Soluble Mesothelin-related Protein Research Articles

A predictive equation to adjust for clinical variables in soluble mesothelin-related protein (SMRP) levels

Malignant mesothelioma (MM) is an aggressive pleural tumor which is difficult to diagnose in its early stages. Thus, biomarkers for MM including soluble mesothelin-related protein (SMRP) are currently an area of intense research interest. However, SMRP is affected by several factors other than malignancy which need to be taken into account in the individual patient. This study aimed to evaluate factors required to adjust SMRP levels for such variables and produce a useful prediction equation for clinical application. Serum SRMP levels were measured in 535 subjects formerly exposed to asbestos and silica, including many with asbestos-related disorders (ARDs). Linear regression analyses were used to quantify the strength and “ direction ” of the relationship between SMRP and several independent variables,and 2 × 2 tables were used to determine the diagnostic accuracy of SMRP levels, taking into account clinical variables. SMRP levels were affected by age and glomerular filtration rate (GFR), which were strong confounders in this study. Body mass index (BMI) was also an initial confounder but lost significance after other factors were taken into account.SMRP was also affected by smoking. Poor sensitivity (15.1 % )for SMRP values among subjects with non-malignant asbestos-related disorders was found when compared to currently healthy subjects with a history of asbestos exposure. The present study proposes an equation based on age and GFR to improve diagnostic accuracy of SMRP.The poor sensitivity of SMRP found in this study suggests that further work is needed to fi nd new candidate biomarkers for diagnosing early stage MM.

HE4 protein and SMRP: Potential novel biomarkers in ovarian cancer detection.

Epithelial ovarian cancer has the highest mortality of all gynecological cancers, and its progression is often without symptoms. Clinical outcome and survival may be improved if the disease is identified in the early stages. The objective of the study was to evaluate the utility of the serum biomarkers human epididymis protein 4 (HE4), soluble mesothelin-related protein (SMRP) and CA125 in the detection of ovarian cancer. In this retrospective study, the serum concentrations of CA125, HE4 protein and SMRP were measured in a cohort of 70 patients with epithelial ovarian cancer (EOC) compared with 78 healthy controls. Median serum levels of CA125 for ovarian cancer cases were 503.55±560.7 U/ml vs. 9.28±14.47 U/ml in the control group (p<0.001); for SMRP 5.13±7.64 nM vs. 1.02±0.89 nM (p<0.01); and for HE4 597.95±934.59 pM vs. 56.75±43.79 pM (p<0.001), respectively. Positive correlations between the clinical stage of EOC and CA125, HE4 and SMRP serum concentrations were found [(R=0.83; p<0.001); (R=0.64; p<0.001); (R=0.45; p<0.001), respectively]. Data analysis for the whole study group also revealed a significant correlation between plasma concentrations of CA125 and HE4 (R=0.45; p<0.001), between CA125 and SMRP (R=0.38; p<0.001) as well as HE4 and SMRP (R=0.51; p<0.001). Similar significant correlations between serum biomarker concentrations were also found in the ovarian cancer group [CA125 and HE4 (R=0.31; p<0.01); CA125 and SMRP (R=0.25; p<0.05); HE4 and SMRP (R=0.44, p<0.001), respectively]. A significant correlation was observed between the serous histological type of EOC and serum concentration of HE4 in the study group compared with other non-serous types of ovarian cancer (p<0.01). In conclusion, measuring CA125 in combination with new biomarkers such as SMRP and HE4 may improve the accuracy of ovarian cancer diagnosis, particularly in early detection of the disease.

Markers for the non-invasive diagnosis of mesothelioma: a systematic review

Background:Numerous markers have been evaluated to facilitate the non-invasive diagnostic work-up of mesothelioma. The purpose of this study was to conduct a structured review of the diagnostic performance of non-invasive marker tests for the detection of mesothelioma in patients with suspected mesothelioma.Methods:Studies on the diagnostic accuracy of serum and cytological markers published till 31 December 2009, available in either PUBMED or Embase, to detect or exclude the presence of mesothelioma were extracted. Study quality was assessed with use of the Quadas criteria.Results:In total, 82 articles were included in this systemic review. Overall, quality of the incorporated studies to address our objective was poor. The most frequently studied immunohistochemical markers for cytological analysis were EMA, Ber-Ep4, CEA, and calretinin. The most frequently investigated serum marker was soluble mesothelin-related protein (SMRP). The markers CEA, Ber-EP4, and calretinin were most valuable in discriminating mesothelioma from other malignant diseases. Markers EMA and SMRP were most valuable in discriminating mesothelioma from non-malignant diseases. No marker performed well in discriminating between mesothelioma and all other diseases.Conclusion:Currently, there is only limited evidence to properly assess the value of non-invasive marker tests in the diagnosis of mesothelioma. Studies were of limited value to address our objective and results showed considerable unexplained study heterogeneity.

