Soluble Mesothelin-related Peptide Levels Research Articles

Variation rs2235503 C > A Within the Promoter of MSLN Affects Transcriptional Rate of Mesothelin and Plasmatic Levels of the Soluble Mesothelin-Related Peptide.

Soluble mesothelin-related peptide (SMRP) is a promising biomarker for malignant pleural mesothelioma (MPM), but several confounding factors can reduce SMRP-based test’s accuracy. The identification of these confounders could improve the diagnostic performance of SMRP. In this study, we evaluated the sequence of 1,000 base pairs encompassing the minimal promoter region of the MSLN gene to identify expression quantitative trait loci (eQTL) that can affect SMRP. We assessed the association between four MSLN promoter variants and SMRP levels in a cohort of 72 MPM and 677 non-MPM subjects, and we carried out in vitro assays to investigate their functional role. Our results show that rs2235503 is an eQTL for MSLN associated with increased levels of SMRP in non-MPM subjects. Furthermore, we show that this polymorphic site affects the accuracy of SMRP, highlighting the importance of evaluating the individual’s genetic background and giving novel insights to refine SMRP specificity as a diagnostic biomarker.

Evaluation of New Biomarkers in the Prediction of Malignant Mesothelioma in Subjects with Environmental Asbestos Exposure.

The purpose of this study was to investigate the potential value of certain biomarkers in predicting the presence of malignant pleural mesothelioma (MPM) in individuals environmentally exposed to asbestos. This prospective study investigated three groups; a control group composed of 41 healthy subjects, an asbestos exposure group consisting of 48 individuals, and a MPM group consisting of 42 patients. Serum levels of soluble mesothelin-related peptide (SMRP), thioredoxin-1 (TRX), epidermal growth factor receptor (EGFR), fibulin-3, syndecan-1 (SDC-1), and mesothelin were determined. Benign pleural plaques were present in 27 (58.3%) of the individuals in the asbestos exposure group. The asbestos exposure group had significantly higher mean TRX, SMRP, and mesothelin levels compared to the control group (p=0.023, p=0.011, and p<0.001, respectively). Compared to the asbestos exposure group, the MPM group had significantly higher mean EGFR, TRX, SMRP, and fibulin-3 levels (p=0.041, p=0.023, p=0.002, and p=0.001, respectively), and significantly lower mean SDC-1 levels (p=0.002). Unlike the other biomarkers, SMRP and TRX levels increased in a graded fashion among the control, asbestos exposure, and MPM groups, respectively. Area under the curve values for SMRP and TRX were 0.86 and 0.72, respectively (95% CI0.79-0.92 and p<0.001 for SMRP, and 95% CI0.62-0.81 and p<0.001 for TRX). The cut-off value for SMRP was 0.62nmol/l (sensitivity: 97.6%, specificity: 68.9%, positive predictive value (PPV): 56.2%, and negative predictive value (NPV): 98.3%) and for TRX was 156.67ng/ml (sensitivity: 92.9%, specificity: 77.6%, PPV: 41.4%, and NPV: 92.1%). The combination of the biomarkers reached a sensitivity of 100%, but had lower specificity (as high as 27.7%). Serum biomarkers may be helpful for early diagnosis of MPM in asbestos-exposed cases. SMRP and TRX increased in a graded fashion from the controls to asbestos exposure and MPM groups. These two seem to be the most valuable biomarkers for the diagnosis of MPM, both individually and in combination.

