Serum Soluble Mesothelin-related Peptide Research Articles

A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Patients With Esophageal Adenocarcinoma.

To investigate the utility of serum soluble mesothelin-related peptide (SMRP) and tumor mesothelin expression in the management of esophageal adenocarcinoma (ADC). Clinical management of esophageal ADC is limited by a lack of accurate evaluation of tumor burden, treatment response, and disease recurrence. Our retrospective data showed that tumor mesothelin and its serum correlate, SMRP, are overexpressed and associated with poor outcomes in patients with esophageal ADC. Serum SMRP and tumoral mesothelin expression from 101 patients with locally advanced esophageal ADC were analyzed before induction chemoradiation (pretreatment) and at the time of resection (posttreatment), as a biomarker for treatment response, disease recurrence, and overall survival (OS). Pre and posttreatment serum SMRP was ≥1nM in 49% and 53%, and pre and post-treatment tumor mesothelin expression was >25% in 35% and 46% of patients, respectively. Pretreatment serum SMRP was not significantly associated with tumor stage ( P = 0.9), treatment response (radiologic response, P = 0.4; pathologic response, P = 0.7), or recurrence ( P =0.229). Pretreatment tumor mesothelin expression was associated with OS (hazard ratio: 2.08; 95% CI: 1.14-3.79; P = 0.017) but had no statistically significant association with recurrence ( P = 0.9). Three-year OS of patients with pretreatment tumor mesothelin expression of ≤25% was 78% (95% CI: 68%-89%), compared with 49% (95% CI: 35%-70%) among those with >25%. Pretreatment tumor mesothelin expression is prognostic of OS for patients with locally advanced esophageal ADC, whereas serum SMRP is not a reliable biomarker for monitoring treatment response or recurrence.

Pilot Study to Evaluate Serum Soluble Mesothelin-Related Peptide (SMRP) as Marker for Clinical Monitoring of Pleural Mesothelioma (PM): Correlation with Modified RECIST Score.

A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker for diagnosis of pleural mesothelioma (PM) and the most used for monitoring treatment. Radiological assessment of PM, based on modified RECIST (mRECIST) criteria, is challenging. This pilot study was designed to evaluate whether SMRP levels correlated over time with mRECIST score. Serial serum samples from PM patients were collected and SMRP levels were measured and compared with the mRECIST score obtained through centralized CT scans by blinded review. The within-patient SMRP-mRECIST relationship over time was estimated through a normal random-effects regression approach applied to the log-transformed mRECIST score. Overall, 58 PM patients were included (46 males and 12 females) with a median age at diagnosis of 67 years (min–max = 48–79), 44 (76%) with epithelioid and 14 (24%) with non-epithelioid histology. The total number of SMRP measurements and CT scans considered for analysis was 183. There was a statistically significant correlation between SMRP and mRECIST score in the 2 cohorts considered both separately and jointly. These results, although exploratory, suggest that SMRP measurement might be considered as an adjunct to monitor PM patients in order to delay CT scans time interval, thus warranting further investigation.

Prediction of pneumoconiosis by serum and urinary biomarkers in workers exposed to asbestos-contaminated minerals.

Workers processing nephrite, antigorite, or talc may be exposed to paragenetic asbestos minerals. An effective screening method for pneumoconiosis in workers exposed to asbestos-contaminated minerals is still lacking. The objective of this study was to assess the diagnostic accuracy of serum and urinary biomarkers for pneumoconiosis in workers exposed to asbestos-contaminated minerals. We conducted a case-control study in a cohort of stone craft workers in Hualien, where asbestos, nephrite, antigorite, and talc are produced. A total of 140 subjects were screened between March 2013 and July 2014. All subjects received a questionnaire survey and a health examination that included a physical examination; chest X-ray; and tests for standard pulmonary function, fractional exhaled nitric oxide, serum soluble mesothelin-related peptide (SMRP), fibulin-3, carcinoembryonic antigen (CEA), and urinary 8-Oxo-2'-deoxyguanosine (8-OHdG)/creatinine. After excluding subjects with uraemia and chronic obstructive pulmonary disease (COPD), we included 48 subjects with pneumoconiosis and 90 control subjects without pneumoconiosis for analysis. In terms of occupational history, 43/48 (90%) case subjects and 68% (61/90) of the control subjects had processed asbestos-contaminated minerals, including nephrite, antigorite, and talc. The case group had decreased pulmonary function in forced vital capacity (FVC), forced expiratory volume in one second, and forced expiratory flow between 25% and 75% of the FVC. The levels of SMRP, fibulin-3, urinary 8-OHdG/creatinine, and CEA were higher in the case group than in the control group. Subjects exposed to nephrite had significantly higher SMRP levels (0.84 ± 0.52 nM) than subjects exposed to other types of minerals (0.60 ± 0.30 nM). A dose-response relationship was observed between the SMRP level and the severity of pneumoconiosis. Machine learning algorithms, including variables of sex, age, SMRP, fibulin-3, CEA, and 8-OHdG/creatinine, can predict pneumoconiosis with high accuracy. The areas under the receiver operating characteristic curves ranged from 0.7 to 1.0. We suggest that SMRP and fibulin-3 could be used as biomarkers of pneumoconiosis in workers exposed to asbestos-contaminated minerals.

