Soluble Mesothelin-related Peptide Research Articles

Pleural Mesothelioma: Advances in Blood and Pleural Biomarkers.

Pleural mesothelioma (PM) is a type of cancer that is highly related to exposure to asbestos fibers. It shows aggressive behavior, and the current therapeutic approaches are usually insufficient to change the poor prognosis. Moreover, apart from staging and histological classification, there are no validated predictors of its response to treatment or its long-term outcomes. Numerous studies have investigated minimally invasive biomarkers in pleural fluid or blood to aid in earlier diagnosis and prognostic assessment of PM. The most studied marker in pleural effusion is mesothelin, which exhibits good specificity but low sensitivity, especially for non-epithelioid PM. Other biomarkers found in pleural fluid include fibulin-3, hyaluronan, microRNAs, and CYFRA-21.1, which have lower diagnostic capabilities but provide prognostic information and have potential roles as therapeutic targets. Serum is the most investigated matrix for biomarkers of PM. Several serum biomarkers in PM have been studied, with mesothelin, osteopontin, and fibulin-3 being the most often tested. A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker in patients with suspected mesothelioma. With different serum and pleural fluid cut-offs, it provides useful information on the diagnosis, prognosis, follow-up, and response to therapy in epithelioid PM. Panels combining different markers and proteomics technologies show promise in terms of improving clinical performance in the diagnosis and monitoring of mesothelioma patients. However, there is still no evidence that early detection can improve the treatment outcomes of PM patients.

B-347 Performance Validation of an In-house Assay for Soluble Mesothelin Related Peptides

Abstract Background Mesothelin is a glycosylated phosphatidylinositol glycoprotein located on the surface of mesothelial cells. Mesothelin is released from the cell in a form denoted as Soluble Mesothelin Related Peptides (SMRP), that can be measured in the blood. Although mesothelin is produced by normal cells, studies have shown an overexpression in individuals suffering malignant mesothelioma, with an increase in serum SMRP concentration associated with the disease. The in-house ARUP MESOMARK® ELISA is a 96-well microtiter plate formatted sandwich immunoassay for the quantitative measurement of SMRP in human serum. The ELISA incorporates two separate monoclonal antibodies specific for SMRP (including megakaryocyte potentiating factor); one (4H3) bound to the microtiter well for capturing SMRP and the second (OV569), enzyme labeled with horseradish peroxidase (HRP), for bound SMRP detection. After several incubation and wash steps to remove unbound materials, color is produced by HRP turnover of a chromogenic substrate during a final incubation step. A direct relationship between the color intensity and the SMRP concentration of the specimen is generated, with results expressed as nmol/L SMRP. Methods Deidentified residual serum specimens sent to ARUP Laboratories for routine testing, as well as serum specimens from healthy volunteers, were collected under University of Utah’s Institutional Review Board approved protocols. Commercial kit (Fujirebio Diagnostics, Inc., Malvern, PA) testing was completed according to manufacturer’s protocol. ARUP ELISA measurements were conducted according to an established in-house protocol. ARUP ELISA performance characteristics evaluated included a method comparison against the commercial assay, linearity, recovery, precision, analytical sensitivity, and dilution studies. A reference limit was also verified. Results A method comparison study against the commercial SMRP ELISA generated a slope of 0.989, intercept of 0.0422, r2 of 0.998 and bias of -1.2% (n = 45, Deming regression, Bland-Altman analysis). Clinical agreement near the 1.5 nmol/L cutoff was 100%. The limit of detection was 0.3 nmol/L (20 determinations each of a blank and low-level serum pool). Linearity was established by combining serum specimens with high and low SMRP concentrations at different ratios, creating 10 specimens of varying SMRP concentrations. Each specimen was tested in triplicate. Regression analysis (measured vs expected concentration) produced a slope of 1.002, intercept of -0.739 and r2 of 0.998, with percent recoveries ranging 86.1 to 100.0%. Precision was determined from two serum pools of differing SMRP concentrations tested over 5 days, four replicates per pool per day. Repeatability and within-laboratory CVs were 3.0 and 5.0% at 1.6 nmol/L, and 1.7 and 1.7% at 17.3 nmol/L, respectively. Back-calculated results from a 10-fold dilution study of four serum specimens were within -9.8 to -8.1% of their corresponding neat values. The previously established reference limit of 1.5 nmol/L was verified for the ARUP ELISA, with 95% of results below the cutoff value (n = 20, sera from healthy volunteers). Conclusions The in-house ARUP MESOMARK ELISA demonstrates acceptable performance for quantifying SMRP in human serum and compares favorably to a well-established commercial ELISA. A reference limit of 1.5 nmol/L was also verified. Overall, the ARUP MESOMARK ELISA is acceptable for serum SMRP testing.