Combined serum and immunohistochemical differentiation between reactive, and malignant mesothelial proliferations

BackgroundMalignant mesothelioma (MM) carries a poor prognosis and response rates to palliative chemotherapy remain low. The diagnosis of malignant mesothelioma is frequently difficult, the most common differential diagnosis being reactive pleural conditions and metastatic adenocarcinoma. Several studies have used immunohistochemical markers to distinguish between reactive and neoplastic mesothelial cells. Soluble mesothelin levels in serum have recently been shown to be highly specific and moderately sensitive for mesothelioma. A combined detection of serum levels of mesothelin and immunohistochemical expression of desmin and EMA are used in order to differentiate between reactive mesothelial proliferations, and malignant mesothelioma of epithelioid type. Patients and methodsThis prospective study includes 17 cases of reactive mesothelial proliferations, 6 cases of atypical mesothelial proliferations and 13 cases of MM. Cases were collected from the Chest Department, Faculty of Medicine, Benha University and International Medical Center (IMC), in the period 2012–2014. Desmin and epithelial membrane antigen (EMA) immunohistochemical staining were performed in all cases and the pattern of expression was analyzed. Soluble mesothelin related peptide (SMRP) was estimated for all cases. ResultsDesmin expression was positive in 88.2%, 0%, and 7.7% of reactive mesothelial proliferations, atypical mesothelial proliferations and MM respectively. EMA was positive in 5.9% of reactive mesothelial proliferation, 100% of atypical mesothelial proliferations and 92.3% of MM cases (P<0.01). The calculated mean SMRP was 6.6nM. SMRP levels were higher than the calculated mean value in 17.6% of studied reactive mesothelial lesions, 66.7% and 76.9% of atypical mesothelial proliferations and MM respectively, which was statistically highly significant correlation (P<0.01). ConclusionCombined estimation of SMRP level and immunohistochemical detection of both EMA and desmin could be a useful tool for differentiation between reactive mesothelial proliferation and malignant mesothelioma.

A Common Polymorphism Within MSLN Affects miR-611 Binding Site and Soluble Mesothelin Levels in Healthy People

Soluble mesothelin related peptide (SMRP) was proposed as a promising diagnostic marker for malignant pleural mesothelioma (MPM). In a previous study, we found that rs1057147 within the 3' untranslated region of MSLN gene was associated with SMRP levels. Thus, we aimed to (1) confirm the previous association on a large series of volunteers and (2) test the hypothesis that the SNP could affect microRNA binding sites. The association analysis was verified in 759 subjects. Then, in silico predictions highlighted miR-611 and miR-887 as candidate miRNAs binding to the polymorphic site. Thus, chimeric constructs bearing the alternative alleles (G > A) were assayed alone or in cotransfection with the miRNA mimics, with dual luciferase reporter assay in non-MPM Met-5A cells. The miRNAs were also assayed by western blot analysis for their ability to down-regulate endogenous mesothelin in the MPM Mero-14 cell line. We confirmed that, among non-MPM volunteers, GG homozygotes have the lowest SMRP levels. When the genotype is taken into account, the specificity of SMRP as biomarker improves from 79.7% to 85.3%. Dual-luciferase assays showed a significantly lower reporter activity when the vector harbored the G allele as compared to A allele. miR-887 mimic caused a reduced reporter activity of vectors harboring A or G alleles, while miR-611 was effective only on the vector harboring the G allele. Transfection of these miRNAs into Mero-14 cells significantly reduced endogenous MSLN protein. SMRP performance as diagnostic biomarker improved by considering the genotype rs1057147. This polymorphism most likely affects a binding site for miR-611.

