Soluble Mesothelin–related Peptides in the Diagnosis of Malignant Pleural Mesothelioma
Arnaud ScherpereelBogdan GrigoriuMassimo ContiThomas GeyMarc GrégoireMarie‐Christine CopinPatrick DevosBachar ChahineHenri PortePhilippe Lassalle
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Abstract:
Diagnosis of malignant pleural mesothelioma is a challenging issue. Potential markers in mesothelioma diagnosis include soluble mesothelin-related peptides (SMRPs) and osteopontin, but no subsequent validation has been published yet.We prospectively evaluated SMRPs in serum and pleural effusion from patients with mesothelioma (n = 74), pleural metastasis of carcinomas (n = 35), or benign pleural lesions associated with asbestos exposure (n = 28), recruited when first suspected for mesothelioma.Mean serum SMRP level was higher in patients with mesothelioma (2.05 +/- 2.57 nM/L [median +/- interquartile range]) than in patients with metastasis (1.02 +/- 1.79 nM/L) or benign lesions (0.55 +/- 0.59 nM/L). The area under the receiver operating characteristic curve (AUC) for serum SMRP was 0.872 for differentiating mesothelioma and benign lesions, cut-off = 0.93 nM/L (sensitivity = 80%, specificity = 82.6%). The AUC for serum SMRP differentiating metastasis and mesothelioma was 0.693, cut-off = 1.85 nM/L (sensitivity = 58.3%, specificity = 73.3%). SMRP values in pleural fluid were higher than in serum in all groups (mesothelioma: 46.1 +/- 83.2 nM/L; benign lesions: 6.4 +/- 11.1 nM/L; metastasis: 6.36 +/- 21.73 nM/L). The AUC for pleural SMRP-differentiating benign lesions and mesothelioma was 0.831, cut-off = 10.4 nM/L (sensitivity = 76.7%, specificity = 76.2%). The AUC for pleural SMRP-differentiating metastasis and mesothelioma was 0.793.We show that SMRPs may be a promising marker for mesothelioma diagnosis when measured either in serum or pleural fluid. The diagnostic value of SMRPs was similar in both types of samples, but pleural fluid SMRPs may better discriminate mesothelioma from pleural metastasis.Keywords:
Pleural disease
Mesothelin
Interquartile range
Abstract Background: Malignant mesothelioma is an aggressive, almost uniformly fatal tumor, primarily caused by exposure to asbestos. Since the recent discovery that serum mesothelin is a sensitive and highly specific biomarker for mesothelioma, one of the key issues raised is whether mesothelin levels represent a useful screening test for asbestos-exposed at-risk individuals. In this study, soluble mesothelin was determined in sequential serum samples collected from asbestos-exposed individuals before the development of mesothelioma. Methods: Archival serum samples from 106 individuals who developed mesothelioma, 99 asbestos-exposed individuals from the Wittenoom Cancer Surveillance Program, and 109 non–asbestos-exposed individuals from the Busselton Health Survey were identified. Serum mesothelin concentrations were determined using the MESOMARK assay. Results: Longitudinal mesothelin levels determined in healthy asbestos-exposed individuals over a period of 4 years were stable (Pearson's r = 0.96; P < 0.0001). There was no correlation between mesothelin concentration and cumulative asbestos exposure. Mesothelin concentrations were greater than the threshold value of 2.5 nmol/L in the penultimate serum sample before the diagnosis of mesothelioma in 17 of 106 people. Using an increase above the 95% confidence interval of the mean of a given individual's longitudinal mesothelin results, 33 of 82 individuals had increasing mesothelin levels before diagnosis. Conclusion: In a population with a high pretest probability of developing mesothelioma, the serum biomarker mesothelin is elevated in absolute terms in 15% and in relative terms in 40% of the group. Impact: Future studies examining a combination of biomarkers could improve sensitivity of screening. Cancer Epidemiol Biomarkers Prev; 19(9); 2238–46. ©2010 AACR.
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Mesothelioma, a rare tumor, is highly correlated with asbestos exposure. Mesothelioma, similar to all asbestos-related diseases, is dose/intensity dependent to some degree, and studies showed the risk of mesothelioma rises with cumulative exposures. Multiple processes occur in an individual before mesothelioma occurs. The impact of mesothelioma in the United States has been continuous over the last half century, claiming between 2,000 and 3,000 lives each year. Mesothelioma is a preventable tumor that is more frequently reported as associated with asbestos exposure among men than women. However, the rate of asbestos-associated mesothelioma is on the rise among women due to better investigation into their histories of asbestos exposure. It is of interest that investigators detected asbestos-associated cases of mesothelioma in women from nonoccupational sources-that is, bystander, incidental, or take-home exposures. It is postulated that asbestos-associated mesotheliomas, in both men and women, are likely underreported. However, with the implementation of the most recent ICD-10 coding system, the correlation of mesothelioma with asbestos exposure is expected to rise to approximately 80% in the United States. This study examined the demographic and etiological nature of asbestos-related mesothelioma.