Phase 1 trial of gavocabtagene autoleucel (gavo-cel, TC-210) in patients (pts) with treatment refractory mesothelioma and other mesothelin-expressing solid tumors.

8537 Background: We have conducted a Phase 1 trial of gavo-cel, an autologous genetically engineered anti-mesothelin T cell receptor fusion construct (TRuC™) cell therapy in pts with refractory mesothelin-expressing mesothelioma (MPM), ovarian cancer (OvC), cholangiocarcinoma (CHO), or non-small cell lung cancer (NCT03907852). Methods: T cells were engineered with a lentiviral vector to express an anti-mesothelin single domain antibody fused to the CD3ε subunit, which upon translation, integrated into and reprogrammed native T cell receptors to target mesothelin-expressing cancer cells in an HLA-independent manner. Eligibility required central laboratory confirmation of 2+ or 3+ mesothelin expression by IHC in ≥50% of tumor cells. Dose escalation followed a modified 3+3 design. Results: At data cut-off date (January 17th, 2023), 32 pts (23 MPM, 8 OvC, 1 CHO) received a gavo-cel infusion at one of 7 dose levels (DL): DL0 (n = 1, no lymphodepletion [LD]) and DL1 (n = 8), 5x107 transduced cells/m2; DL2 (n = 1, no LD) and DL3 (n = 13), 1x108 transduced cells/m2; DL3.5 (n = 5), 3x108 transduced cells/m2; DL4 (n = 1, no LD) and DL5 (n = 3), 5x108 transduced cells/m2. Median number of prior therapies was 5 (range, 1-13), including immune checkpoint inhibitors (ICI) in 87% of MPM pts. Bridging therapy was required in 24 (75%) pts. Two DLTs were reported: grade (gr) 3 pneumonitis at DL1 and gr5 bronchoalveolar hemorrhage at DL5. At the RP2D (1x108/m2 after LD) 2/13 (15%) pts had reversible gr≥3 CRS. The ORR and disease control rate was 20% and 77%, respectively. The 6-month OS rate was 70.2%. The ORR of pts with MPM or OvC receiving gavo-cel after LD was 21% and 29%, respectively. The median PFS and OS in MPM was 5.6 and 11.1 mos and in OvC was 5.8 and 9.4 mos. Responses correlated with declines in soluble mesothelin related peptides. Peak expansion and persistence correlated with dose and LD administration. At the RP2D, the median Cmax was 14,385 copies/ug gDNA (range, 64.4–100,782) and the median peripheral blood (PB) persistence was 84 days (range: 0-170). Consistent elevation in IL-6 and IFN-γ levels but minimal IL-8 and TNF-α were observed. Gavo-cel expanded preferentially in cancerous tissues, where it was detected long after becoming undetectable in PB. Gavo-cel therapy led to increased CD3+CD8+ T cell tumor infiltration. Non-responders exhibited upregulation of immunoinhibitory ligands (CD155, PDL1), indicating potential resistance mechanisms. Conclusions: A single IV gavo-cel infusion at the RP2D was associated with a manageable toxicity profile and high rates of disease control, including objective responses in pts with refractory MPM and OvC. A phase 2 study is underway testing the safety and efficacy of gavo-cel in combination with checkpoint inhibitors in pts with mesothelin-expressing solid tumors. Clinical trial information: NCT03907852 .

Phase 2 randomized trial of neoadjuvant or palliative chemotherapy with or without immunotherapy for peritoneal mesothelioma (Alliance A092001).