Soluble Mesothelin-related Protein Levels in Subjects With Malignant Mesothelioma

PP-30-155 Background/Aims: Malignant mesothelioma is a highly aggressive tumor associated mostly with asbestos exposure. Soluble mesothelin-related protein (SMRP) is a potential tumor marker for mesothelioma. The aim of this study was to determine the differences in serum SMRP levels at various phases of the disease before and during treatment. Methods: The study included all 78 subjects with mesothelioma treated at the Institute of Oncology, Ljubljana, between 2007 and 2009. According to the cumulative asbestos exposure, they were divided into 4 groups (nonexposed, low, medium, and high). Serum samples were collected in all subjects before the treatment and/or in different responses to treatment (complete response, partial response, stagnation, progressive disease). Serum SMRP levels were determined by enzyme-linked immunosorbent assay with 2 monoclonal antibodies. Results: Asbestos exposure was confirmed in 67 (85.9%) subjects. Only occupational exposure was observed in 32 subjects, only environmental in 12 subjects, and both occupational and environmental exposures in 23 subjects. The cumulative asbestos exposure was classified as low in 24, medium in 21, and high in 22 subjects. Mean serum SMRP was 5.75 nM before the treatment, 0.00 nM in complete response, 1.33 nM in partial response, 2.97 nM in stagnation, and 9.67 nM in progressive disease. The SMRP levels were significantly higher before the treatment compared to the stagnation, partial and complete responses to treatment (t = 2.49; P = 0.016), as well as in the progressive disease if compared to the stagnation, partial and complete responses to treatment (t 5.48; P 0.000). Conclusion: Asbestos exposure was confirmed in almost 86% of subjects with mesothelioma and among them, the exposure was low in 36% of subjects. As the findings of the study suggest that SMRP might be a useful tumor marker for detecting the progression of mesothelioma and tumor response to treatment, a thorough follow-up of a prospective cohort is needed.

Factors affecting soluble mesothelin related protein levels in an asbestos-exposed population

Soluble mesothelin-related protein (SMRP) is increased in the sera of patients with malignant mesothelioma (MM), and has been suggested as a diagnostic tool for MM in an asbestos exposed population. However, factors affecting SMRP concentrations in normal subjects and those with other asbestos related disorders have not been investigated in any large population based study. Five hundred and thirty-eight subjects with a history of asbestos exposure were studied. Age, height, weight, body mass index (BMI), serum creatinine and glucose, estimated glomerular filtration rate (eGFR) and lung function were compared with SMRP concentrations. The mean age [+/- standard deviation (SD)] of participants was 66.9 (+/-10.1) years, and mean (+/-SD) serum SMRP concentration was 0.91 (+/-0.67) nmol/L. SMRP values were inversely associated with weight (Pearson r=-0.1254, p=0.0036), BMI (Pearson r=-0.1594, p=0.0002), blood glucose (Pearson r=-0.1515, p=0.0004), single-breath carbon monoxide diffusing capacity (DLco) % predicted (Pearson r=-0.1847, p<0.0001), eGFR (Pearson r=-0.2835, p<0.0001) and single-breath carbon monoxide diffusing capacity per unit alveolar volume (DLco/VA)% predicted (Pearson r=-0.1872, p<0.0001) but were positively associated with age (Pearson r=0.2315, p<0.0001) and creatinine (Pearson r=0.3833, p<0.0001). This study has shown that demographic variables, physiological factors and lung function are associated with serum SMRP concentrations. Confounding factors should be considered when interpreting serum SMRP.

