Soluble Mesothelin-related Peptide Research Articles

Pleural effusion biomarkers and computed tomography findings in diagnosing malignant pleural mesothelioma: A retrospective study in a single center.

In this study, we aimed to examine the clinical value of the pleural effusion (PE) biomarkers, soluble mesothelin-related peptide (SMRP), cytokeratin 19 fragment (CYFRA 21–1) and carcinoembryonic antigen (CEA), and the utility of combining chest computed tomography (CT) findings with these biomarkers, in diagnosing malignant pleural mesothelioma (MPM). We conducted a retrospective cohort study in a single center. Consecutive patients with undiagnosed pleural effusions who underwent PE analysis between September 2014 and August 2016 were reviewed. This study included 240 patients (32 with MPM and 208 non-MPM). SMRP and the CYFRA 21-1/CEA ratio had a sensitivity and specificity for diagnosing MPM of 56.3% and 86.5%, and 87.5% and 74.0%, respectively. Using receiver operating characteristics (ROC) curve analysis of the ability of these markers to distinguish MPM from all other PE causes, the area under the ROC curve (AUC) for SMRP and the CYFRA 21-1/CEA ratio was 0.804 and 0.874, respectively. The sensitivity and specificity of SMRP combined with the CYFRA 21-1/CEA ratio were 93.8% and 64.9%, respectively. The sensitivity of the combination of SMRP, the CYFRA 21-1/CEA ratio, and the presence of Leung’s criteria (a chest CT finding that is suggestive of malignant pleural disease) was 93.8%. In conclusion, the combined PE biomarkers had a high sensitivity for diagnosing MPM, although the addition of chest CT findings did not improve the sensitivity of SMRP combined with the CYFRA 21-1/CEA ratio. Combination of these biomarkers helped to rule out MPM effectively among patients at high risk of suffering MPM and would be valuable especially for old frail patients who have difficulty in undergoing invasive procedures such as thoracoscopy.

Soluble Mesothelin-Related Peptides to Monitor Recurrence After Resection of Pleural Mesothelioma

Most patients undergoing surgical resection of malignant pleural mesothelioma (MPM) will experience recurrence, and radiographic diagnosis of recurrence can be difficult in the postoperative chest. Our objective was to determine the utility of the serum biomarker soluble mesothelin-related peptide (SMRP; or mesothelin) in monitoring of the postoperative MPM patient. We retrospectively evaluated a prospectively maintained single institution clinical database. SMRP levels were evaluated preoperatively and postoperatively in patients undergoing surgical resection of MPM. One hundred two patients underwent pleurectomy/decortication (58%), extrapleural pneumonectomy (20%), chest wall resection (2%), or exploratory thoracotomy (20%) for MPM of 81% epithelial histology. Sixty percent received heated intraoperative chemotherapy and 57% received perioperative systemic chemotherapy. Patients with epithelial histology had substantially greater mean (± SD) preoperative SMRP levels (4.5 ± 7.3 nmol/L) than did patients with biphasic (1.9 ± 2.5 nmol/L) or sarcomatoid (1.2 ± 1.0 nmol/L) histology. Radiologic 3-dimensional tumor volume and tumor mesothelin gene (MSLN) expression correlated with preoperative SMRP. In patients with epithelial histology undergoing complete resection (n= 66), preoperative SMRP (3.4 ± 4.9 nmol/L) dramatically decreased immediately after operation (0.8 ± 0.5 nmol/L), and preoperative SMRP was independently associated with poor disease-free survival. Percentage of change in serial postoperative SMRP values at the best statistical cutoff at 48% revealed high predictive capability of disease recurrence with 90% sensitivity and 93% specificity (area under the curve= 0.96, p < 0.001). SMRP is a promising serum biomarker for the detection of recurrence after resection of epithelial MPM that may have value in clinical practice and should be studied in a prospective cohort.

Diagnostic and prognostic biomarkers for malignant mesothelioma: an update.

Malignant mesothelioma (MM) is an aggressive and lethal cancer, mostly related to inhalation of asbestos and erionite fibers. MM is associated with poor prognosis, because of its resistance to current therapies, even if higher survival occurs in patients diagnosed and treated when at stage I of the disease. However, these do not exceed 5% of the total number of cases, due to the inadequacy of the existing biomarkers for early and accurate diagnosis. Therefore, new effective biomarkers are needed for MM detection at earlier stages and to develop tailored therapies. Here we review the most promising biomarkers in MM to date: mesothelin, soluble mesothelin-related peptides (SMRPs), megakaryocyte potentiating factor (MPF), Osteopontin (OPN), Fibulin-3, high mobility group B1 (HMGB1), microRNAs (miRNAs), multiplex protein signatures. The validation of these biomarkers will allow their use, alone or in combination, for monitoring individuals from cohorts at risk of MM and attaining early detection of MM that is instrumental in improving patient survival.