TPS8603 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients (pts) who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude pts with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in pts with newly diagnosed peritoneal mesothelioma. Methods: Alliance for Clinical Trials in Oncology A092001 is a prospective, randomized phase 2 clinical trial. All pts with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Pts who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine if frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible pts per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 pts are enrolled. Stratification factors include eligibility for cytoreductive surgery at diagnosis and histologic subtype. Secondary endpoints include progression-free survival, overall survival and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Clinical trial information: NCT05001880 .

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

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

Serum diagnostic markers for malignant pleural mesothelioma: a narrative review.

The prognosis of patients with malignant pleural mesothelioma (MPM) is poor, and early diagnosis is key to improving the prognosis. Pleural biopsy is the gold reference for diagnosing MPM, but it is an invasive method that can cause operation-related complications such as bleeding and infection. Serum biomarkers, with the advantages of mini-invasiveness, short turnaround time and objectiveness, represent a promising diagnostic tool for MPM. We searched the PubMed database to identify clinical studies published between 1990 to July 2022 that investigated the diagnostic accuracy of serum biomarkers for MPM. The major findings of the verified studies were summarized. Currently, there are many available serum markers for MPM, including mesothelin, soluble mesothelin-related peptides, osteopontin, fibulin-3, high mobility group box 1, and microRNA. Systematic review and meta-analysis evidence indicates that the sensitivity and specificity of these serum markers are less than 0.90. In addition, a large portion of previous studies have limitations, especially the representativeness of the study cohort. The diagnostic accuracy of currently available serum biomarkers is unsatisfactory, and further studies are needed to investigate novel serum biomarkers.

Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma.

In previous studies, non-invasive diagnostic biomarkers showed great benefit in the early-stage diagnosis of malignant pleural mesothelioma (MPM). However, the accuracy of different biomarkers was controversial. In this study, meta-analysis and bioinformatics analysis were conducted to compare the accuracy of the following three biomarkers and explore the relationship between the gene expression levels and MPM. A systematic search of meta-analysis was conducted using PubMed, EMBASE and Cochrane Library to identify relevant studies from the inception to March 2021. QUADAS-2 for Quality Assessment of Diagnostic Accuracy Studies was used to evaluate the quality of eligible studies. The meta-analysis was performed utilizing Stata 15.0 and Review Manager 5.4 software. The meta-analysis results showed that 31 studies that involved 8750 participants were included. The pooled sensitivity and specificity (SPE) were 0.90 (95% CI: 0.74, 0.97) and 0.91 (95% CI: 0.84, 0.95) for Fibulin-3, 0.66 (95% CI, 0.51–0.78) and 0.91 (95% CI, 0.82–0.96) for mesothelin (MSLN), 0.68 (95% CI: 0.63,0.73) and 0.86 (95% CI: 0.82,0.90) for soluble mesothelin-related peptides (SMRP), and 0.74 (95% CI, 0.66-0.80) and 0.89 (95% CI, 0.85–0.91) for MSLN + SMRP + Fibulin-3. Compared with the other two biomarkers, Fibulin-3 may be more appropriate to be one of the indicators for combined diagnosis. Bioinformatics analysis showed that the low expression level of the MSLN gene was significantly related to longer survival time and better prognosis of MPM patients. However, considering the limitation in the quality and sample size of the included research, further studies are required.

Assessment of the value of mesothelin in differentiating between different pleural malignancies by different interventional modalities

Abstract Context Malignant mesothelioma is an insidious neoplasm, with malignant pleural mesothelioma as the most common type, which is characterized by poor prognosis in most patients owing to late presentation. The use of noninvasive markers for early diagnosis of malignant pleural mesothelioma is of great importance in decreasing the incidence of associated morbidity and mortality. Aims To evaluate the value of soluble mesothelin level in serum and pleural fluid as a diagnostic marker in patients with pleural malignancies and in differentiation of different causes of pleural effusion. Patients and methods We included 48 patients who were classified into three groups: group A (mesothelioma), group B (metastatic malignancy), and group C (transudative effusion). History taking, clinical examination, and laboratory assessment were performed in all groups, in addition to measuring mesothelin level in serum and pleural fluid. Histopathological examination of pleural biopsies was performed in groups A and B. Results Mesothelin levels in serum and pleural fluid demonstrated a statistically significant increase in group A as compared with the cases in groups B and C (P<0.001). Moreover, mesothelin levels in serum and pleural fluid demonstrated a statistically significant increase in the samples taken from the cases in group B as compared with the cases in group C (P<0.001). Conclusion Soluble mesothelin-related peptides (SMRP) could be used as a valuable marker in diagnosis of different causes of pleural effusion. The diagnostic accuracy of pleural fluid SMRP was higher as compared with the serum SMRP.

