Combination of calretinin, MALAT1, and GAS5 as a potential prognostic biomarker to predict disease progression in surgically treated mesothelioma patients.

BACKGROUND: The role of cytoreductive surgery for epithelioid pleural mesothelioma within a multimodal treatment approach remains controversial. Carefully selected patients benefit from cytoreductive surgery and adjuvant chemotherapy, but there is no established biomarker to predict tumor recurrence or progression during the course of the disease. The aim of this study was to identify potential biomarkers to predict therapeutic response in terms of progression-free survival. METHODS: Between 03/2014 and 08/2022, preoperative blood samples were collected from 76 patients with epithelioid pleural mesothelioma who underwent cytoreductive surgery as part of a multimodal treatment approach. Identification of potential biomarkers was performed by determination of mesothelin and calretinin, as well as specific long non-coding RNAs and microRNAs. Receiver operating characteristic analysis, Kaplan-Meier survival analysis, and Cox regression were used to assess the association between biomarker concentrations and patient recurrence status and survival. RESULTS: MALAT1, GAS5, and calretinin showed statistically significant increased biomarker levels in patients with recurrence in contrast to recurrence-free patients after surgical treatment (p < 0.0001, p = 0.0190, and p = 0.0068, respectively). The combination of the three biomarkers resulted in a sensitivity of 68 % and a specificity of 89 %. CONCLUSION: MALAT1, GAS5, and calretinin could be potential biomarkers for the prediction of tumor recurrence, improving the benefit from multimodal treatment including cytoreductive surgery.

Club cell protein (CC16) in serum as an effect marker for small airway epithelial damage caused by diesel exhaust and blasting fumes in potash mining.

OBJECTIVE: The effect marker club cell protein (CC16) is secreted by the epithelium of the small respiratory tract into its lumen and passes into the blood. Increased amounts of CC16 in serum are observed during acute epithelial lung injury due to air pollutants. CC16 in serum was determined as part of this cross-sectional study in underground potash miners on acute and chronic health effects from exposures to diesel exhaust and blasting fumes. METHODS: Nitrogen oxides, carbon monoxide, and diesel particulate matter were measured in 672 workers at a German potash mining site on a person-by-person basis over an early shift or midday shift, together with CC16 serum concentrations before and after the respective shift. CC16 concentrations and CC16 shift-differences were evaluated with respect to personal exposure measurements and other quantitative variables by Spearman rank correlation coefficients. CC16 shift-differences were modeled using multiple linear regression. Above-ground workers as reference group were compared to the exposed underground workers. RESULTS: Serum concentrations of CC16 were influenced by personal characteristics such as age, smoking status, and renal function. Moreover, they showed a circadian rhythm. While no statistically significant effects of work-related exposure on CC16 concentrations were seen in never smokers, such effects were evident in current smokers. CONCLUSION: The small airways of current smokers appeared to be vulnerable to the combination of measured work-related exposures and individual exposure to smoking. Therefore, as health protection of smokers exposed to diesel exhaust and blasting fumes, smoking cessation is strongly recommended.

Tasks and Experiences of the Prospective, Longitudinal, Multicenter MoMar (Molecular Markers) Study for the Early Detection of Mesothelioma in Individuals Formerly Exposed to Asbestos Using Liquid Biopsies.

Mesothelioma is an aggressive cancer, strongly associated with prior exposure to asbestos. Commonly, tumors are detected at late stages of the disease. Detection at early stages might be meaningful, because therapies might be more effective when the tumor burden is relatively low and the tumor has not spread to distant sites. Circulating biomarkers in blood might be a promising tool to improve the early detection of mesothelioma, but for screening in asymptomatic subjects, candidate biomarkers need to be validated in appropriate studies. This study was conducted to assess the performance of biomarkers in liquid biopsies to detect mesothelioma at early stages. Over a period of 10 years, 2769 volunteers formerly exposed to asbestos were annually examined and liquid biopsies were collected. A follow-up was completed 17 months after the last blood collection. The article provides a detailed overview of our lessons learned and experiences of conducting a prospective, longitudinal, multicenter study. The existing cohort of individuals at risk is highly suitable for the validation of blood-based biomarkers for the early detection of mesothelioma as well as lung cancer.

Impact of diesel exhaust exposure on urinary 1-hydroxypyrene in underground salt and potash workers.

BACKGROUND: Diesel engine exhaust (DEE) and some of the polycyclic aromatic hydrocarbons (PAH) it contains are carcinogenic to humans (for example benzo(a)pyrene) and can cause lung cancer in workers. The objective of this study was to assess exposures to DEE and its component PAH and the potential associations between these two health hazards in a salt and potash mining population. METHODS: Between 2017 and 2019, 1003 underground workers (mining n = 801, maintenance n = 202) and 243 above-ground facility workers from two German mines participated. Personal exposure to DEE was assessed in air as elemental carbon for diesel particulate matter (EC-DPM), whereas exposure to PAH was assessed in pre- and post-shift urine samples in terms of 1-hydroxypyrene (1-OHP). Associations between EC-DPM and 1-OHP were studied using linear regression models. RESULTS: The highest EC-DPM exposures were measured in mining workers (median 0.06 mg/m³) followed by workers in the maintenance (0.03 mg/m3) and facility areas (<0.02 mg/m3). Exposures above the current German occupational threshold level of 0.05 mg/m3 were observed in 56%, 17%, and 5% of mining, maintenance and facility workers, respectively. 1-OHP increased statistically significantly across a work shift in underground workers but not in facility workers. Regression analyses revealed an increase of post-shift 1-OHP by almost 80% in mining and 40% in maintenance compared with facility workers. 1-OHP increased with increasing EC-DPM among underground workers. However, internal exposure of 1-OHP mainly remained at levels similar to those of the German general population in more than 90% of the urine samples. CONCLUSIONS: While exposures to DEE above the current German OEL for EC-DPM are quite common in the studied population of underground salt and potash miners (39.5% overall), urinary concentrations of 1-OHP did not reflect these findings.