Individual predictors of increased serum mesothelin in asbestos-exposed workers

The soluble mesothelin-related peptide (SMRP), a candidate marker for screening of subjects with asbestos exposure, is influenced by some individual and clinical factors. The aim of this study was to quantify the role of age, smoking, weight, presence of diseases and exposure to asbestos on serum SMRP levels in a large series of subjects exposed to asbestos, possible candidates for mesothelioma screening. One thousand seven hundred and four participants underwent clinical examination and were interviewed on medical anamnesis, occupation, smoking and weight. SMRP was measured by an ELISA assay. Overall, median SMRP was 0.4 (IQR 25-75: 0.3-0.7) nmol/l. It was higher in current smokers and in subjects with a cumulative asbestos exposure >50 ff/cc/years than in all the other subjects (p < 0.001 and p = 0.002, respectively). SMRP was positively correlated with age (ρ = 0.11, p < 0.001) and, inversely, with BMI (ρ = -0.15, p < 0.001). SMRP was lower in healthy subjects (n = 1,217: median 0.4 nmol/l) than in subjects with malignant tumors (n = 118: 0.5 nmol/l; p = 0.01), asbestos-related pleural lesions (plaques or thickenings, n = 152: 0.6 nmol/l; p < 0.001) and other benign diseases (n = 182: 0.5 nmol/l; p = 0.04). Multivariate analysis revealed significant predictors of increased SMRP: age >57 years, current smoking, a positive anamnesis for cancer and for asbestos-related pleural lesions, and BMI < 25. Some clinical and demographic variables are associated with serum SMRP levels. The degree of these associations is low, nevertheless they should be accounted for in the interpretation of SMPR as a candidate marker predictive of mesothelioma. The potential predictive value of serum SMRP in screening/surveillance programs must be validated in prospective studies.

Evaluation of Soluble Mesothelin-related Peptide as a Diagnostic Marker of Malignant Pleural Mesothelioma Effusions: Its Contribution to Cytology

Soluble mesothelin-related peptide (SMRP) is regarded as an FDA approved biomarker for the diagnosis and monitoring of pleural malignant mesothelioma (MPM). We detected the SMRP levels in pleural effusions (PE) by means of an ELISA and analyzed their diagnostic relevance to differentiate MPM from benign pathology and from non-MPM pleural metastasis. Comparison with cytology in MPM-PE was also performed. We found that SMRP detection in MPM-PE can help the diagnosis of MPM and provide additional diagnostic value to cytology. We concluded that SMRP test may be incorporated into clinical practice of PE from patients suspicious for MPM.

Mesothelioma

Mesothelioma

Evaluation of soluble mesothelin-related peptide as a marker additional to cytology for diagnosing malignant pleural mesothelioma effusions.

e17533 Background: Detection of soluble mesothelin-related peptide (SMRP) levels in serum has been proposed to help the diagnosis of malignant pleural mesothelioma (MPM). In this study we evaluated the SMRP levels in pleural effusions of MPM (MPM-PE), the clinical importance and usefulness of SMRP detection in MPM-PE and whether it can have an additional value to cytological analysis (Cyt). Methods: We studied 52 MPM-PE, 129 benign PE (B-PE) and 94 non-MPM pleural metastasis PE (Mts-PE). In all PE samples, both cytology and SMRP detection were performed. SMRP levels were estimated by means of the MesoMark ELISA kit (Fujirebio Diagnostic, Malvern, PA). Diagnostic performance parameters were estimated through the ROC analysis, Youden's index was applied to obtain the best cut-off level and the degree of correlation was estimated by Diagnostic Odds Ratio (DOR) and by P-value (P) with Chi-square test. Results: The median SMRP levels were significantly higher in MPM-PE (28.2 nM) than in B-PE (3.2 nM) or Mts-PE (3.8 nM). MPM-PE vs B-PE yielded an AUC of 84.5 (P&lt;0.001) whereas MPM-PE vs Mts-PE yelded an AUC of 79.6 (P&lt;0.001). The cut off level in MPM-PE was estimated in 9.30 nM at which value we established Se=75%, Sp=93% for MPM-PE vs BPE and SP=81% for MPM-PE vs Mts-PE. We found SMRP positive cases (≥ cut off) in 38/52 (73%) MPM-PE, in 9/129 (7%) B-PE (DOR=40, P&lt;0.001) and in 18/94 (19%) Mts-PE (DOR=13, P&lt; 0.001).Cyt was negative in 29/52 (56%) of MPM-PE, among which SMRP was positive in 20/29 (69%) cases. Cyt was positive in 15/52 (29%) of MPM-PE, among which SMRP was negative in 4/15 (27%) cases. Finally, in 8/52 (15%) MPM-PE Cyt diagnosis was suspicious and SMRP was found positive in 7/8 (88%) cases. Conclusions: Our results demonstrate that SMRP levels in PE are significantly higher in MPM-PE than in PE from other pathologies. However the test cannot be alternative to cyt but it may provide additional diagnostic value to Cyt. SMRP detection in MPM-PE can be applied in the workup of patients with a PE of unknown origin.