Phase 2 randomized trial of neoadjuvant or palliative chemotherapy with or without immunotherapy for peritoneal mesothelioma (Alliance A092001).

TPS8598 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude patients with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in patients with newly diagnosed peritoneal mesothelioma. Methods: A092001 is a prospective, randomized phase 2 clinical trial. All patients with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed, and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Patients who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible patients per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 patients are enrolled. As stratification factors we have included eligibility for cytoreductive surgery at diagnosis, and histologic subtype. Secondary endpoints include assessment of progression-free survival, overall survival, and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Support: U10CA180821, U10CA180882. Clinical trial information: NCT05001880.

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

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

Serum Calretinin as a Biomarker in Malignant Mesothelioma.

The early diagnosis of malignant mesothelioma (MM) could improve the prognosis of MM patients. To confirm an MM diagnosis, an immunohistochemical analysis of several tumor tissue markers, including calretinin, is currently required. Our aim is to evaluate serum calretinin as a potential biomarker in asbestos-related diseases, especially in MM. Our study includes 549 subjects: 164 MM patients, 117 subjects with asbestosis, 195 subjects with pleural plaques and 73 occupationally asbestos-exposed subjects without asbestos-related diseases. The serum calretinin concentration was determined with a commercially available enzyme immunoassay. Data on the soluble mesothelin-related peptides (SMRP) concentration are available from previous studies. MM patients had a significantly higher calretinin concentration than subjects without disease, subjects with pleural plaques or subjects with asbestosis (all p < 0.001). The histological type was significantly associated with serum calretinin: patients with sarcomatoid MM had lower calretinin than patients with the epithelioid type (p = 0.001). In a ROC curve analysis, the area under the curve for calretinin concentration predicting MM was 0.826 (95% CI = 0.782–0.869; p < 0.001). At the cutoff value of 0.32 ng/mL, sensitivity was 0.683, while specificity was 0.886. The combination of calretinin and SMRP had the highest predictive value. Calretinin is a useful biomarker that can distinguish MM from other asbestos-related diseases and could, therefore, contribute to an earlier non-invasive diagnosis of MM.

Significance of secretory leukocyte peptidase inhibitor in pleural fluid for the diagnosis of benign asbestos pleural effusion

Secretory leukocyte peptidase inhibitor (SLPI) is a biomarker present in the respiratory tract that protects against tissue destruction and aids in wound healing. We examined whether SLPI in pleural effusion can be used to distinguish benign asbestos pleural effusion (BAPE) from early-stage malignant pleural mesothelioma (MPM) and other diseases. We measured the levels of SLPI, hyaluronic acid (HA), soluble mesothelin-related peptides (SMRP), CCL2, galectin-3, and CYFRA21-1 in 51 patients with BAPE, 37 patients with early-stage MPM, 77 patients with pleural effusions due to non-small-cell lung cancer (LCa), and 74 patients with other pleural effusions. SLPI levels in the pleural fluid of patients with BAPE were significantly lower than those in patients with MPM, LCa, and other pleural effusions (p < 0.0001). The area under the curve (AUC) for SLPI’s ability to distinguish BAPE from MPM was 0.902, with a sensitivity of 82.4% and a specificity of 86.5%. This AUC was not only favourable but was better than the AUC for the ability of CYFRA21-1 to distinguish BAPE (0.853). The combination of SLPI and CYFRA21-1 achieved an AUC of 0.965 for the differentiation between BAPE and MPM. Pleural fluid SLPI as well as CYFRA21-1 and HA is useful as a biomarker to diagnose BAPE, which needs to be distinguished from early-stage MPM.