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Background: The diagnosis of malignant mesothelioma is frequently difficult, the most common differential diagnosis being reactive pleural conditions and metastatic adenocarcinoma. Soluble mesothelin levels in serum have recently been shown to be highly specific and moderately sensitive for mesothelioma. As most patients with mesothelioma present with exudative effusions of either the pleura or the peritoneum, a study was undertaken to determine if levels of mesothelin were raised in these fluids and if the increased levels could help to distinguish mesothelioma from other causes of exudative effusion. Methods: Pleural fluid was collected from 192 patients who presented to respiratory clinics (52 with malignant mesothelioma, 56 with non-mesotheliomatous malignancies and 84 with effusions of non-neoplastic origin). Peritoneal fluid was collected from 42 patients (7 with mesothelioma, 14 with non-mesotheliomatous malignancies and 21 with benign effusions). Mesothelin levels were determined in effusion and serum samples by ELISA. Results: Significantly higher levels of mesothelin were found in effusions of patients with mesothelioma; with a specificity of 98%, the assay had a sensitivity of 67% comparing patients with mesothelioma and those with effusions of non-neoplastic origin. In 7 out of 10 cases mesothelin levels were raised in the effusion collected 3 weeks to 10 months before the diagnosis of mesothelioma was made; in 4 out of 8 of these, mesothelin levels were increased in the effusion but not in the serum. Conclusions: Measurement of mesothelin concentrations in the pleural and/or peritoneal effusion of patients may aid in the differential diagnosis of mesothelioma in patients presenting with effusions.
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To investigate if the preventive measures taken to reduce the occupational exposure to asbestos have resulted in a decreased incidence of pleural mesothelioma in Sweden.The incidence of pleural mesothelioma between 1958 and 1995 for birth cohorts born between 1885 and 1964 was investigated. The cases of pleural mesothelioma were identified through the Swedish Cancer Register.In 1995, around 80 cases of pleural mesothelioma could be attributed to occupational exposure to asbestos. There is an increasing incidence in more recent birth cohorts in men. The incidence was considerably higher in the male cohort born between 1935 and 1944 than in men born earlier.The annual incidence of pleural mesothelioma attributable to occupational exposure to asbestos is today larger than all fatal occupational accidents in Sweden. The first asbestos regulation was adopted in 1964 and in the mid 1970s imports of raw asbestos decreased drastically. Yet there is no obvious indication that the preventive measures have decreased the risk of pleural mesothelioma. The long latency indicates that the effects of preventive measures in the 1970s could first be evaluated around 2005.
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A 45-year-old male, non smoker and lecturer by profession was diagnosed as an advanced case of bilateral mesothelioma involving lung and pleura. He was never exposed to asbestos, which makes it a rare case.
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A series of 144 cases of mesothelioma among asbestos workers indicated important divergences from the epidemiological pattern shown to exist for asbestos-related lung cancer. Consideration of exposure duration and intensity and the latent period between first exposure and death suggests that asbestos does not act as a complete carcinogen, but as a promoter. A threshold seems probable for both duration and intensity of exposure in the induction of mesothelioma. This threshold may, in part, be related to the passage of fibers from the lungs to the pleura or peritoneum, and would, in any case, be masked in lung cancer by the retention of asbestos in the lungs. Reported cases of mesothelioma in immediate family members indicate the existence of an additional factor in mesothelioma induction, acting earlier in life than the first asbestos exposure.
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Malignant mesothelioma is an uncommon, but increasingly important, neoplasm. The existing English-language medical literature concerning non-asbestos-related malignant mesotheliomas was reviewed for evidence of other agents associated with the induction of malignant mesothelioma. Both animal and human data were reviewed. In most reviews of malignant mesothelioma, there are a significant proportion of cases without documented asbestos exposure (range, 0% to 87%). Furthermore, there are several fairly well-documented agents other than asbestos that induce malignant mesothelioma in animals, and strong evidence exists that such is the case in man. In reviews of malignant mesothelioma, the percentage of cases with asbestos exposure varies, but a significant number are apparently not asbestos related. It is believed that sufficient evidence exists to suggest that non-asbestos agents can induce malignant mesotheliomas in man, and additional epidemiologic studies in this area are needed.
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Abstract Background: Because mesothelioma initially progresses on the surface of the pleura and peritoneum without forming masses, it has been difficult to diagnose at an early stage. It would be very useful to identify a tumor marker that could be used for screening to enable more diagnoses to be made at an early, treatable stage. Materials and Methods: We had previously identified N-ERC/mesothelin as a potential biomarker for mesothelioma. In the current work, we used a newly developed ELISA system to gain data on N-ERC/mesothelin levels in various clinical settings. A total of 102 healthy volunteers were recruited. In addition, 39 patients were diagnosed with mesothelioma, 53 patients were diagnosed with diseases that should be distinguished from mesothelioma, and 201 subjects were diagnosed with asbestos-related nonmalignant diseases (including simple exposure to asbestosis) who were treated at any of the cooperating hospitals were enrolled. Results: Serum N-ERC/mesothelin levels measured by a new ELISA system showed that the median values from patients with mesothelioma were extremely high compared with levels obtained from other patients. Analysis in terms of histologic type showed that serum levels of N-ERC/mesothelin were elevated in epithelioid type mesothelioma, especially. In four important models of clinical settings, the sensitivity and specificity of N-ERC/mesothelin were about 71% to 90% and 88% to 93%, respectively. Conclusion: N-ERC/mesothelin is a very promising tumor marker for mesothelioma, especially epithelioid mesothelioma.
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