Tissue and Serum Mesothelin Are Potential Markers of Neoplastic Progression in Barrett's Associated Esophageal Adenocarcinoma

Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's esophagus (BE) and in esophageal adenocarcinoma (EAC). Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum. Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs. 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean = 0.89 nmol/L; range: 0.03-3.77 nmol/L), but not in patients with acid reflux and/or BE. Mesothelin is commonly expressed in BE-associated EAC. On the basis of this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin which are potential markers of neoplastic progression in BE and in EAC (NCT01393483). Current surveillance methods in Barrett's esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation.

Biomarkers in Malignant Mesothelioma: Diagnostic and Prognostic Role of Soluble Mesothelin-Related Peptide

Soluble mesothelin-related peptide (SMRP) is a biomarker that has been proposed for differential diagnosis from pleural metastatic cancer, as well as prognosis and treatment monitoring of malignant pleural mesothelioma (MM). The aim of this study was to evaluate the role of SMRP in clinic management of MM. We assayed the SMRP concentrations in 354 subjects: 109 healthy volunteers with no history of exposure to asbestos, 26 patients with previous occupational asbestos exposure but who were free from pleural or parenchymal disease, 48 patients with asbestosis, 110 patients with pleural plaques, 25 patients with lung cancer, and 36 patients with MM. We also tested SMRP titers in 2 patients with MM at 5 different times of the disease, to evaluate the trend of the biomarker in the course of therapy. Our data confirm previous experiences with the use of SMRP as a diagnostic marker of MM. Low SMRP levels at diagnosis seem to have a positive prognostic significance.

Two Novel Polymorphisms in 5' Flanking Region of the Mesothelin Gene are Associated with Soluble Mesothelin-Related Peptide (SMRP) Levels

Increased concentrations of soluble mesothelin-related peptides (SMRP) have been found in sera of patients with malignant pleural mesothelioma (MPM) even if a relatively high rate of false positives has hampered their clinical use as a tumor marker. Individual SMRP levels could be affected by polymorphic elements. The aim of this study was to investigate the association between single nucleotide polymorphisms within the promoter-5'UTR regions and SMRP levels in healthy asbestos-exposed individuals and patients suffering from MPM.? The promoter-5'UTR regions of the mesothelin gene were genotyped in 59 healthy asbestos-exposed subjects and 27 MPM patients. SMRP levels were measured using a commercially available ELISA kit.? Two novel polymorphisms, an A>C variant (called New1) and a C>T variant (called New2), were identified. In healthy subjects, high SMRP levels were associated with the C-variant of New1, with an average 1.62-fold increase compared with AA homozygotes (p<0.0001). Most of the C-allele carriers had SMRP levels above the threshold of 1.00 nM. We set two different SMRP cutoffs on the basis of the combined New1+New2 genotypes.? New1-New2 genotypes could be employed as markers for setting individualized and appropriate thresholds of "normality" when SMRP is used in surveillance programs of asbestos-exposed people.