Three tumor markers for improved efficacy in the management of patients with malignant pleural mesothelioma.

BackgroundEvaluation of tumor markers may facilitate follow-up of malignant pleural mesothelioma (MPM). We aimed was to evaluate the value of tumor markers for monitoring and predicting recurrence in patients with MPM.MethodsIn total, 152 patients who underwent curative-intent surgery after induction chemotherapy for MPM between July 2004 and December 2017 were retrospectively reviewed. Preoperative and postoperative (≤3 months after surgery) levels of soluble mesothelin-related peptide (SMRP), cytokeratin 19 fragment (Cyfra21-1), and tissue polypeptide antigen (TPA) and rates of recurrence and non-recurrence were evaluated. Factors associated with recurrence-free survival (RFS) were assessed using the Kaplan-Meier method and Cox proportional hazards model.ResultsOf the 152 patients, the positive rates of preoperative SMRP, Cyfra21-1, and TPA, levels were 26.7%, 8.6%, 9.6%, respectively; the respective postoperative levels were 4.0%, 6.3%, and 6.5%; the respective levels in patients with recurrence were 39.3%, 31.4%, 28.6%; the respective levels in patients with no recurrence were 3.7%, 0.0%, 3.8%. Nearly half (45.2%) of the patients with recurrence exhibited an increase in one or more tumor marker levels. Multivariate analysis revealed that the preoperative positive rates of one or more of the three tumor markers (hazard ratio: 1.8, 95% confidence interval: 1.1–2.8; P=0.02) were independent significant predictors of recurrence.ConclusionsThe positive rates of SMRP, Cyfra21-1, and TPA in recurrence-free patients were extremely low, with high specificity. Preoperative levels of SMRP, Cyfra21-1, and TPA, which identified patients with a high risk for recurrence, could improve management of patients with MPM.

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

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

Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901

BackgroundThe role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS). Patients and MethodsEligible patients with unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression, stratified by number of cycles (< 6 or 6), cis- or carboplatin containing regimen, and histology. Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months. ResultsA total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049). ConclusionMaintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.

Evaluation of soluble mesothelin-related peptides and MSLN genetic variability in asbestos-related diseases.

BackgroundAsbestos exposure is associated with increased risk of several diseases, including malignant mesothelioma (MM). Cell surface glycoprotein mesothelin is overexpressed in MM and serum soluble mesothelin-related peptides (SMRP) were already proposed as a diagnostic or prognostic biomarker in MM. However, interindividual variability in serum SMRP levels limits the clinical usefulness. Our primary objective was to investigate the influence of MSLN rs1057147 on serum SMRP levels in asbestos-exposed subjects and patients with asbestos-related diseases as well as on survival in MM.Subjects and methodsAmong 782 asbestos-exposed subjects and patients with asbestos-related diseases, 154 had MM. Serum SMRP levels were determined using sandwich enzyme-linked immunosorbent assay. All subjects were genotyped for MSLN rs1057147 polymorphism using competitive allele-specific polymerase chain reaction. Nonparametric tests, logistic and Cox regression were used in statistical analysis to compare different subject groups.ResultsMM patients had significantly higher SMRP levels than all other subjects (p < 0.001). Compared to wild-type MSLN rs1057147 genotype, both heterozygotes and carriers of two polymorphic alleles had significantly higher SMRP levels among subjects without MM (p < 0.001), but not in MM patients (p = 0.424). If genotype information was included, specificity of SMRP increased from 88.5% to 92.7% for the optimal cutoff value. Overall survival was significantly shorter in MM patients carrying at least one polymorphic rs1057147 allele (HR = 1.72, 95% CI = 1.15-2.55, p = 0.008).ConclusionsMSLN genetic variability affects serum SMRP levels and was associated with shorter survival of MM patients. Combination of genetic and serum factors could therefore serve as a better diagnostic or prognostic biomarker in MM patients.

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

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

Diagnostic value of soluble mesothelin-related peptides in pleural effusion for malignant pleural mesothelioma: An updated meta-analysis.