Mesothelin promoter variants are associated with increased soluble mesothelin-related peptide levels in asbestos-exposed individuals

BackgroundSoluble mesothelin-related peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hinder its usefulness in surveillance programmes. We previously showed that a single nucleotide...

Serum Mesothelin, Osteopontin and Vimentin: Useful Markers for Clinical Monitoring of Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a relatively rare tumor, with the epithelioid type occurring more frequently. Several biomarkers have been suggested for screening and early diagnosis of MPM. Currently, high levels of soluble mesothelin-related peptides (SMRP), plasma osteopontin (pOPN) and vimentin have been reported in patients with MPM as promising markers for diagnosis, but their clinical use in monitoring is still discussed. The aim of our study was to evaluate the usefulness of these substances as markers of the clinical response to treatment in patients suffering from epithelioid mesothelioma. 219 serum samples from 56 patients were collected during follow-up and the clinical response to therapy was recorded. Percentage differences between 2 consecutive measurements of SMRP, osteopontin and vimentin (Δ markers) by means of commercially available kits were correlated with changes in the clinical course. Δ SMRP, Δ pOPN and Δ vimentin showed statistically significant differences between the disease categories stable disease, partial response and disease progression (p = 0.0001, p = 0.035 and p = 0.0025 for SMRP, pOPN and vimentin, respectively). Moreover, contingency table analysis showed statistically significant differences between clinical response and Δ of each marker clustered into 3 groups (<-20%, between -20% and +20%, >+20%). The time course of Δ SMRP and Δ vimentin was strongly associated with disease status, and so was the time course of pOPN, albeit to a lesser extent. These markers appear to be particularly effective in cases of partial response and disease progression, while their possible use in stable disease should be better investigated.

P3.03-047 Diagnostic Value of Secretary Leukocyte Peptide Inhibitor (SLPI) in Pleural Fluid in Malignant Pleural Mesothelioma: Topic: Mesothelioma Clinical

There is no established diagnostic marker for malignant pleural mesothelioma (MPM). The aim of this study was to evaluate the usefulness of secretary leukocyte peptide inhibitor (SLPI) in pleural fluid for the diagnosis of MPM. The study included 52 MPM patients, 69 patients of lung cancer with pleural effusion (LC), and 50 patients with benign asbestos pleural effusion (BAPE) that were included as a control group. Pleural fluid was collected from these patients and SLPI was determined using Quantikine ELISA Human SLPI (R＆D Systems). Pleural fluid hyaluronic acid (HA) and soluble mesothelin related peptide (SMRP) were also determined as comparison. Median values of pleural fluid SLPI in MPM, LC, and BAPE were 108.1 ng/ml, 87.4 ng/ml, and 48.6 ng/ml, respectively. SLPI value in patients with MPM were significantly higher than those in other groups (P=0.000). SLPI value was higher in epithelioid subtype of MPM than in other subtypes. Median values of pleural fluid HA in MPM, LC, and BAPE were 86950 ng/ml, 20700 ng/ml, and 31500 ng/ml, respectively. Median values of pleural fluid SMRP in MPM, LC, and BAPE were 15.38 ng/ml, 5.70 ng/ml, and 7.31 ng/ml, respectively. Pleural fluid HA and SMRP in MPM were also significantly higher than in other groups (P=0.000). Receiver operating characteristics analysis was performed to examine the usefulness of these 3 markers for the differentiation of MPM and BAPE, and demonstrated that area under the curve values were 0.823 for SLPI, 0.760 for HA, and 0.743 for SMRP. Pleural fluid SLPI is a useful biomarker for differential diagnosis of MPM.

Glycodelin is a potential novel follow-up biomarker for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a short survival time arising from the mesothelial cells of the pleura. Soluble mesothelin-related peptide (SMRP), osteopontin or EFEMP1 (Fibulin-3) are well described biomarkers for malignant mesothelioma with moderate sensitivity and specificity. In this study, we characterized the expression of glycodelin, a marker for risk pregnancy, in MPM by RNA and protein analyses and investigated its potential as a MPM biomarker. We were able to detect glycodelin in the serum of MPM patients. Compared to benign lung diseases, the serum levels were significant increased. Patients with high glycodelin serum levels revealed a worse overall survival. The glycodelin serum levels correlated with the tumor response to treatment. A comparison of SMRP and glycodelin serum measurement in a large patient cohort demonstrated that the detection of both soluble factors can increase the reliable diagnostic of MPM. Glycodelin was highly expressed in MPM tumors. Analyses of a tissue micro array indicated that the immunomodulatory form glycodelin A was expressed in MPM and correlated with the survival of the patients. Altogether, glycodelin seems to be a new potential biomarker for the aggressive malignant pleural mesothelioma.

