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Abstract Background Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin‐related protein (SMRP) and cancer antigen 125 (CA‐125) are established blood‐based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). Methods Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post‐operation, and (3) recurrence. Results Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow‐up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p

Background: Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin‐related protein (SMRP) and cancer antigen 125 (CA‐125) are established blood‐based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). Methods: Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post‐operation, and (3) recurrence. Results: Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow‐up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p < 0.013), advanced TNM (p < 0.001) stage, and clinical stage (p < 0.001). Preoperative CA‐125 levels were not significantly associated with clinical covariates. Neither biomarker was associated with survival or disease‐free survival. With respect to nonpleural and nonlymphatic recurrences, mean SMRP levels were elevated in patients with pleural (p = 0.021) and lymph node (p = 0.042) recurrences. CA‐125 levels were significantly higher in patients with abdominal (p < 0.001) and lymph node (p = 0.004) recurrences. Among patients with all three timepoints available, we observed an average decrease in SMRP levels by 1.93 nmol/L (p < 0.001) postoperatively and again an average increase at recurrence by 0.79 nmol/L (p < 0.001). There were no significant changes in levels of CA‐125 across the study timepoints (p = 0.47). Conclusions: Longitudinal changes in SMRP levels corresponded with a radiographic presence of disease in a subset of patients. SMRP surveillance could aid in detection of local recurrences, whereas CA‐125 could be helpful in recognizing abdominal recurrences. [ABSTRACT FROM AUTHOR]

Diagnosis of diffuse malignant peritoneal mesothelioma (DMPM) is challenging due to the lack of efficient biomarkers for early-stage DMPM. This study was designed to characterize three serum-soluble mesothelium-related proteins, including soluble mesothelin-related protein (SMRP), high mobility group box 1 (HMGB1), and cancer antigen 125 (CA125) in diagnosing DMPM. Serum samples of DMPM patients and healthy controls were collected and an enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of HMGB1, CA125, and SMRP. Correlations between these three serum proteins were examined and the diagnostic values of the biomarkers were assessed by receiver operating curve (ROC) analysis. The combined expression levels of the three markers were also analyzed in terms of predicting patient survival. Higher levels of CA125, SMRP, and HMGB1 was found to be a prominent characteristic of DMPM patients (with > two-fold higher for all levels in DMPM patients compared to control patients, all p <.001), particularly for those with higher-stage DMPM (stage III-IV) compared with lower-stage DMPM (stage I-II) (all p <.05). HMGB1, CA125, and SMRP were all significantly inter-correlated with each other (all p <.05), the combination of the three serum markers had high sensitivity and specificity for diagnosing DMPM. Combined values of the three markers demonstrated a high AUC of 0.85, sensitivity of 78.95%, specificity of 82.75% for identifying DMPM. The combined level of the three markers also demonstrated a significant positive correlation with poor survival of DMPM patients (p =.022). CA125, SMRP, and HMGB1 are potentially valuable diagnostic biomarkers to facilitate the diagnosis of DMPM. [ABSTRACT FROM AUTHOR]

Background: Asbestos exposure is associated with the development of the cancer malignant mesothelioma (MM). Measurement of soluble mesothelin-related protein (SMRP) has been suggested as a method for detection of MM in its early stages. We prospectively examined SMRP levels in participants with asbestos exposure who are a group at a high risk of development of MM. Methods: This study was a follow-up of our cohort of 322 asbestos-exposed participants. No further participants developed MM or malignancy over the study period. Mean follow-up time was 22.9 months. Results: Mean (standard deviation) SMRP levels at baseline and follow-up were 0.94 (0.79) and 0.91 (0.86) nmol/L (p = 0.1033), respectively. Mean SMRP levels of the healthy individuals exposed to asbestos at baseline was significantly lower than those of participants with asbestosis and pleural plaques alone; similar patterns were found on follow-up measurements. There was a statistically significant effect of age on serial SMRP measurements. Our study confirms higher levels in participants with nonmalignant asbestos-related disorders. Levels decreased in asbestos-related disorders other than asbestosis, where a small increase was observed. We did not detect any further cases of malignancy. Conclusion: Monitoring programs for early detection of MM need to take into account increased SMRP levels found in benign asbestos-related diseases.