Serum soluble mesothelin-related peptide (SMRP): a potential diagnostic and monitoring marker for epithelial ovarian cancer

To explore the potential and diagnostic performance of soluble mesothelin-related peptide (SMRP) as a tumor marker for epithelial ovarian cancer (EOC). Sera were obtained from 78 EOC patients, 84 benign ovarian tumor patients, 58 healthy volunteers, and 22/78 EOC patients 1 week after surgery. SMRP levels and diagnostic performance were assessed by ELISA using the MESOMARK kit. The combination of SMRP and CA125 in the diagnosis of EOC was assessed. SMRP concentrations were higher in EOC patients than in benign tumor patients and healthy volunteers, and SMRP levels were shown to decrease in EOC patients after surgery. Histological EOC subtypes showed significant differences in SMRP levels. Stage III-IV patients had a higher level of SMRP than stage I-II patients (P < 0.001). Elevated SMRP levels were also found in higher grade tumors (P < 0.001). The receiver operating characteristic curve for SMRP was 0.891. The best statistical cut-off for SMRP was 1.3109 nM, with 0.821 sensitivity and 0.979 specificity. When compared with CA125, SMRP performed better in specificity, omission diagnostic rate, positive predictive value, and correction rate, but worse for sensitivity and negative predictive value. The combination of SMRP and CA125 gave a sensitivity of 98.4 % and a specificity of 88.9 %. Serum SMRP is a promising marker for the diagnosis and monitoring of EOC, especially in combination with CA125.

Combined serum mesothelin and carcinoembryonic antigen measurement in the diagnosis of malignant mesothelioma.

Malignant mesothelioma (MM) is a highly aggressive tumor associated with asbestos exposure. The identification of a marker specific for MM may be of considerable value for the early detection of this tumor and may be used in particular to screen groups with a history of asbestos exposure. The aim of this study was to evaluate serum soluble mesothelin-related peptide (SMRP) levels as a diagnostic marker for MM and investigate whether its diagnostic value is enhanced by combination with other biomarkers. Serum SMRP levels were measured using a quantitative enzyme-linked immunosorbent assay in 96 patients with MM, 55 patients with lung cancer and 39 individuals with a history of asbestos exposure. Receiver operating characteristic curves were constructed for performance evaluation. Stepwise logistic regression analysis was used to select marker combinations (MCs). Serum SMRP levels in patients with MM were significantly higher compared to those in the other groups (P<0.001). The sensitivity of SMRP levels in diagnosing MM was 56% and its specificity for MM vs. lung cancer and individuals with asbestos exposure was 87 and 92%, respectively. The area under the curve (AUC) was 0.76 [95% confidence interval (CI): 0.68-0.83] for the differentiation between MM and lung cancer and 0.78 (95% CI: 0.71-0.86) for the differentiation between MM and individuals with asbestos exposure. For the MC of presence of effusion, SMRP and carcinoembryonic antigen (CEA) levels, the AUC for the differentiation between MM and lung cancer (0.92; 95% CI: 0.88-0.97) and the differentiation between MM and individuals with asbestos exposure (0.93; 95% CI: 0.87-1.0) was significantly higher compared to that for SMRP alone (P=0.0001 and 0.0058, respectively). While the specificity of this MC was comparable to SMRP alone, its sensitivity was ∼20% higher compared to that of SMRP alone. Therefore, combining SMRP and CEA improves the diagnostic performance of SMRP alone. A combination of serum biomarkers, including SMRP, may facilitate the non-invasive diagnosis of MM.

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.

192P - Mesothelin and Individual Characteristics in a Cohort of Asbestos Exposed Workers

ABSTRACT Headings The soluble mesothelin-related peptide (SMRP) is a candidate marker in the diagnosis and prognosis of mesothelioma, as well as in the screening of subjects with asbestos exposure. SMRP seems to be influenced by some individual characteristics and clinical factors. Objective The objective of this study was to evaluate the association between serum SMRP and some individual characteristics in 1704 subjects exposed to asbestos for working reasons. Design and methods Participants underwent clinical examination and were interviewed on medical history, occupational exposure, smoking and weight. SMRP was measured by a ELISA assay. Results Median SMRP was 0.45 (IQR 0.30-0.67) nmol/l. SMRP was correlated with age (p Conclusions Data on a large series of subjects with asbestos exposure confirmed that serum SMRP is associated to a number of clinical and demographic variables. Disclosure All authors have declared no conflicts of interest.

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.

An In Vivo Platform for Tumor Biomarker Assessment

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers – serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response – a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research.

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.

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.

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.