Soluble Mesothelin-Related Peptide and Osteopontin As Markers of Response in Malignant Mesothelioma

In malignant mesothelioma (MM), radiologic assessment of disease status is difficult. Both soluble mesothelin-related peptide (SMRP) and osteopontin (OP) have utility in distinguishing MM from benign pleural disease. We evaluated whether SMRP and OP also correlated with the disease course of MM. Serial plasma samples from patients with MM were prospectively collected, and SMRP and OP levels were measured. Radiologic tests across time periods showing disease progression, stability, or shrinkage were compared with corresponding changes in SMRP/OP levels. From 41 patients, 165 samples were collected (range, 2 to 10; median 4). At study entry, 37 of 41 patients had measurable disease, of whom 92% (34 of 37) had elevated baseline SMRP levels; four of 41 patients had no evidence of recurrence and each had normal baseline SMRP levels. In 21 patients receiving systemic therapy, percentage change in SMRP more than 10% correlated with the radiologic assessment by a trained thoracic radiologist (P < .001), by formal Response Evaluation Criteria in Solid Tumors (RECIST; P = .008), or by modified RECIST (P < .001). All seven patients who underwent surgical resection with negative margins had elevated preoperative SMRP levels that fell to normal postoperatively. Rising SMRP was observed in all patients with radiologic disease progression. No associations were found with OP. Percentage changes in SMRP levels, but not changes in OP levels, are a potentially useful marker of disease course. These findings should be validated prospectively for a role as an objective adjunctive measure of disease course in both clinical trials and clinical practice.

Abstract 3229: Biomarker validation for a rare malignancy in a mouse model

Abstract Purpose: Malignant pleural mesothelioma (MPM) is a rare malignancy often diagnosed at an advanced stage. Clinical validation of a biomarker that would allow for earlier diagnosis as well as detection of recurrence following therapy is limited by the rarity of the tumor. Soluble mesothelin-related peptide (SMRP), which can be detected in patients’ serum, is a cleavage product of mesothelin, a tumor-associated cell surface protein over-expressed in &amp;gt;80% of MPMs. The purpose of this study is to validate the pharmacodynamics of SMRP as a tumor biomarker of prognosis and therapy response using a clinically and pathologically relevant orthotopic xenograft model of MPM. Experimental Design: Orthotopic MPM xenograft mice (athymic nude and SCID-beige) were established by direct pleural injection of human mesothelioma cells (MSTO-211H) retrovirally transduced to stably express mesothelin and the GFP-Firefly Luciferase fusion gene. Quantitative bioluminescence imaging (BLI) and MRI were used to serially monitor tumor burden and progression and were correlated with serum SMRP levels (Mesomark® ELISA assay). Kaplan-Meier survival analyses were performed following xenografting of mesothelin and non-mesothelin expressing tumors. The utility of SMRP as a biomarker of therapeutic response was validated by treating MPM mice with either: (a) Cisplatin (4mg/kg IP weekly), (b) thoracic radiation (20Gy total in 5 fractions), (c) combination chemoradiation, or (d) no treatment and correlating serial SMRP levels to survival and BLI signal. Results: MPM cells secreting SMRP demonstrated increased invasion and migration in vitro as assessed by the modified Boyden Chamber assay compared to cells without SMRP secretion, 124 vs 48 cells per high-powered field (p&amp;lt;0.0001) and 49 vs 32 cells (p=0.017), respectively. In MPM xenograft mice, increasing SMRP levels correlated with tumor progression by quantitative BLI (spearman r=0.89, p=0.04) and decreased survival (p=0.001). SMRP demonstrated improved sensitivity for detecting early MPM tumors compared to MRI. SMRP levels significantly decreased following treatment versus control mice (p=0.03) and were predictive of survival (hazard ratio = 4.5, 95%CI 1.53-13.1). In addition, SMRP detected tumor recurrence following treatment earlier than MRI. Conclusions: We have shown that a serum biomarker of tumor progression and therapy response can be successfully studied in a clinically relevant animal model. To our knowledge, this is the first report utilizing BLI as a reproducible tool, in conjunction with an orthotopic animal model, to quantitatively assess pleural tumor burden and biomarker pharmacodynamics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3229.