Background:Soluble mesothelin-related peptide (SMRP) is a widely studied tumor marker for diagnosing malignant pleural mesothelioma (MPM). This study discussed the diagnostic value of SMRPs in pleural effusion (PE) for MPM.Methods:Medline, Embase, Web of Science, and Cochrane library system were systematically searched on the data of SMRPs in PE for MPM diagnosis. Pooled diagnostic sensitivity, specificity, and symmetric receiver operating characteristic curve were calculated.Results:Thirteen studies fulfilled the inclusion criteria and a total of 3359 cases including 759 MPM cases, 1061 non-MM (malignant mesothelioma) malignant PE, and 1539 benign PE were brought into this meta-analysis. The pooled results of SMRPs in PE for diagnosing MPM were as follows: sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.68 (95% confidence interval [CI]: 0.64–0.72), 0.91 (95% CI: 0.86–0.94), 7.8 (95% CI: 5.0–12.0), 0.35 (95% CI: 0.31–0.40), and 22 (95% CI: 14–35), respectively. The area under the summary receiver operating characteristic curves (AUC) was 0.75 (95% CI: 0.72–0.80). Subgroup analyzes revealed that the AUC of cohort group using histological diagnosis could be improved to 0.86 (95% CI: 0.83, 0.89). The Deek's funnel plot asymmetry test showed no publication bias.Conclusion:Although the sensitivity of SMRPs was low, PE-SMRPs can be a good indicator of the existence of MPM.

1809P - Development and validation of a deep learning model using biomarkers in pleural effusion for prediction of malignant pleural mesothelioma

Background: Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related disease that is challenging to diagnose. The value of tumour biomarkers in pleural effusion fluid is limited in patients with the disease. We have developed and validated a deep learning model that can predict a diagnosis of MPM using pleural tumour biomarkers and patient characteristics. Methods: This retrospective cohort study included patients who underwent thoracentesis for undiagnosed pleural effusion at a single tertiary medical centre between September 2014 and August 2016. The diagnosis was established by two independent physicians who were blinded to the pleural effusion data. A deep learning model was constructed to differentiate MPM from other diseases and evaluated using biomarkers in pleural effusion (carcinoembryonic antigen, cytokeratin 19 fragment, soluble mesothelin-related peptides, lactate dehydrogenase), total protein in pleural effusion, and patient age and sex as input parameters. Missing data were handled by single imputation. The model consisted of three hidden layers and was trained for 4000 steps. The data were divided into a training set and a test data set and processed using TensorFlow 1.7.0 and Python 3.6 software. The performance of the model was evaluated by accuracy and the area under the receiver-operating characteristic curve (AUROC). Results: Twenty-eight of the 188 patients who underwent thoracentesis were diagnosed to have MPM and divided into a training data set (containing first 150 records with 20 MPM patients) and a test data set (38 records with 8 MPM patients). The accuracy values for the training and test data sets were 0.99 and 0.97, respectively, and the respective AUROC were 1.00 and 0.92. Conclusions: Our deep neural network model had good diagnostic accuracy for MPM and may help in making a definitive diagnosis when there is an indication for invasive pleural biopsy. Legal entity responsible for the study: Hyogo Prefectural Amagasaki General Medical Center. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Serum mesothelin and other biomarkers: what have we learned in the last decade?

In the last decade there is been much interest in noninvasive, economic and well-accepted diagnostic tests for screening of subjects exposed to asbestos, and in patients with malignant pleuric mesothelioma (MPM) for diagnosis or monitoring response to treatment. Several biomarkers have been suggested as tools for screening and early diagnosis of MPM. Currently, in patients with MPM, have been reported high levels of soluble mesothelin-related peptides (SMRP), plasmatic osteopontin (pOPN), vimentin, fibulin-3 and many others as promising marker for diagnosis, even their use in prevention monitoring is still discussed. In this type of disease, a key role could be played by miRNAs, which expression has been investigated in a large series of MPM to examine new pathways useful in diagnosis, prognosis and therapy. An altered expression of some proteins has been reported, useful as biomarkers, in comparative proteomic analysis of malignant pleural mesothelioma. New promising markers are nowadays under study and alone or better in combination, they'll be very helpful in diagnosing, monitoring mesothelioma patients or for screening of risk groups.