MESOMARK™: A potential test for malignant pleural mesothelioma

Research and Development Division, Fujirebio Diagnostics, Inc., Malvern, PA 19355, USA.
Clinical Chemistry (Impact Factor: 7.91). 05/2007; 53(4):666-72. DOI: 10.1373/clinchem.2006.079327
Source: PubMed


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.

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    • "It is predominantly expressed in epithelioid subtype mesotheliomas, with little/no expression in sarcomatoid sub-types. MPF and mesothelin isoforms 1 and 3 can be detected as soluble proteins in plasma or serum, which may be detected using a validated commercial dual antibody ELISA platform [16]. Mesothelin level seems to correlate with MM disease bulk and can potentially predict relapse in patients who had previously resected mesothelioma [22]. "
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    ABSTRACT: Background Malignant mesothelioma (MM) carries a poor prognosis and response rates to palliative chemotherapy remain low. Identifying patients with MM that are unlikely to respond to chemotherapy could prevent futile treatments and improve patient quality of life. Studies have suggested that soluble mesothelin is a potential biomarker for early diagnosis and prognosis of MM. We set out to explore the utility of serum mesothelin in routine clinical practice. Methods We conducted a prospective exploratory study of serum mesothelin levels in 53 consecutive patients with MM at our institution between April 2009 and February 2011. Survival was assessed and analysed by mesothelin level as both continuous and categorical variables using Cox regression models. Differences in response rate between treatment groups were assessed by the Kruskal-Wallis Test. Results All 53 patients, who had been given study information agreed to participate. The patients’ median age was 69 (range 24–90). Median mesothelin level was 2.7 nM and this value was used to dichotomize categories: ≤2.7 nM (low) and >2.7 nM (high). The progression free survival (PFS) for low vs high mesothelin was 8.0 vs 5.1 months (HR 1.8, p-0.058). When mesothelin was accessed as a continuous variable for PFS the HR was 1.03 (95% CI: 1.01 - 1.06; p = 0.013). The overall survival (OS) for low vs high mesothelin was 17.2 vs 11.3 months (HR 1.9, p = 0.088). When mesothelin was assessed as a continuous variable for OS the HR was 1.02 (95% CI: 0.99 - 1.04; p = 0.073). Thirty patients received chemotherapy of which 18 had a pre-chemotherapy serum mesothelin level. In these 18 patients, the pre-chemotherapy mesothelin level did not correlate with response. Conclusions A single random sample provides information about patient prognosis but does not predict treatment response. We suggest further prospective validation of mesothelin testing as a prognostic biomarker.
    Full-text · Article · Sep 2014 · BMC Cancer
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    • "We compared the discriminatory performance of the six glycopeptides panel to that of the FDA approved ELISA assay for mesothelin (Mesomark®) [28] (Additional file 10: Figure S3). In the 75 subjects above (23 MPM, 26 HD and 26 NSCLC, Additional file 3: Table S2) for which ELISA measurements were available, mesothelin ELISA discriminated MPM from HD with AUC of 0.92 (95% CI, [0.83, 0.99]) and accuracy of 82% (95% CI, [71, 94]) at the 2 nM cut-off proposed in the literature [10]. "
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    ABSTRACT: Serum biomarkers can improve diagnosis and treatment of malignant pleural mesothelioma (MPM). However, the evaluation of potential new serum biomarker candidates is hampered by a lack of assay technologies for their clinical evaluation. Here we followed a hypothesis-driven targeted proteomics strategy for the identification and clinical evaluation of MPM candidate biomarkers in serum of patient cohorts. Based on the hypothesis that cell surface exposed glycoproteins are prone to be released from tumor-cells to the circulatory system, we screened the surfaceome of model cell lines for potential MPM candidate biomarkers. Selected Reaction Monitoring (SRM) assay technology allowed for the direct evaluation of the newly identified candidates in serum. Our evaluation of 51 candidate biomarkers in the context of a training and an independent validation set revealed a reproducible glycopeptide signature of MPM in serum which complemented the MPM biomarker mesothelin. Our study shows that SRM assay technology enables the direct clinical evaluation of protein-derived candidate biomarker panels for which clinically reliable ELISA's currently do not exist.
    Full-text · Article · Nov 2013 · Clinical Proteomics
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    • "MSLN is also upregulated in other cancers including ovarian cancer, and pancreatic ductal adenocarcinoma [43] and in its original description, soluble mesothelin was found to be a serum marker for ovarian cancer [17]. This has implications for the MESOMARK [12], [13] kit for detection of soluble mesothelin as other tumor types including some lung cancers with similar presentations may produce soluble mesothelin. "
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    ABSTRACT: Mesothelioma is a highly malignant tumor that is primarily caused by occupational or environmental exposure to asbestos fibers. Despite worldwide restrictions on asbestos usage, further cases are expected as diagnosis is typically 20-40 years after exposure. Once diagnosed there is a very poor prognosis with a median survival rate of 9 months. Considering this the development of early pre clinical diagnostic markers may help improve clinical outcomes. Microarray expression arrays on mesothelium and other tissues dissected from mice were used to identify candidate mesothelial lineage markers. Candidates were further tested by qRTPCR and in-situ hybridization across a mouse tissue panel. Two candidate biomarkers with the potential for secretion, uroplakin 3B (UPK3B), and leucine rich repeat neuronal 4 (LRRN4) and one commercialized mesothelioma marker, mesothelin (MSLN) were then chosen for validation across a panel of normal human primary cells, 16 established mesothelioma cell lines, 10 lung cancer lines, and a further set of 8 unrelated cancer cell lines. Within the primary cell panel, LRRN4 was only detected in primary mesothelial cells, but MSLN and UPK3B were also detected in other cell types. MSLN was detected in bronchial epithelial cells and alveolar epithelial cells and UPK3B was detected in retinal pigment epithelial cells and urothelial cells. Testing the cell line panel, MSLN was detected in 15 of the 16 mesothelioma cells lines, whereas LRRN4 was only detected in 8 and UPK3B in 6. Interestingly MSLN levels appear to be upregulated in the mesothelioma lines compared to the primary mesothelial cells, while LRRN4 and UPK3B, are either lost or down-regulated. Despite the higher fraction of mesothelioma lines positive for MSLN, it was also detected at high levels in 2 lung cancer lines and 3 other unrelated cancer lines derived from papillotubular adenocarcinoma, signet ring carcinoma and transitional cell carcinoma.
    Full-text · Article · Oct 2011 · PLoS ONE
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