Soluble mesothelin-related protein in pleural effusion from patients with malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm primarily arising from surface serosal cells of the pleura and is strongly associated with asbestos exposure. Patients with MPM often develop pleural fluid as initial presentation. However, cytological diagnosis using pleural fluid is usually difficult and has limited utility. A useful molecular marker for differential diagnosis particularly with lung cancer (LC) is urgently needed. The aim of the present study was to investigate the diagnostic value of soluble mesothelin-related protein (SMRP) in pleural fluid. Pleural fluids were collected from 23 patients with MPM, 38 with LC, 26 with benign asbestos pleurisy (BAP), 5 with tuberculosis pleurisy (TP) and 4 with chronic heart failure (CHF), and the SMRP concentration was determined. All data were analyzed by using non-parametric two-sided statistical tests. The median concentration of SMRP in MPM, LC, BAP, TP and CHF were 11.5 (range 0.90-82.80), 5.20 (0.05-36.40), 6.65 (1.45-11.25), 3.20 (1.65-6.50) and 2.03 (1.35-2.80) nmol/l, respectively. The SMRP concentration was significantly higher in MPM than in the other diseases (P=0.001). The area under the ROC curve (AUC) values of the MPM diagnosis was 0.75 for the differential diagnosis from the other groups. Based on the cut-off value of 8 nmol/l, the sensitivity and specificity for diagnosis of MPM were 70.0 and 68.4%, respectively. These results indicate that the SMRP concentration in pleural fluid is a useful marker for the diagnosis of MPM.

Polymorphisms in the putative micro-RNA-binding sites of mesothelin gene are associated with serum levels of mesothelin-related protein

BackgroundSerum mesothelin, also known as soluble mesothelin-related protein (SMRP), reportedly shows increased levels in epithelial-type malignant pleural mesothelioma, but sometimes also arrives at high values in healthy asbestos-exposed subjects.ObjectivesThis study...

Protein Profiling of Pleural Effusions to Identify Malignant Pleural Mesothelioma Using SELDI-TOF MS

Diagnosis of malignant pleural mesothelioma (MM) is limited. Novel proteomic techno_logies can be utilized to discover changes in expression of pleural proteins that might have diagnostic value. The objective of this study was to detect protein profiles that could be used to identify malignant pleural mesothelioma with surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS). Pleural effusions were collected from patients with confirmed mesothelioma (n = 41) and from patients with effusions due to other causes ([n = 48] cancerous and non-cancerous). Samples were fractionated using anion exchange chromatography and bound to different types of ProteinChip array surfaces. All samples were also subjected to other commercially available immunoassays (human epididymes protein 4 [HE4], osteopontin [OPN], soluble mesothelin-related proteins [SMRP], and the cytokeratin 19 fragment [CYFRA 21-1]). Peak intensity data obtained by SELDI-TOF were subjected to classification algorithms in order to identify potential classifier peaks. A protein peak at m/z 6614 was characterized as apolipoprotein (Apo) CI. In this setting, the sensitivity and specificity of this potential biomarker was 76 % and 69 %, respectively. The area under the receiver operating characteristic curve (AUC) for Apo CI was 0.755, thereby outperforming OPN, HE4, and CYFRA 21-1. SMRP performed best with an AUC of 0.860 with a sensitivity of 83% and specificity of 74%. Our study validates the use of SMRP as a diagnostic marker for pleural mesothelioma and furthermore suggests that Apo CI levels could be used in the future to discriminate pleural mesothelioma from other causes of exudates.

Glomerular Filtration Rate Is a Confounder for the Measurement of Soluble Mesothelin in Serum

The mesothelin gene encodes a 71-kDa precursor protein that is subsequently cleaved into a soluble megakaryocyte potentiating factor and a membrane-bound part, mesothelin. Mesothelin can be shed as “soluble mesothelin” or “soluble mesothelin-related protein” (SMRP),1 which is an approximately 40-kDa biomarker of malignant mesothelioma, an asbestos-related cancer (1). Mesothelioma typically occurs in middle-aged men, and the renal function or the glomerular filtration rate (GFR) can occasionally decrease in these patients and in individuals at risk of developing mesothelioma. Renal impairment leads to the accumulation of low molecular weight proteins in the blood [e.g., cystatin C (13 kDa) and β-trace protein (BTP) (23–29 kDa)], and these proteins have been used as markers of the GFR. Such renal impairment can also cause the accumulation of soluble mesothelin, as has previously been reported for a limited number of cases(2). Our aim, therefore, was to thoroughly investigate the impact of renal function on serum SMRP concentrations. We enrolled 66 individuals (49 men and 17 women; median age, 58 years; range, 24–80 years), who were referred for measurement of 51Cr-EDTA clearance to estimate the GFR. We excluded patients with asbestos-related diseases/malignancies, patients with endometrial, ovarian, cervix, lung, breast, pancreatic, or gastrointestinal cancer, and patients with leukemia, because these conditions can overexpress mesothelin (3)(4). The study was approved by the ethics committee of both participating hospitals, and participants gave written informed consent. …