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.

Validity of mesothelin in occupational medicine practice.

Malignant mesothelioma (MM) is the most serious asbestos-related disease. Its increasing incidence is alarming, suggesting the need for as early diagnosis as possible. This 4.5-year prospective longitudinal study aimed at assessing the benefit of measuring serum mesothelin as a marker for diagnosing malignant mesothelioma in individuals with previous occupational exposure to asbestos, as a part of their clinical follow-up care. The study comprised 309 participants (235 males, 74 females) with a mean age of 58.9 years (standard deviation (SD) = 9.8) and a mean duration of exposure to asbestos dust of 13.4 years (SD = 9.3). From 2009 to June 2013, all subjects were followed at a department of occupational medicine in Olomouc. Apart from the standard parts of medical examination (history, physical examination, simple chest radiographs and spirometry), the patients' serum mesothelin levels were determined by the Mesomark immunoenzymatic diagnostic assay. Statistical analysis of the validity of serum mesothelin level measurement was carried out with respect to the diagnosis of MM. Among the participants, 16 (5.2%) individuals (14 males and 2 females) were diagnosed with malignant mesothelioma. Based on the detected mesothelin levels, their validity for prediction of malignant mesothelioma was calculated as follows: sensitivity - 0.75, specificity - 0.962, positive predictive value - 0.706, negative predictive value - 0.969, positive and negative likelihood ratios - 19.95 and 0.26, respectively, and diagnostic odds ratio - 76.8, at a 95% confidence interval. The high specificity was identified indicating the low false positivity as well. In the case of detecting elevated soluble mesothelin-related peptides (SMRP) levels in formerly asbestos-exposed individuals, the possibility of the presence of MM should be included into the clinical consideration. The high negative predictive value denotes a lower probability of the presence of MM in patients with normal SMRP levels but due to the limiting lower sensitivity this possibility cannot be entirely excluded.

Fibulin-3 as a biomarker of response to treatment in malignant mesothelioma.

BackgroundFibulin-3 is a new potential biomarker for malignant mesothelioma (MM). This study evaluated the potential applicability of fibulin-3 plasma levels as a biomarker of response to treatment and its prognostic value for progressive disease within 18 months. The potential applicability of fibulin-3 in comparison with or in addition to soluble mesothelin-related peptides (SMRP) was also assessed.Patients and methods.The study included 78 MM patients treated at the Institute of Oncology Ljubljana between 2007 and 2011. Fibulin-3 levels in plasma samples obtained before treatment and in various responses to treatment were measured with the enzyme-linked immunosorbent assay.ResultsIn patients evaluated before the treatment, fibulin-3 levels were not influenced by histopathological sub-types, tumour stages or the presence of metastatic disease. Significantly higher fibulin-3 levels were found in progressive disease as compared to the levels before treatment (Mann-Whitney [U] test = 472.50, p = 0.003), in complete response to treatment (U = 42.00, p = 0.010), and in stable disease (U = 542.00, p = 0.001). Patients with fibulin-3 levels exceeding 34.25 ng/ml before treatment had more than four times higher probability for developing progressive disease within 18 months (odds ratio [OR] = 4.35, 95% confidence interval [CI] 1.56–12.13). Additionally, patients with fibulin-3 levels above 34.25 ng/ml after treatment with complete response or stable disease had increased odds for progressive disease within 18 months (OR = 6.94, 95% CI 0.99–48.55 and OR = 4.39, 95% CI 1.63–11.81, respectively).ConclusionsOur findings suggest that in addition to SMRP fibulin-3 could also be helpful in detecting the progression of MM.

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.