Background: Immune checkpoint therapy (ICT) has significantly impacted the treatment of malignant pleural mesothelioma (MPM). Despite some promising results from combination therapies, nearly half of MPM patients do not benefit, underscoring the urgent need for reliable predictive biomarkers. This study assesses the prognostic value of serum soluble mesothelin-related peptide (SMRP) and PD-L1 levels in MPM patients receiving ICT., Methods: We conducted a retrospective analysis of 125 MPM patients treated with ICT by measuring pre-ICT serum levels of SMRP and PD-L1. We also examined the correlation of these serum levels with tumor mRNA expressions of mesothelin and PD-L1. Both univariable and multivariable Cox regression analyses were used to determine independent prognosticators for overall survival (OS). A prospective ICT clinical trial and our historical cohort were included for validation., Results: Seventy-seven patients (62%) were treated with either anti-PD-(L)1 monotherapy, and the remaining 38% received combination ICT. Higher pre-ICT SMRP levels were observed in epithelioid MPM compared to nonepithelioid MPM. Serum PD-L1 levels did not differ significantly between the different histologic groups. Univariable analysis identified durable clinical benefit, development of immune-related adverse events, and SMRP levels as significantly associated with OS. Multivariable analysis confirmed SMRP as an independent prognostic factor, with lower levels (≤1.35 nmol/L) correlating with improved OS. The association of high SMRP with worse prognosis was validated in the prospective ICT clinical trial cohort and not in our historical cohort treated without ICT., Conclusions: SMRP is a promising serum biomarker for predicting survival in MPM patients treated with ICT and warrants prospective investigation., Competing Interests: Conflict of Interest Statement H.S.L. reports research funding from the National Institutes of Health, the Department of Defense, the Cancer Prevention Research Institute of Texas, the Helis Medical Research Foundation, and Dan L. Duncan Comprehensive Cancer Center, and investigator-initiated preclinical and clinical research funding from Samyang Biopharm and Momotaro-Gene. B.M.B. reports research funding from the National Institute of Health and Cancer Prevention Research Institute of Texas; clinical trial funding from AstraZeneca, Novartis, and Momotaro-Gene; and serving as a consultant in non–small cell lung cancer for AstraZeneca. R.T.R. reports research support from the National Institutes of Health, the American Association of Thoracic Surgery, and the DeGregorio Family Foundation; serving on the board of directors of the Mesothelioma Applied Research Foundation (nonremunerated); and providing expert legal opinion and serving on a speakers bureau for Merck. S.H.B has received IIT funding from Natera, Steris, and Medtronic; codeveloped instruments with Scanlan and holds other patents with Mayo Clinic; and has served as a speaker for Medtronic, AstraZeneca, and Medela. S.S.G. reports proctor and speaker honoraria from Intuitive Surgical. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

• Pleural effusion KL-6 levels were highly diagnostic in two PM cohorts. • Patients with epithelioid or biphasic tumors had highest KL-6 levels. • Effusion KL-6 levels were associated with overall survival in PM. • MUC1 tumor expression congruently associated with corresponding patient outcome. Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM. Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro. PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort. This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM. [ABSTRACT FROM AUTHOR]

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.

Purpose: To explore the potential and diagnostic performance of soluble mesothelin-related peptide (SMRP) as a tumor marker for epithelial ovarian cancer (EOC). Methods: 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. Results: 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 %. Conclusion: Serum SMRP is a promising marker for the diagnosis and monitoring of EOC, especially in combination with CA125. [ABSTRACT FROM AUTHOR]

Abstract: Background: Blood-based markers for malignant mesothelioma (MM), particularly soluble mesothelin and osteopontin, are currently of great clinical interest. As there is some concern about the sensitivity of osteopontin in serum versus plasma, we compared them in the same patient population to mesothelin. Methods: Soluble mesothelin and osteopontin concentrations were determined by commercial assays in blood samples from 66 patients with pleural MM, 47 patients with non-malignant asbestos-related lung or pleural disease, 42 patients with other benign pleural and lung diseases and 21 patients with lung cancer. Results: Soluble mesothelin and osteopontin in serum and plasma were significantly elevated in MM patients compared to patients with benign lung and pleural disease. At a level of specificity of 95% relative to patients with benign disease, the sensitivity of mesothelin in serum and plasma at presentation with symptoms was 67%, and for osteopontin in the plasma was 40% and in the serum was 20% for MM patients. Combining the serum mesothelin and plasma osteopontin markers using a logistic regression model did not significantly increase the area under the receiver operator curve. Conclusion: Plasma osteopontin has a superior diagnostic accuracy to serum. As the choice of blood sample type has limit effect on soluble mesothelin sensitivity, plasma should be collected for biomarker evaluation in patients suspected of having mesothelioma. [Copyright &y& Elsevier]

