Early Detection Of Malignant Mesothelioma Research Articles

ATG5 as biomarker for early detection of malignant mesothelioma

ObjectivesMalignant pleural mesothelioma (MPM) is an aggressive disease with grim prognosis due to lack of effective treatment options. Disease prediction in association with early diagnosis may both contribute to improved MPM survival. Inflammation and autophagy are two processes associated with asbestos-induced transformation. We evaluated the level of two autophagic factors ATG5 and HMGB1, microRNAs (miRNAs) such as miR-126 and miR-222, and the specific biomarker of MPM, soluble mesothelin related proteins (Mesothelin) in asbestos-exposed individuals, MPM patients, and healthy subjects. The performance of these markers in detecting MPM was investigated in pre-diagnostic samples of asbestos-subjects who developed MPM during the follow-up and compared for the three groups.ResultsThe ATG5 best distinguished the asbestos-exposed subjects with and without MPM, while miR-126 and Mesothelin were found as a significant prognostic biomarker for MPM. ATG5 has been identified as an asbestos-related biomarker that can help to detect MPM with high sensitivity and specificity in pre-diagnostic samples for up to two years before diagnosis. To utilize this approach practically, higher number of cases has to be tested in order to give the combination of the two markers sufficient statistical power. Performance of the biomarkers should be confirmed by testing their combination in an independent cohort with pre-diagnostic samples.

Integrative approach to cytologic and molecular diagnosis of malignant pleural mesothelioma.

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.

Diagnostic and prognostic biomarkers for malignant mesothelioma: an update.

Malignant mesothelioma (MM) is an aggressive and lethal cancer, mostly related to inhalation of asbestos and erionite fibers. MM is associated with poor prognosis, because of its resistance to current therapies, even if higher survival occurs in patients diagnosed and treated when at stage I of the disease. However, these do not exceed 5% of the total number of cases, due to the inadequacy of the existing biomarkers for early and accurate diagnosis. Therefore, new effective biomarkers are needed for MM detection at earlier stages and to develop tailored therapies. Here we review the most promising biomarkers in MM to date: mesothelin, soluble mesothelin-related peptides (SMRPs), megakaryocyte potentiating factor (MPF), Osteopontin (OPN), Fibulin-3, high mobility group B1 (HMGB1), microRNAs (miRNAs), multiplex protein signatures. The validation of these biomarkers will allow their use, alone or in combination, for monitoring individuals from cohorts at risk of MM and attaining early detection of MM that is instrumental in improving patient survival.

Early recognition of lung cancer in workers occupationally exposed to asbestos

Despite the fact that working with asbestos and placing it on the market have been banned in Germany since 1993 according to the Ordinance on Hazardous Substances, asbestos-related diseases of the lungs and pleura are still the leading cause of death in occupational diseases. The maximum industrial usage of asbestos was reached in former West Germany in the late 1970s and in former East Germany the late 1980s. Occupational diseases, mainly mesotheliomas and lung cancer emerging now are thus caused by asbestos exposure which occurred 30-40years earlier. It is known that the combination of smoking and asbestos exposure results in a superadditive increase in the risk to develop lung cancer. No suitable screening methods for early detection of malignant mesothelioma are currently available and the therapeutic options are still very limited; however, the national lung screening trial (NLST) has shown for the first time that by employing low-dose computed tomography (LDCT) in heavy smokers, lung cancer mortality can be significantly reduced. According to current knowledge the resulting survival benefits far outweigh the potential risks involved in the diagnostic work-up of suspicious lesions. These results in association with the recommendations of international medical societies and organizations were pivotal as the German statutory accident insurance (DGUV) decided to provide LDCT as a special occupational medical examination for workers previously exposed to asbestos and with a particularly high risk for developing lung cancer.