Serum and intracavitary soluble mesothelin-related peptide (SMRP) levels in pleural and peritoneal malignant mesothelioma

22103 Background: Mesothelin is a 40kDa cell surface protein known to be overexpressed in mesothelioma. Soluble mesothelin related protein (SMRP) is theorized to be a useful blood test marker of mesothelioma tumor load. We examined whether serum SMRP is related to site (pleural or peritoneal), histological subtype (epithelioid, sarcomatous, biphasic), or CRP levels, and whether SMRP is detectable in cavitary effusions. Methods: Serum SMRP and CRP were measured on 1 or more occasions from May to December 2007 in 69 patients with malignant mesothelioma of the pleura (n = 20), peritoneum (n = 43), or both (n = 6); of epithelioid (n = 58), sarcomatoid (n = 5), or biphasic (n = 6) histology. Pleural effusion or peritoneal fluid SMRP was measured in 12 of these patients. These were grouped by site and histology and compared by 2-tailed Welch t-test, with levels below limit of detection (0.3 nM) recorded as 0. Results: Serum SMRP were higher in pleural (6.2 ± 1.1 nM) than peritoneal (4.3 ± 1.1 nM) patients (p = 0.015). 42% of pleural patients had an average serum SMRP within normal limits (<1.5 nM), vs 57% of peritoneal patients. Differences between epithelioid (4.5 ± 0.8 nM) and the small subset of sarcomatoid/biphasic (5.7 ± 3.8 nM) patients were not statistically significant (p = 0.574). Cavitary SMRP was higher than serum in all 3 pleural patients and in 5 of 9 peritoneal patients. Serial samples from individual treated patients, often but not always paralleled increased or decreased tumor burden after surgery or chemotherapy. No correlation was found between SMRP and CRP in any group. Conclusions: Changes in SMRP levels in individual patients, especially with pleural disease, can reflect tumor burden after operation or chemotherapy, and might be explored as a means of detecting residual or progressive disease in pleural effusions. The relationship between cavitary and serum SMRP is less predictable in abdominal ascites than in pleural effusions. SMRP elevations are distinct from elevated CRP, and may reflect different processes. No significant financial relationships to disclose.

Soluble Mesothelin-Related Peptide Level Elevation in Mesothelioma Serum and Pleural Effusions

Soluble mesothelin-related peptide (SMRP) is a potential marker for malignant pleural mesothelioma (MPM), which may be useful for screening high-risk asbestos-exposed individuals. We evaluated SMRP in serum from MPM patients (n = 90), lung cancer patients (n = 170), age and tobacco-matched asbestos-exposed individuals (n = 66), and in MPM pleural effusions (n = 45), benign effusions (n = 30), and non-MPM effusions (n = 20) using the MesoMark enzyme-linked immunosorbent assay kit (Fujirebio Diagnostics, Malvern, PA). Receiver operating characteristic (ROC) curves were used to define true and false positive rates at various cutoffs. Mean serum SMRP levels were higher in MPM compared with lung cancer (5.67 +/- 0.82 nM [mean +/- standard error of the mean vs 1.99 +/- 0.43 nM, p < 0.001), and stage I MPM SMRP levels (n = 12; 2.09 +/- 0.41 nM) were significantly higher than those in asbestos-exposed individuals (0.99 +/- 0.09 nM, p = 0.02, respectively). Stage 2 to 4 SMRP serum levels were significantly higher than those for stage 1 MPM. The area under the ROC curve for serum SMRP was 0.81 for differentiating MPM and asbestos-exposed individuals; cutoff = 1.9 nM (sensitivity = 60%, specificity = 89%). The MPM pleural effusion SMRP was significantly higher than benign or other non-MPM pleural effusions (65.57 +/- 11.33 nM vs 27.46 +/- 11.25 nM [p = 0.003] and 18.99 +/- 7.48 nM [p = 0.044], respectively). These data support SMRP as a promising marker for MPM in both serum and pleural effusion fluid, and justify prospective screening studies of SMRP in combination with other markers for screening of asbestos-exposed cohorts.

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.