Abstract: Purpose: Malignant mesothelioma (MM) carries a poor prognosis and remains a major public health issue in many countries. Outcomes may be improved with earlier detection and this justifies screening the at-risk asbestos-exposed population. Soluble mesothelin is a potential biomarker for MM, but it has been observed to be elevated in patients with reduced kidney function. Defining the relationship between mesothelin concentrations and kidney function will allow more accurate interpretation of this assay. Materials and methods: A cross-sectional study consisting of 144 patients with chronic kidney disease (CKD) was conducted at Sir Charles Gairdner Hospital and Royal Perth Hospital in Western Australia. Only patients with CKD stages II–V were recruited while those with a history of renal transplant, dialysis, or malignancy were excluded. Serum and urine mesothelin and creatinine concentrations were determined. Results: There were 33, 49, 31 and 31 patients in CKD stages II, III, IV and V, respectively recruited. Serum mesothelin increased significantly with increasing serum creatinine (p <0.0001), and worsening stage of CKD (p <0.0001). A significant correlation between urine mesothelin to creatinine ratio and serum mesothelin concentration was detected (p =0.002). No significant difference was found in urine mesothelin to creatinine ratios across the four CKD stage groups. Conclusion: Serum mesothelin concentration is elevated in individuals with renal impairment. Renal function should therefore be taken into account during interpretation of this assay. [Copyright &y& Elsevier]

Abstract: Inhalation of asbestos, a mineral extensively used in a variety of applications, is strongly associated with malignant mesothelioma (MM), a fatal cancer of the pleura. Soluble mesothelin-related peptides (SMRP) are a promising biomarker suggested for the screening of MM in healthy asbestos-exposed subjects. In the present study a comparison of micronucleus (Mn) frequencies in peripheral blood lymphocytes (PBL) between 44 asbestos-exposed and 22 control individuals has been performed, and the correlation with serum SMRP has been examined. SMRP levels were found to be significantly higher in subjects exposed to asbestos and in their various subgroups than in controls. Concerning micronucleated lymphocytes, a statistically significant difference from controls was seen in the percentages of both micronucleated mononucleated lymphocytes (MnMNL) and micronucleated binucleated lymphocytes (MnBNL), but the difference was markedly higher for the percentage of micronucleated polynucleated lymphocytes (MnPNL). With respect to the correlation between the frequency of the three types of micronucleated lymphocytes and serum-SMRP values of asbestos-exposed subjects, it was statistically significant for MnMNL, but not for MnBNL and MnPNL. [Copyright &y& Elsevier]

The aim of the study is to examine the cancer-predictive values of SMRP (soluble mesothelin-related peptides), CA125, and CYFRA21-1 as potential tumor markers for lung cancer and malignant mesothelioma in a cohort of workers formerly exposed to asbestos. A voluntary surveillance program has been established for German workers with former asbestos exposure. A subgroup of 626 subjects with a mean age of 63 years (range 53-70 years) at baseline was enrolled in an extended health examination program with high-resolution computer tomography (HRCT) of the chest and blood drawing between 1993 and 1997. Serum concentrations of SMRP, CA125, and CYFRA21-1 were measured in archived serum samples in 2005 and 2006. A mortality follow-up was conducted through 2007. So far, 12 cases with lung cancer and 20 cases with malignant mesothelioma have been observed in this cohort. The average time between sample collection and diagnosis was 4.7 years. Analyzed biomarkers showed low sensitivities (5-25%) and positive predictive values (4-30%) for both cancer sites. Marker combinations resulted in sensitivities between 5 and 50% and positive predictive values ranging from 3 to 14%. Even in those cases, where biomarker concentrations were available within 36 months before diagnosis, no trend for increasing biomarker levels was observed. The analyzed tumor markers were characterized by high specificities, but low sensitivities. SMRP, CA125, and CYFRA21-1 alone or in combination were less suitable to serve as predictors for the diagnosis of lung cancer or malignant mesothelioma. However, a prospective study with annual sampling might reveal a better predictive value of these markers. [ABSTRACT FROM AUTHOR]