In vivo Optical Coherence Tomography Imaging of the Mesothelium Using Developed Window Models

The mesothelium is an essential lining for maintaining the normal homeostasis of the closed body cavity and a central component of pathophysiologic processes. The mesothelium has been known as the end target for asbestos which induces asbestos-related lung diseases. Malignant mesothelioma (MM) is a rare and fatal neoplasm predominantly due to asbestos exposure. Adaptation of an advanced and reliable technology is necessary for early detection of MM because it is difficult to diagnose this disease in its early stages. Optical coherence tomography (OCT) provides cross-sectional images of micro-tissue structures with a resolution of <TEX>$2-10{\mu}m$</TEX> that can image the mesothelium with a thickness of <TEX>${\sim}100{\mu}m$</TEX> and, therefore, enable investigation of early development of MM. The mesothelium is typically located at the pleura and tunica vaginalis of the scrotum. In this study, we developed animal window models in the above two anatomical sites to visualize mesothelial layers within the mesothelium. OCT images at the two locations were also acquired.

Abstract 4153: Usefulness of sensitive digital PCR assay to quantify microRNA-34b/c methylation in the circulating serum DNA of malignant mesothelioma patients

Abstract . Background: Malignant mesothelioma (MM) is an aggressive tumor but it can sometimes be cured if its clinical stage is not advanced. It is very expected to establish a useful screening test for early detection of MM. Recently we have found that DNA methylation of microRNA-34bc (miR34b/c) plays a dismal role on pathogenesis of MM and is frequently observed in MM. Circulating DNA from malignant tumors is known to be found in the serum of the patient. Digital polymerase chain reaction (PCR) is a high sensitive quantitative assay using real time PCR assay. In order to establish a new early detection system for MM, we quantify the extent of DNA methylation of miR-34b/c using a digital PCR assay in the circulating serum DNA from MM. Material and methods: We collected serum samples from 30 MM patients, 22 patients with benign asbestos pleurisy (BAP), and 10 healthy volunteers (HV) at Okayama Rosai Hospital, NHO Yamaguchi Ube Medical Center and our institute during January 2006 to August 2009. The circulating serum DNA was extracted using QIAamp Circulating Nucleic Acid Kit (Qiagen) followed by bisulfite conversion using EpiTect Bisulfite Kits (Qiagen) according to manufactural protocols. The real time PCR assay of methylation-specific PCR (MSP) for miR-34b/c was performed using SYBR Green method. In addition, the digital PCR of real time MSP assay was explored for 40 wells per each sample with a suitable dilution to aim the increase of sensitivity of PCR reaction, and we quantified the extent of methylation in each sample by counting the number of positive well of PCR reaction per sample. As positive and negative controls, the supernatant cultured medium of NCI-H290 harboring heavy methylation of miR-34b/c and water blank was used, respectively. Results: By melting curve analysis, we distinguished the miR-34b/c methylated wells from unmethylated wells based on the temperatures of PCR products of them (78.2 degree on methylated samples vs. 76.2 degree on un-methylated samples). Using the criteria above, each 40 wells per sample was defined as positive or negative for miR-34b/c methylation. The miR-34b/c methylated samples were defined as having more than three positive wells by ROC curve analyses. Finally, we found that the number of positive wells was significantly higher in MMs than that in other groups, and the miR-34b/c methylated samples was observed in 87% of MM patients, 45% of the patients with BAP, and 10% of HV, respectively, indicating that the miR-34b/c methylation in MM patients were significantly frequent than that in others (P &amp;lt;0.0001). Conclusion: The digital PCR assay can detect miR-34b/c methylation in the circulation serum DNA of MM patients to find that miR-34b/c methylation is more frequent in MM than in BAP, suggesting that it may become a useful high-sensitive screening test to distinguish MM patients from the patients with BAP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4153. doi:1538-7445.AM2012-4153

Association of Biomarker Levels with Severity of Asbestos-Related Diseases

ObjectivesAsbestos-related diseases (ARDs) have increased globally over the decades, causing an economic burden and increased health care costs. It is difficult to predict the risk of development of ARDs and of respiratory disability among workers with a history of asbestos exposure. Blood based biomarkers have been reported as promising tools for the early detection of malignant mesothelioma. This study investigated whether serum soluble mesothelin-related peptide (SMRP) would reflect severity of disablement in compensable ARDs.MethodsSMRP levels were measured in a cohort of 514 asbestos-exposed subjects. Severity of ARDs was assessed by a Medical Authority comprising four specially qualified respiratory physicians. Severity of ARDs and SMRP levels were compared.ResultsMean (standard deviation) serum SMRP level in the population with compensable ARDs (n = 150) was 0.95 (0.65) nmol/L, and was positively associated with disability assessment (p = 0.01). Mean SMRP level in healthy asbestos-exposed subjects was significantly lower than those with pleural plaques (p < 0.0001) and in subjects with ARDs who received compensation (p < 0.01).ConclusionThis study indicates that serum SMRP levels correlate with severity of compensable ARDs. Serum SMRP could potentially be applied to monitor progress of ARDs. Further prospective work is needed to confirm the relationship between SMRP and disability assessment in this population.

