Soluble Mesothelin-related Peptide Research Articles

MESOMARK®in vitrodiagnostic test for mesothelioma

Mesothelioma is a highly progressive tumor with a poor prognosis. In this article, the authors give a thorough introduction into and evaluation of the MESOMARK(®) in vitro test - the only blood test for the management of patients with mesothelioma approved by the US FDA. In Europe, Australia, New Zealand and Canada, the test is approved or licensed for the measurement of the soluble mesothelin, also termed as soluble mesothelin-related peptides. In the US, it is approved for the monitoring of patients with epithelioid and biphasic malignant mesothelioma.

Biomarkers for mesothelioma

Mesothelioma is an incurable cancer and its global incidence continues to increase. There has been strong interest in the search for a biomarker that would be of value for the diagnosis, prognosis and disease monitoring of mesothelioma. Large series evaluating the use of novel candidate markers have recently been published. To date, global gene profiling studies have failed to find a molecule that reliably captures all subtypes of mesothelioma, and differentiates it from benign pathologies and metastatic carcinomas. Soluble mesothelin-related peptide (SMRP), osteopontin and megakaryocyte potentiating factor have been assessed as markers. SMRP testing is clinically available and provides reasonable diagnostic sensitivity and specificity when applied to serum or pleural fluid. Elevated SMRP levels can occur in metastatic, especially ovarian and pancreatic, adenocarcinomas. False negatives are common with sarcomatoid mesothelioma. SMRP levels may reflect tumor load and disease progression. The role of SMRP in predicting mesothelioma development in subjects exposed to asbestos has raised interest. Osteopontin lacks specificity as a diagnostic marker for mesothelioma but may have value in disease monitoring. The proposed markers have insufficient accuracy to replace cytohistology as the gold standard for diagnosis for mesothelioma. Elevated SMRP levels raise suspicion of mesothelioma although negative values do not exclude disease. Its role in disease monitoring in patients and in predicting disease development in at-risk individuals warrant further study.

MESOMARK™: A Potential Test for Malignant Pleural Mesothelioma

Soluble mesothelin-related peptides (SMRP)have been reported to be potential biomarkers for malignant pleural mesothelioma (MPM). We report analytical and preliminary clinical studies of MESOMARK, a quantitative assay for SMRP. The MESOMARK assay is a 2-step immunoenzymatic assay in an ELISA format with a 6-point calibration curve (0-32 nmol/L). We assessed analytical imprecision, analyte stability, and analytical interferences. We measured SMRP by this assay in 409 apparently healthy individuals (reference interval study), 177 patients with nonmalignant conditions, and 500 cancer patients, including 88 with MPM. The limit of detection was 0.16 nmol/L. At 2-19 nmol/L, intraassay imprecision (CV) was 1.1%-5.3%, and total imprecision was 4.0%-11.0%. The mean dilution recovery for 5 samples was 109% (range, 99%-113%). No interference was seen from added bilirubin (200 mg/L), hemoglobin (500 mg/L), triglycerides (30 g/L), chemotherapeutic agents, or other tested substances. Recombinant mesothelin was stable in serum upon freeze/thaw at -70 degrees C and upon storage for at least 7 days at 2-8 degrees C. The 99(th) percentile of the reference group was 1.5 nmol/L [95% confidence interval (CI), 1.2-1.6 nmol/L; n = 409], and mean SMRP was significantly higher in sera from patients with MPM (7.5 nmol/L; 95% CI, 2.8-12.1 nmol/L; n = 88). SMRP was increased in 52% and 5% of MPM patients and asbestos-exposed individuals, respectively. Concentrations in other nonmalignant and malignant conditions were similar to those in healthy controls. The MESOMARK assay is analytically robust and may be useful for the detection and management of mesothelioma.

9 Diagnostic and prognostic utility of soluble mesothelin-related peptides in malignant pleural mesothelioma

arrays, and found a similar pattern of overexpression in the U95 and U133 AB Affymetrix cohorts from our mesothelioma archive. When serum from asbestos exposed individuals was compared to that of mesotheliomas, the area under the curve for the Receiver Operating Characteristics (ROC) curve was 0.890.91. Osteopontin levels rose in the asbestos exposed population as a function of duration of asbestos exposure and radiographic evidence of fibrosis and plaque. Conclusions: Osteopontin is the first genomically discovered early detection marker which will move to validation studies in mesothelioma. Validation plans as well as new data in other cohorts will be discussed.

Soluble Mesothelin–related Peptides in the Diagnosis of Malignant Pleural Mesothelioma

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.

Soluble mesothelin related peptides: A potential biomarker for malignant pleural mesothelioma

9532 Background: At this time there are no biomarkers that can monitor therapy or predict asbestos-related malignant pleural mesothelioma (MPM). Fujirebio Diagnostics, Inc. developed MESOMARK™ a quantitative dual-monoclonal ELISA for soluble members of a family of proteins expressed by mesothelial cells called soluble mesothelin related peptides (SMRP). We assessed whether (1) SMRP levels in sera and pleural effusions (PE) differed between MPM, non-MPM tumors, asbestos-exposed non-MPM individuals (ASB) and normal volunteers (NL), and (2) SMRP could predict recurrence of MPM after surgery. Methods: Archived frozen serum from 26 ASB, 50 NLs, 54 MPMs, and 14 non-MPMs, and PE from 30 NL, 20 non-MPM tumors, and 45 MPMs were analyzed by MESOMARK™. Blinded longitudinal serum samples (preoperative to 47 month range) from 16 patients having cytoreduction and identical adjuvant therapy were investigated for post surgery SMRP levels and correlation with computerized tomographic (CT) follow-up scans. One-way ANOVA with post-hoc Tamhane test was used for statistical analyses. ROC curves were constructed for the serum and PE groups. Results: Serum SMRP levels were equivalent between ASB (1.166, range 0.004–2.821 nM), and NL (1.222, range 0.216–3.430 nM), but were significantly different from MPM (17.275, range 0.219–278.356 nM, p = 0.003). Stage I MPMs had higher levels of serum SMRP than ASB (p=0.046). Comparing the ASB and NL combined to MPMs, ROC curve analysis revealed an AUC of 0.793 (95%CI: 0.705 to 0.880). No differences were seen in the PE SMRP levels between non-MPM tumors and NL (p=0.521), however, MPM PE SMRP (65.573 nM, range 0.421–255.166) was significantly increased compared to NL PE SMRP (18.997 nM, range 0.291–140.121, p=0.003). The AUC under the PE ROC curve was 0.742 (95%CI: 0.637 to 0.847). SMRP levels decreased in 13/16 patients immediately following surgery, and increased significantly and preceded detection by CT in 10/13 patients who subsequently displayed postoperative progression. Conclusions: These data establish SMRP as a promising marker for MPM, and studies to further refine and validate these data in larger cohorts should be initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fujirebio Diagnostics Fujirebio Diagnostics Fujirebio Diagnostics

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.