Current Status of Screening for Malignant Pleural Mesothelioma

Malignant mesothelioma is characterized by its association with asbestos, its long latency period, and the propensity for the diagnosis to be obtained in the later stages of the disease. Because the high-risk cohorts for mesothelioma are fairly well defined by the association with asbestos, and the exposure is usually in the workplace, it is hypothesized that early detection of the disease could (1) find patients at an earlier, more treatable stage and (2) result in prolonged survival over the present median 12 months from the start of therapy. Many studies have used standard chest X-ray to characterize changes associated with asbestos-exposed individuals, but the insensitivity of X-ray in screening patients with mesothelioma has never supported the wide-scale adaptation of such an effort. With the advent of computerized tomography, prospective trials, many of which are chiefly prevalence detection studies, have been performed and stress the importance for proper detailing by carefully qualifying suspicious changes, as well as defining the correct cohort to screen. Most recently, serum biomarkers with the potential to discriminate asbestos-exposed, non-cancer-bearing individuals from those with mesothelioma have been investigated both at single institutions and with multi-institutional-blinded trials. These markers, including soluble mesothelin-related protein, osteopontin, and megakaryocyte potentiating factor, may, in the future, be incorporated into a screening algorithm for high-risk asbestos-exposed individuals to help monitor these cohorts in a noninvasive fashion and guide the use of computerized tomography.

Early detection of malignant pleural mesothelioma through measurement of soluble mesothelin‐related protein and positron emission tomography

A 51-year-old man with no known history of asbestos exposure presented with hydropneumothorax. Soluble mesothelin-related protein testing and combined positron emission tomography and computed tomography were used to diagnose malignant pleural mesothelioma. One year after radical surgery and radiotherapy, there was no clinical recurrence.

Manejo de la patología pleural

In view of the presentations in the First National Forum of Trainee Pneumologists, the present article focusses on infectious pleural effusions and on the study of possible markers of malignant disease in asbestos-exposed individuals. The yield of the distinct techniques for the diagnosis of tuberculous pleural effusion is assessed, with emphasis on analysis of sputum and pleural samples (fluid and tissue) for Mycobacterium tuberculosis. The utility of adenosine deaminase (ADA) (in the absence of empyema, ADA > 70 U/l is diagnostic of tuberculous pleurisy, while values of less than 40 U/l exclude this diagnosis) and interferon gamma in pleural fluid (cut off: 3.7 Ul/ml) is also discussed. The management of complicated parapneumonic pleural effusions is stratified in four categories, depending on the anatomical and morphological (size and eventual presence of loculations), bacteriological (positivity or negativity of pleural fluid culture) and biochemical (pH/glucose) characteristics of the effusion. Finally, recently developed markers for the evaluation and follow-up of asbestos-exposed individuals are described, with special emphasis on serum determination of mesothelin levels, which seem highly promising as a marker of the development of mesothelioma in these cases. A multicenter study currently being performed in Spain found that soluble mesothelin-related protein (SMRP) levels higher than 0.55 nmol/L showed a sensitivity and specificity of 72% for the diagnosis of epithelial malignant mesothelioma.

Diagnostic and Prognostic Value of Soluble Mesothelin-Related Proteins in Patients with Malignant Pleural Mesothelioma in Comparison with Benign Asbestosis and Lung Cancer