Improved diagnosis of mesothelioma by a combination of soluble mesothelin-related peptide and CYFRA 21-1

Abstract Background: Soluble mesothelin-related peptide (sMRP) has shown great potential for malignant mesothelioma detection. However, data on comparison with other cancer and benign diseases as well as with other established lung cancer biomarkers are rare. Methods: In this study, SMRP was investigated in sera from 1506 individuals including 147 healthy donors, 285 patients with diverse benign diseases and 1074 patients with mesothelioma (n=39) and various malignant tumors (lung, gastrointestinal, gynecological, urological). For differential diagnosis of lung diseases, carcinoembryonic antigen, cytokeratin 19-fragments (CYFRA 21-1), neuron-specific enolase and squamous cell cancer antigen were determined additionally. Results: Ninety-fifth percentiles of sMRP serum levels in healthy persons were 1.2 nM, in patients with benign diseases between 2.0 and 3.8 nM and in cancer patients between 1.5 and 44.3 nM. Highest values were observed in mesothelioma (median 2.3 nM; 95th percentile 44.3 nM). When differential diagnostic capacity of cancer detection vs. the relevant benign control group was tested, sMRP showed best results for mesothelioma and ovarian cancer with a sensitivity of 45% and 37%, respectively, at 95% specificity. At 100% specificity vs. normal controls, sensitivity for mesothelioma detection was found to be 59% for sMRP, 73% for CYFRA 21-1 and 88% for the combination of both. At 95% specificity vs. all other lung diseases, sensitivity for mesothelioma was 48% for sMRP, 15% for CYFRA 21-1 and 46% for the combination of both. Conclusions: In summary, SMRP is a valuable serum biomarker that is specific at high concentrations for the detection of malignant mesothelioma. For screening purposes, the combination with CYFRA 21-1 improves the sensitivity at high specificity.

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.

Diagnostic values of soluble mesothelin-related peptides for malignant pleural mesothelioma: updated meta-analysis

ObjectiveAlthough the values of soluble mesothelin-related peptides (SMRPs), including mesothelin and megakaryocyte potentiating factor, in serum and/or pleural fluid for diagnosing malignant pleural mesothelioma (MPM) have been extensively studied, the...

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.

Is Soluble Mesothelin-Related Protein an Upfront Predictive Marker of Pleural Mesothelioma? A Prospective Study on Italian Workers Exposed to Asbestos

Objective: Soluble mesothelin-related peptide (SMRP) may be useful in the diagnosis and detection of early stage mesothelioma. We investigated the SMRP upfront predictive role for mesothelioma in asbestos-exposed workers. Methods: A total of 1,715 subjects underwent a first visit and were invited for a follow-up after 1 and 2 years, with a clinical examination and blood sampling. SMRP was measured by an ELISA assay. Results: Median SMRP at the first visit was 0.45 [interquartile range (IQR) i.e. 25th-75th percentile: 0.30-0.67 nmol/l]. In all, 1,676 subjects (97.8%) were followed up for a median period of 47.1 months. SMRP was measured at the first visit and at both follow-up visits in 1,536 subjects. At follow-up, 3 subjects were diagnosed with an epithelioid mesothelioma. In these cases, SMRP at the first visit ranged from 0.17 to 0.52 nmol/l. Malignant pleural mesothelioma was diagnosed 9-17 months after the last SMRP evaluation. No SMRP variation was observed during the follow-up. Other 61 miscellaneous cancers were diagnosed (median SMRP at first visit: 0.50 nmol/l, IQR: 0.34-0.71 nmol/l). Conclusions: Our results did not support the usefulness of SMRP as an early marker for the detection of the disease for a time interval of 1 year.

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.

Clinical value of mesothelin in pleural effusions versus histology by medical thoracoscopy: brief report

The aim of this study based on the third phase of the architecture of diagnostic research was to assess the sensitivity and specificity of soluble mesothelin-related peptide (SMRP) in pleural exudative effusions (PE) compared to the histology obtained by medical thoracoscopy as the diagnostic gold standard examination. We assessed 104 consecutive thoracoscopies. SMRP concentrations were obtained using an ELISA test. We had 34 mesotheliomas (25 epithelioid and 9 sarcomatoid), 35 pleural metastases, and 35 benign diseases. PE-SMRP were significantly higher in patients with epitheliomorphic mesothelioma (mean ± SD 46.55 ± 44.29 nM) than in patients with sarcomatoid mesothelioma (16.11 ± 25.02 nM; p = 0.061), pleural metastasis (7.52 ± 10.77 nM; p < 0.0001), or benign diseases (5.82 ± 8.86 nM; p < 0.0001). Using ROC curve analysis, PE-SMRP offered an AUC of 0.767 in its ability to differentiate between patients with mesothelioma and all other diagnoses. The diagnostic sensitivity and specificity of PE-SMRP for distinguishing mesothelioma from all other causes of pleural effusion, at a cut-off value of 19.6 nM, were 58.8 and 97.1 %, respectively. PE-SMRP higher than the assumed cut-off of 19.6 nM were observed in 18/25 (72.0%) epitheliomorphic mesotheliomas, 2/9 (22.2%) sarcomatoid mesotheliomas, 5/35 (14.3%) pleural metastases, and 1/35 (2.9%) benign diseases. We conclude that PE-SMRP adds some clinical information in the work-up of patients with a PE of unknown origin: (1) thoracoscopy should always be done in patients with a positive mesothelin; (2) a negative mesothelin does not exclude a malignant disease.

