater than other positive markers for MPMs including calretinin (81%), WT-1 (50%), and D2-40 (81%). In 50 lung adenocarcinoma sections, four cases were positive for CLDN15 and the specificity (92%) was comparable with other markers (90-100%). Notably, CLDN15 was rarely detected in 24 non-mesothelial tumors in the tissue microarray (12/327 cases). In conclusion, CLDN15 can be used in the clinical setting as a positive marker for MPM diagnosis.
| S-EPMC8206149 | biostudies-literature
Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.
2005-06-01 | GSE2549 | GEO
Project description:Malignant pleural mesothelioma (MPM) is a tumour related to a historical exposure to asbestos fibres. Currently, the definite diagnosis is made only by the histological examination of a biopsy obtained through an invasive thoracoscopy. However, diagnosis is made too late for curative treatment because of non-specific symptoms mainly appearing at advanced stage disease. Hence, due to its biologic aggressiveness and the late diagnosis, survival rate is low and the patients' outcome poor. In addition, radiological imaging, like computed tomographic scans, and blood biomarkers are found not to be sensitive enough to be used as an early diagnostic tool. Detection in an early stage is assumed to improve the patients' outcome but is hampered due to non-specific and late symptomology. Hence, there is a need for a new screening and diagnostic test which could improve the patients' outcome. Despite extensive research has focused on blood biomarkers, not a single has been shown clinically useful, and therefore research recently shifted to "breathomics" techniques to recognize specific volatile organic compounds (VOCs) in the breath of the patient as potential non-invasive biomarkers for disease. In this review, we summarize the acquired knowledge about using breath analysis for diagnosing and monitoring MPM and asbestos-related disorders (ARD). Gas chromatography-mass spectrometry (GC-MS), the gold standard of breath analysis, appears to be the method with the highest accuracy (97%) to differentiate MPM patients from at risk asbestos-exposed subjects. There have already been found some interesting biomarkers that are significantly elevated in asbestosis (NO, 8-isoprostane, leukotriene B4, ?-Pinene…) and MPM (cyclohexane) patients. Regrettably, the different techniques and the plethora of studies suffer some limitations. Most studies are pilot studies with the inclusion of a limited number of patients. Nevertheless, given the promising results and easy sampling methods, we can conclude that breath analysis may become a useful tool in the future to screen for MPM, but further research is warranted.
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Project description:The diagnosis of malignant pleural mesothelioma is difficult, with the most common differential diagnoses being benign pleural diseases and metastatic adenocarcinomas (ADCA). To identify novel markers that would be able to improve diagnostic accuracy, we performed a genome-wide gene expression analysis on tumor cell lines established from pleural effusions (malignant pleural mesothelioma and lung ADCA). This analysis led to the identification of genes encoding novel and pertinent cellular and soluble markers, for which the expression was validated by real-time RT-PCR. Immunohistochemical staining of tumor biopsy specimens with anti-type III collagen antibodies showed positive labeling for mesothelioma cells but not for ADCA cells. Using enzyme-linked immunosorbent assay, we showed that the C-C motif chemokine 2 (CCL2) concentration was significantly higher in pleural effusions from patients with mesothelioma (n = 61) than in subjects with ADCA (n = 25) or with benign pleural effusions (n = 15): median (interquartile range) = 2.99 ng/ml (1.76 to 6.01) vs 0.99 ng/ml (0.51 to 1.83) and 1.47 ng/ml (0.80 to 1.56), respectively, P < 0.0001. Conversely, the galectin-3 concentration was lower in mesothelioma: 11.50 ng/ml (6.73 to 23.53) vs 24.74 ng/ml (20.42 to 70.35) and 17.64 ng/ml (14.81 to 24.68), respectively, P < 0.0001. The areas under the curve for CCL2 were 0.8030 and 0.7716 for the differentiation of mesothelioma from ADCA or benign pleural effusions, respectively. Similarly, the areas under the curve obtained for galectin-3 were 0.7980 and 0.6923, respectively. In conclusion, type III collagen, CCL2, and galectin-3 are promising new diagnostic markers for mesothelioma.
| S-EPMC3070574 | biostudies-literature
Project description:IntroductionEarly-stage accurate diagnosis of malignant pleural mesothelioma (MPM) has always been a formidable challenge. DNA and protein as biomarkers for the diagnosis of MPM have received considerable attention, and yet the outcomes are inconsistent.MethodsIn this study, a systematic search employing PubMed, EMBASE, and Cochrane Library to identify relevant studies from the first day of databases to October 2021. Moreover, we adopt the QUADAS-2 to evaluate the quality of eligible studies and Stata 15.0 and Review Manager 5.4 software programs to perform the meta-analysis. Additionally, bioinformatics analysis was performed at GEPIA for the purpose of exploring relationship between related genes and the survival time of MPM patients.ResultsWe included 15 studies at the DNA level and 31studies at the protein level in this meta-analysis. All results demonstrated that the diagnostic accuracy of the combination of MTAP + Fibulin-3 was the highest with the SEN 0.81 (95% CI: 0.67, 0.89) and the SPE 0.95 (95% CI: 0.90, 0.97). And the bioinformatics analysis indicated that the higher MTAP gene expression level was beneficial to enhance the survival time of MPM patients.DiscussionNonetheless, as a result of the limitations of the included samples, it may be necessary to conduct additional research before drawing conclusions.Systematic review registrationhttps://inplasy.com/inplasy-2022-10-0043/, identifier INPLASY2022100043.
| S-EPMC10126368 | biostudies-literature
Project description:Although cytology and pleural biopsy of pleural effusion (PE) are the gold standards for diagnosing malignant pleural effusion (MPE), these tools' diagnostic accuracy is plagued by some limitations such as low sensitivity, considerable inter-observer variation and invasiveness. The assessment of PE biomarkers may hence be seen as an objective and non-invasive diagnostic alternative in MPE diagnostics. In this review, we summarize the characteristics and diagnostic accuracy of available PE biomarkers, including carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), carbohydrate antigens 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3), a fragment of cytokeratin 19 (CYFRA 21-1), chitinase-like proteins (CLPs), vascular endothelial growth factor (VEGF) and its soluble receptor, endostatin, calprotectin, cancer ratio, homocysteine, apolipoprotein E (Apo-E), B7 family members, matrix metalloproteinase (MMPs) and tissue-specific inhibitors of metalloproteinases (TIMPs), reactive oxygen species modulator 1 (Romo1), tumor-associated macrophages (TAMs) and monocytes, epigenetic markers (e.g., cell-free microRNA and mRNA). We summarized the evidence from systematic review and meta-analysis for traditional tumor markers' diagnostic accuracy. According to the currently available evidence, we conclude that the traditional tumor markers have high specificity (around 0.90) but low sensitivity (around 0.50). The diagnostic accuracy of novel tumor markers needs to be validated by further studies. None of these tumor biomarkers would have sufficient diagnostic accuracy to confirm or exclude MPE when used alone. A multi-biomarker strategy, also encompassing the use of artificial intelligence algorithms, may be a valuable perspective for improving the diagnostic accuracy of MPE.
| S-EPMC8044497 | biostudies-literature
Project description:Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.
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