Identification of miRNA-103 in the Cellular Fraction of Human Peripheral Blood as a Potential Biomarker for Malignant Mesothelioma – A Pilot Study

BackgroundTo date, no biomarkers with reasonable sensitivity and specificity for the early detection of malignant mesothelioma have been described. The use of microRNAs (miRNAs) as minimally-invasive biomarkers has opened new opportunities for the diagnosis of cancer, primarily because they exhibit tumor-specific expression profiles and have been commonly observed in blood of both cancer patients and healthy controls. The aim of this pilot study was to identify miRNAs in the cellular fraction of human peripheral blood as potential novel biomarkers for the detection of malignant mesothelioma.Methodology/Principal FindingsUsing oligonucleotide microarrays for biomarker identification the miRNA levels in the cellular fraction of human peripheral blood of mesothelioma patients and asbestos-exposed controls were analyzed. Using a threefold expression change in combination with a significance level of p<0.05, miR-103 was identified as a potential biomarker for malignant mesothelioma. Quantitative real-time PCR (qRT-PCR) was used for validation of miR-103 in 23 malignant mesothelioma patients, 17 asbestos-exposed controls, and 25 controls from the general population. For discrimination of mesothelioma patients from asbestos-exposed controls a sensitivity of 83% and a specificity of 71% were calculated, and for discrimination of mesothelioma patients from the general population a sensitivity of 78% and a specificity of 76%.Conclusions/SignificanceThe results of this pilot study show that miR-103 is characterized by a promising sensitivity and specificity and might be a potential minimally-invasive biomarker for the diagnosis of mesothelioma. In addition, our results support the concept of using the cellular fraction of human blood for biomarker discovery. However, for early detection of malignant mesothelioma the feasibility of miR-103 alone or in combination with other biomarkers needs to be analyzed in a prospective study.

Exploratory Study on the Detection of Markers for Diagnosing Early-Stage Malignant Mesothelioma

Malignant mesothelioma (MM) is a highly aggressive, incurable neoplasm associated with asbestos exposure. Early detection of MM is not easy and radiological surveillance is imperfect. The use of blood-based biomarkers might solve this difficulty and allow detection of MM at an early stage when combined treatment involving surgery, chemotherapy and radiotherapy might be effective. In the research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)", we conducted an exploratory study on the detection of markers for diagnosing early-stage MM. In this study, we have shown that serum soluble mesothelin-related peptide (SMRP) is a highly specific and moderately sensitive biomarker for diagnosing MM. SMRP levels in pleural effusion were elevated not only in advanced-stage malignant pleural mesothelioma (MPM), but also in early-stage disease. SMRP in pleural effusion can be an MPM-specific biomarker with greater sensitivity than in serum, especially for the early stage of the disease. Circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were considered to be useful surrogate markers of disease progression in MPM, although the lack of sensitivity for early-stage disease remains to be improved. Cytological analysis with gene expression profiling has been more effective in detecting early-stage MPM with pleural effusion. In conclusion, blood or effusion-based biomarkers, possibly in combination with other new modalities, such as a thoracoscopy combined with the advanced imaging systems consisting of autofluorescence imaging (AFI) and narrow band imaging (NBI), will show some promise for curing MPM if the disease is detected at an early stage.

Biomarkers for early detection of malignant mesothelioma: diagnostic and therapeutic application.