We investigated the diagnostic and prognostic value of soluble mesothelin-related proteins (SMRP) in sera from patients with newly diagnosed malignant pleural mesothelioma (MPM) (n = 100), MPM patients at tumor relapse (n = 29), primary lung cancer (n = 139), and benign asbestosis (n = 75) using Mesomark--enzyme-linked immunosorbent assay kit (Fujirebio Diagnostics, Malvern, PA). SMRP concentrations were significantly higher in MPM compared with benign asbestosis (p < 0.001) or lung cancer (p < 0.001). The median values were 1.4 nM, 0.9 nM, and 0.8 nM, respectively. The best statistical cutoff was found to be 1.35 nM resulting in a sensitivity of 53% and a specificity of 82.7%. Receiver operating characteristics curves gave an area under curve of 0.72 for the discrimination between MPM and non-MPM patients (p < 0.001). No significant differences in SMRP levels were found among histologies and stages of MPM. The highest median SMRP levels (4.2 nM) were measured in 29 MPM patients with relapse/progression (75.8% > 1.35 nM). Univariately, SMRP discriminated significantly (p < 0.003) between favorable (n = 71, median survival: 17.1 month; 1-year survival: 63.1%) and worse prognosis (n = 20, median survival: 8.4 months, 1-year survival: 32%) at 3.5 nM. In multivariate analysis, histology, therapy, and SMRP were shown to be independent prognostic factors in all MPM patients (hazard ratio for SMRP: 1.96; p = 0.025). Nevertheless, subtype-driven reanalysis showed only a trend in epithelial MPM. In conclusion, SMRP add limited information to the diagnosis of MPM. Nevertheless, SMRP might be a useful measure in treatment and monitoring of MPM. The prognostic impact of SMRP in MPM is not conclusive and needs further evaluation.

Soluble Mesothelin-related Protein in an Asbestos-exposed Population

Soluble mesothelin-related protein (SMRP) is raised in epithelial-type malignant mesothelioma (MM), but the utility of SMRP in screening for MM is unknown. We aimed to evaluate SMRP in an asbestos-exposed cohort. A total of 538 subjects were studied. Those with elevated SMRP (> or =2.5 nM) underwent further investigation including positron emission tomography/computed tomography. Mean (+/-SD) SMRP in healthy subjects exposed to asbestos (n = 223) was 0.79 (+/-0.45) nM. Fifteen subjects had elevated SMRP, of whom one had lung cancer, which was successfully resected. Another with lung cancer was undetected by SMRP. No subjects were diagnosed with MM. Mean SMRP in healthy subjects was significantly lower than in subjects with pleural plaques alone (P < 0.01). This is the first large-scale prospective study of SMRP for screening for malignancy in asbestos-exposed individuals. A high false-positive rate was observed. SMRP seems unlikely to prove useful in screening for MM.

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.

Mesothelin-related predictive and prognostic factors in malignant mesothelioma: A nested case–control study

Soluble mesothelin-related protein (SMRP) in serum is potentially a sensitive marker of malignant mesothelioma (MM) diagnosis and progression, and may be useful as screening marker. Mesothelin expression in tumors is regarded as a sensitive marker for diagnosis and disease progression, and is a candidate prognostic marker. Levels of SMRP, CA125 and CYFRA 21-1 in pre-diagnostic (1-30 years) serum samples from 47 mesothelioma cases and 141 matched controls were analysed. Mesothelin expression in tumors was assessed. The association between biomarker level and mesothelioma risk and survival was analysed, adjusting for asbestos exposure. Survival related to tumor mesothelin expression, age, sex, histological type, location, asbestos exposure and pre-clinical SMRP was analysed. There was no significant association between biomarker levels and mesothelioma risk when analysed as continuous variables or as tertiles. Biomarker levels <10, 10-19 and >or=20 years before diagnosis were not significantly associated to mesothelioma risk. Mesothelin expressed in >50% of tumor cells was seen in 36 of 47 (77%) tumors. Mesothelin expression in <50% of tumor cells was a significant negative prognostic marker in all cases of malignant mesothelioma (median survival=6 months vs. 12 months, hazard ratio (HR)=2.49, 95%CI 1.17-5.27), and also when only epithelial mesothelioma was analysed (median=6 months vs. 14 months, HR=2.36, 95%CI 1.07-5.22). When adjusted for age and gender, the prognosis was still dismal, but non-significant (HR=1.85, 95%CI 0.85-4.05). High age (>65 years) was an independent negative prognostic factor that was related to both mesothelin expression and asbestos exposure. Mesothelioma of the epithelial type of the peritoneum had a significantly longer survival than epithelial type in pleura and was also related to mesothelin expression.