The purpose of this analysis was to evaluate if serum levels of potential tumor markers for the diagnosis of malignant mesothelioma and lung cancer are affected by confounding factors in a surveillance cohort of workers formerly exposed to asbestos. SMRP, CA125, and CYFRA21-1 concentrations were determined in about 1,700 serum samples from 627 workers formerly exposed to asbestos. The impact of factors that could modify the concentrations of the tumor markers was examined with linear mixed models. SMRP values increased with age 1.02-fold (95% CI 1.01-1.03) and serum creatinine concentration 1.32-fold (95% CI 1.20-1.45). Levels differed by study centers and were higher after 40 years of asbestos exposure. CA125 levels increased with longer storage of the samples. CYFRA21-1 values correlated with age 1.02-fold (95% CI 1.01-1.02), serum creatinine 1.21-fold (95% CI 1.14-1.30) and varied by study centers due to differences in sample handling. Tumor marker concentrations are influenced by subject-related factors, sample handling, and storage. These factors need to be taken into account in screening routine. [ABSTRACT FROM AUTHOR]

Summary: 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 ≥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. [Copyright &y& Elsevier]

Abstract: ERC/mesothelin is expressed on the normal mesothelium and some cancers such as mesothelioma or ovarian carcinoma. A splicing isoform of ERC/mesothelin (known as SMRP), which has an 82-bp insertion and codes for a C-terminus with a hydrophilic, presumably soluble, tail instead of a GPI-anchoring signal, has been reported as a useful marker for the diagnosis of mesothelioma. However, the existence of SMRP has not yet been demonstrated in the serum of mesothelioma patients. To elucidate the existence of SMRP, we have established a new enzyme-linked immunosorbent assay (ELISA) system for SMRP. The ELISA study revealed that N- and C-ERC/mesothelin were detected in sera from mesothelioma patients, but not SMRP, even in these samples. This result showed that the SMRP detected with MESOMARK kit should be lack of soluble C-terminus and indistinguishable from C-ERC/mesothelin. Further study might be necessary to demonstrate the relationship between SMRP and mesothelin. [Copyright &y& Elsevier]

SMRP (soluble mesothelin-related peptides) is a promising marker for detection of malignant mesotheliomas (MM) in serum that has not yet been validated in appropriate epidemiological studies. Field studies might not always provide optimal conditions for storage and transport of samples, and follow-up studies have to rely on sample integrity. Proper validation of the marker would require sufficient stability of the antigen and robustness of the assay. SMRP concentrations were evaluated in serum samples of 98 healthy donors, using the MESOMARK ELISA kit. The SMRP distribution in the healthy study population was determined and biological and pre-analytical variations were examined regarding their influence on SMRP concentrations. For diagnostic decisions a best statistical and unbiased cut-off between 1.5 and 1.6 nmol/L was determined (95th percentile). No age- or gender-specific differences could be observed. SMRP exhibits excellent stability regarding short-term storage, long-term storage, and repeated freeze/thaw cycles. Scientific studies as well as real life applications that employ SMRP would not be limited by sample stability issues. [ABSTRACT FROM AUTHOR]

The article discusses the study which aims to determine the CA125 which improves the sensitivity of mesothelin in diagnosing mesothelioma. The study shows that combining CA125 and mesothelin serum levels does not improve the accuracy of diagnosis of malignant mesothelioma over the mesothelin marker. Moreover, the use of mesothelin and CA125 biomakers increases the number of patients who can be monitored.

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.

Summary: Identification of tumor marker for mesothelioma (MM) might prove useful in diagnosis as well as for monitoring tumor in response to therapy and for screening at-risk individuals. We tested the hypothesis that soluble mesothelin-related protein (SMRP), a mesothelin family member, in the serum would be such a marker. Our data show that determination of SMRP in serum is a marker of MM with a sensitivity of sensitivity 83% and specificity 95% in the first 48 MM patients tested. Changes in serum SMRP levels parallel clinical course/tumor size and SMRP is elevated in 75% of patients at diagnosis. SMRP should also be useful for monitoring disease progression, and importantly, may prove useful for screening asbestos-exposed individuals for early MM. [Copyright &y& Elsevier]