Combination of Mesothelin and CEA Significantly Improves the Differentiation between Malignant Pleural Mesothelioma, Benign Asbestos Disease, and Lung Cancer

Soluble mesothelin-related peptides (SMRP) have been reported as potential markers for the diagnosis of malignant pleural mesothelioma (MPM). We wondered, whether a combination with a carcinoembryonic antigen (CEA) test might improve the relatively low diagnostic yield of the SMRP test. In a retrospective study, SMRP (mesothelin) and CEA serum concentrations were measured, using commercially available kits, in 93 previously untreated MPM patients, 75 patients with benign asbestos disease, and 139 patients suffering from lung cancer (LC). The differentiation between MPM, LC, and benign asbestos disease could be improved by applying the ratio mesothelin/CEA. Whereas CEA expression was found to be low in MPM, most LC patients had elevated CEA serum levels. The area under curve (AUC) of the receiver operator characteristics curve for mesothelin alone was found to be only 0.708. For mesothelin/CEA the AUC of the receiver operator characteristics curve increased to 0.978. The sensitivity was 93% (69%) at 95% (100%) specificity for the differentiation between MPM and LC. Comparison of MPM and benign asbestos disease showed that the AUC was 0.887 and the sensitivity 56% (47%) at 95% (100%) specificity. In contrast, the AUC for the mesothelin test alone was only 0.715, and for the CEA test alone it was 0.16. An average increment in sensitivity of 38% (range, 16%-63%) could be achieved by the quotient mesothelin/CEA compared with the sensitivity of mesothelin alone. The diagnostic yield of the mesothelin test can be considerably improved when combined with a CEA test with regard to the differential diagnosis between MPM and LC and between MPM and benign asbestos disease.

SMRP in screening of mesothelioma in asbestos-exposed workers: A study of 1,704 subjects.

e12518 Background: The soluble mesothelin-related peptide (SMRP) is a marker in the diagnosis for mesothelioma. The role of SMRP as a potential screening tool in subjects with a past asbestos exposure is being debated. Objective: to evaluate SMRP and incidence of malignant mesothelioma in an asbestos exposed cohort. Methods: 1,704 subjects (Median Age 62) occupationally exposed to asbestos were enrolled in the study. A questionnaire on individual characteristics, disease history, and occupational or non-occupational exposure to asbestos was administered. All subjectsunderwent clinical examination and collection of serum sample for SMRP measurement that were repeated after 1 and 2 years. The samples were stored at -80 °C until assayed. Results: Median baseline SMRP was 0.45 nmol/l (range 0.1-4.45). SMRP was higher than 1.5 nmol/l (defined as cut-off) in 40 participants. 9 subjects had recognized lung cancer at the time of screening (median baseline SMRP 0.65 nmo/l, range 0.1-1.7) and 109 had recognized tumors at other sites (median 0.52 nmol/l, range 0.1-3.0). Overall, median follow-up of all subjects was 31.5 months During follow-up, recurrent or metastatic tumors were observed in 23 out of 118 tumors. Sixty-one subjects developed a new tumor. An epithelioid pleural mesothelioma occurred in two subjects, 13 and 17 months after the last SMRP evaluation, respectively. Baseline SMRP was 0.52 nmol/l and 0.17 nmol/l, respectively. In subjects with tumor, SMRP increased of 20-50% in 13 subjects (15%), two of them with abnormal SMRP (1 bladder and 1 prostate cancer). An increase greater than 50% was found in 19 subjects (22%). SMRP was higher than the threshold value in 3 tumors (1 lung, 1 colon and 1 prostate, diagnosed 2 months from last SMRP measure). Overall, mesothelin was above the cut-off in 58 subjects without any evidence of neoplastic disease. Conclusions: we cannot confirm the predictive role of SMRP for mesothelioma because we found two cases with low mesothelin levels 13 and 17 months before the diagnosis. The low number of mesotheliomas could be due to the low median age of our population. It will be intriguing to follow up in the future the subjects that showed an increase of SMRP.