Malignant mesothelioma (MM) is a rare and aggressive tumour of the serosal cavities linked to asbestos exposure. Improved detection methods for diagnosing this type of neoplastic disease are essential for an early and reliable diagnosis and treatment. Thus, focus has been placed on finding tumour markers for the non-invasive detection of MM. Recently, some blood biomarkers have been described as potential indicators of early and advanced MM cancers. The identification of tumour biomarkers alone or in combination could greatly facilitate the surveillance procedure for cohorts of subjects exposed to asbestos, a common phenomenon in several areas of western countries.

Blood-Based Early Detection of Malignant Mesothelioma

Blood-Based Early Detection of Malignant Mesothelioma

Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study

Improved detection methods for diagnosis of asymptomatic malignant mesothelioma (MM) are essential for an early and reliable detection and treatment of this type of neoplastic disease. Thus, focus has been on finding tumor markers in the blood that can be used for noninvasive detection of MM. Ninety-four asbestos-exposed subjects defined at high risk, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the clinical significance of 8-hydroxy-2'-deoxyguanosine (8OHdG) in WBCs and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors [platelet-derived growth factor beta, hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor beta (VEGFbeta)], and matrix proteases [matrix metalloproteinase (MMP) 2, MMP9, tissue inhibitor of metalloproteinase (TIMP) 1, and TIMP2] for potential early detection of MM. The area under receiver operating characteristic (ROC) curves indicate that 8OHdG levels can discriminate asbestos-exposed subjects from healthy controls but not from MM patients. Significant area under ROC curve values were found for SMRPs, discriminating asbestos-exposed subjects from MM patients but not from healthy controls. Except for platelet-derived growth factor beta, the hepatocyte growth factor, basic fibroblast growth factor, and VEGFbeta can significantly differentiate high-risk individuals from healthy control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, and TIMP2. In addition to the diagnostic performance defined by the ROC analysis, the sensitivity and specificity results of markers with clinical significance were calculated at defined cutoffs. The combination of 8OHdG, VEGFbeta, and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

Serum hyaluronate in malignant pleural mesothelioma.

The diagnostic value of hyaluronate concentration in effusions of malignant mesothelioma has been extensively reported but no information is available about serum hyaluronate in patients with this cancer. Using a new enzymoimmunologic assay based on hyaluronate-hyaluronectin interaction, serum levels of hyaluronate were measured in 16 patients with malignant pleural mesothelioma, 50 patients with other pleural effusions, and 94 healthy blood donors. The mean serum hyaluronate level in patients with mesothelioma (mean, 750 micrograms/l; range, 29 to 5833 micrograms/l) was significantly higher than in patients with other pleural effusions (mean, 56 micrograms/l; range, 4 to 137 micrograms/l) and than in blood donors (mean, 24 micrograms/l; range, 0 to 94 micrograms/l). Comparison of serum hyaluronate values observed in mesotheliomas with the clinical course of the disease suggests that serum hyaluronate might increase only at an advanced stage of the cancer. Therefore, serum hyaluronate determination has probably no clinical value for early detection of malignant mesothelioma, but might be useful to evaluate the clinical course of this malignancy.

The Control of Tuberculosis in Industry A Responsibility and a Profit

Objectives: Asbestos-related diseases (ARDs) have increased globally over the decades, causing an economic burden and increased health care costs. It is difficult to predict the risk of development of ARDs and of respiratory disability among workers with a history of asbestos exposure. Blood based biomarkers have been reported as promising tools for the early detection of malignant mesothelioma. This study investigated whether serum soluble mesothelin-related peptide (SMRP) would reflect severity of disablement in compensable ARDs.Methods: SMRP levels were measured in a cohort of 514 asbestos-exposed subjects. Severity of ARDs was assessed by a Medical Authority comprising four specially qualified respiratory physicians. Severity of ARDs and SMRP levels were compared.Results: Mean (standard deviation) serum SMRP level in the population with compensable ARDs (n = 150) was 0.95 (0.65) nmol/L, and was positively associated with disability assessment (p = 0.01). Mean SMRP level in healthy asbestos-exposed subjects was significantly lower than those with pleural plaques (p < 0.0001) and in subjects with ARDs who received compensation (p < 0.01).Conclusion: This study indicates that serum SMRP levels correlate with severity of compensable ARDs. Serum SMRP could potentially be applied to monitor progress of ARDs. Further prospective work is needed to confirm the relationship between SMRP and disability assessment in this population.