Aberrant splicing and protease involvement in mesothelin release from epithelioid mesothelioma cells

Elevated amounts of soluble mesothelin-related proteins (SMRP) have already been reported in sera and pleural effusions from mesothelioma patients, providing a useful diagnostic marker for malignant pleural mesothelioma (MPM). However, the origin of SMRP is not yet understood. Production of SMRP could be related to abnormal splicing events leading to synthesis of a secreted protein (release) or to an enzymatic cleavage from membrane-bound mesothelin (ectodomain shedding). To test these hypotheses, we used a panel of mesothelioma cells established in culture from pleural effusions of MPM patients. Our in vitro results confirmed specific mesothelin expression and SMRP production in supernatants from epithelioid MPM cell lines, thus providing a relevant cellular model to study soluble mesothelin production mechanisms. The expression of mesothelin-encoding RNA variants was screened by reverse transcription-polymerase chain reaction experiments. Protease involvement in mesothelin cleavage from the cellular surface was investigated by treatment of MPM cells with GM6001, a broad-spectrum MMP- and ADAM-family inhibitor. GM6001 treatment significantly impaired SMRP production by MPM cell lines, in favor of an enzymatic-mediated shedding process. In addition, a splice variant transcript of mesothelin (variant 3) was detected in these MPM cell lines, in accordance with the release of a secreted part of the protein. Our results indicate that both mechanisms could be implicated in soluble mesothelin production by epithelioid mesothelioma cells.

Non-invasive diagnosis of pleural malignancies: The role of tumour markers

Serum markers have been tested in patients with malignant effusions for their ability to differentiate malignant pleural mesothelioma from other causes. We have assessed three different serum markers and report our findings in a series of patients with different thoracic malignancies and a group of healthy controls. A retrospective analysis of 179 patients and 50 healthy controls was performed. Seventy-four patients had a confirmed mesothelioma, and 106 patients had non-small cell lung cancer (NSCLC), 55 had adenocarcinoma. Soluble mesothelin-related protein (SMRP), Cyfra 21.1, and carcino-embrionic antigen (CEA) were tested in serum at time of presentation. Cyfra 21.1 was the best single marker discriminating healthy from any malignant disease (area under receiver operating characteristics curve (AUC): 0.92; 95% confidence interval (CI): 0.89-0.96). By combining all three markers the discriminatory power improved marginally (AUC: 0.95; CI: 0.93-0.98; p=0.015). The combination of CEA and SMRP was most accurate in differentiating mesothelioma from NSCLC (AUC: 0.94; 95% CI: 0.90-0.97) and could correctly identify 152 of 179 (85%) cases. By using two serum markers (CEA and SMRP) we were able to discriminate mesothelioma from NSCLC with high sensitivity, while Cyfra 21.1 is useful in the discrimination of normal versus malignancy.

P1-144: Soluble Mesothelin related Proteins in Patients with Malignant Pleural Mesothelioma in Comparison to Asbestos Diseases and Lung Cancer

P1-144: Soluble Mesothelin related Proteins in Patients with Malignant Pleural Mesothelioma in Comparison to Asbestos Diseases and Lung Cancer

Pooling of Case Specimens to Create Standard Serum Sets for Screening Cancer Biomarkers

Multiple identical sets of sera from cancer cases and controls would facilitate standardized testing of biomarkers. We describe the creation and use of standard serum sets developed from healthy donors and pooled sera from ovarian, breast, and endometrial cancer cases. Two hundred seventy-five 0.3-mL aliquots of sera were created for each of the 95 healthy women, and residual serum was pooled to create 275 identical sets of 20 0.3-mL aliquots. Aliquots (1.0-1.5 mL) from 441 women were combined to create 12 breast and pelvic disease pools with at least 115 0.3-mL aliquots. Sets were assembled to contain aliquots from individual controls, replicates, and disease pools. Cancer antigens (CA), CA 125, CA 19.9, and CA 15.3, and carcinoembryonic antigen were measured in one set and in 217 women comprising six of the pelvic disease pools. Use of a set was illustrated for mesothelin (soluble mesothelin-related protein). Statistical output included concentration differences between pooled cases and controls (z values for single analytes; Mahalanobis distances for pairs), correlation between z values and sensitivities, coefficient of variations, and standardized biases. Marker concentrations in the six pelvic disease pools were generally within 0.25 SD of the actual average, and z values correlated well with sensitivities. CA 125 remains the best single marker for nonmucinous ovarian cancer, complemented by CA 15.3 or soluble mesothelin-related protein. There is no comparable breast cancer biomarker among the current analytes tested. The potential value of standard serum sets for initial assessment of candidate biomarkers is illustrated. Sets are now available through the Early Detection Research Network to evaluate biomarkers for women's cancers.