Mesothelin Gene Variants Affect Soluble Mesothelin-Related Protein Levels in the Plasma of Asbestos-Exposed Males and Mesothelioma Patients from Germany.

Malignant mesothelioma (MM) is a severe disease mostly caused by asbestos exposure. Today, one of the best available biomarkers is the soluble mesothelin-related protein (SMRP), also known as mesothelin. Recent studies have shown that mesothelin levels are influenced by individual genetic variability. This study aimed to investigate the influence of three mesothelin (MSLN) gene variants (SNPs) in the 5'-untranslated promoter region (5'-UTR), MSLN rs2235503 C > A, rs3764246 A > G, rs3764247 A > C, and one (rs1057147 G > A) in the 3'-untranslated region (3'-UTR) of the MSLN gene on plasma concentrations of mesothelin in 410 asbestos-exposed males without cancer and 43 males with prediagnostic MM (i.e., with MM diagnosed later on) from the prospective MoMar study, as well as 59 males with manifest MM from Germany. The mesothelin concentration differed significantly between the different groups (p < 0.0001), but not between the prediagnostic and manifest MM groups (p = 0.502). Five to eight mutations of the four SNP variants studied were associated with increased mesothelin concentrations (p = 0.001). The highest mesothelin concentrations were observed for homozygous variants of the three promotor SNPs in the 5'-UTR (p < 0.001), and the highest odds ratio for an elevated mesothelin concentration was observed for MSLN rs2235503 C > A. The four studied SNPs had a clear influence on the mesothelin concentration in plasma. Hence, the analysis of these SNPs may help to elucidate the diagnostic background of patients displaying increased mesothelin levels and might help to reduce false-positive results when using mesothelin for MM screening in high-risk groups.

Assessment of miR-103a-3p in leukocytes-No diagnostic benefit in combination with the blood-based biomarkers mesothelin and calretinin for malignant pleural mesothelioma diagnosis.

Malignant pleural mesothelioma (MPM) is a cancer associated with asbestos exposure and its diagnosis is challenging due to the moderate sensitivities of the available methods. In this regard, miR-103a-3p was considered to increase the sensitivity of established biomarkers to detect MPM. Its behavior and diagnostic value in the Mexican population has not been previously evaluated. In 108 confirmed MPM cases and 218 controls, almost all formerly exposed to asbestos, we quantified miR-103-3a-3p levels in leukocytes using quantitative Real-Time PCR, together with mesothelin and calretinin measured in plasma by ELISA. Sensitivity and specificity of miR-103-3a-3p alone and in combination with mesothelin and calretinin were determined. Bivariate analysis was performed using Mann-Whitney U test and Spearman correlation. Non-conditional logistic regression models were used to calculate the area under curve (AUC), sensitivity, and specificity for the combination of biomarkers. Mesothelin and calretinin levels were higher among cases, remaining as well among males and participants ≤60 years old (only mesothelin). Significant differences for miR-103a-3p were observed between male cases and controls, whereas significant differences between cases and controls for mesothelin and calretinin were observed in men and women. At 95.5% specificity the individual sensitivity of miR-103a-3p was 4.4% in men, whereas the sensitivity of mesothelin and calretinin was 72.2% and 80.9%, respectively. Positive correlations for miR-103a-3p were observed with age, environmental asbestos exposure, years with diabetes mellitus, and glucose levels, while negative correlations were observed with years of occupational asbestos exposure, creatinine, erythrocytes, direct bilirubin, and leukocytes. The addition of miR-103a-3p to mesothelin and calretinin did not increase the diagnostic performance for MPM diagnosis. However, miR-103a-3p levels were correlated with several characteristics in the Mexican population.

Lung cancer and mesothelioma risks in a prospective cohort of workers with asbestos-related lung or pleural diseases.

BACKGROUND: Asbestos causes mesothelioma and lung cancer. In the European Union, asbestos was banned in 2005, but it is still in use in many other countries. The aim of this study was to estimate the lung cancer and mesothelioma incidence risk of men with benign asbestos-related lung or pleural diseases. METHODS: Between 2008 and 2018, 2439 male participants of a German surveillance program for asbestos workers were included in the cohort. All participants had a recognized occupational asbestos-related disease of the pleura or lung. We estimated the mesothelioma and lung cancer risks by calculating standardized incidence ratios (SIR) with corresponding 95% confidence intervals (95% CI). RESULTS: We observed 64 incident lung cancer and 40 mesothelioma cases in the cohort. An SIR of 17.60 (95% CI: 12.57-23.96) was estimated for mesothelioma and 1.27 (95% CI: 0.98-1.62) for lung cancer. The presence of pleural plaques was associated with a strongly increased risk (SIR: 13.14; 95% CI: 8.51-19.40) for mesothelioma, but not for lung cancer (SIR: 1.05; 95% CI: 0.76-1.41). The highest lung-cancer risk (SIR: 2.56; 95% CI 1.10-5.04) was revealed for cohort members with less than 40 years since first asbestos exposure. Lung cancer risks by duration of asbestos exposure did not show a consistent time trend, but for time since last exposure a trend for mesothelioma was seen. CONCLUSIONS: Compared to the general population, we demonstrated an association between benign asbestos-related lung or pleural disease and mesothelioma risk in workers with a history of occupational asbestos exposure. Because lung-cancer risk is dominated by smoking habits, a possible effect of asbestos exposure may have been masked. Efforts should be made to ban production and use of asbestos worldwide and to establish safe handling rules of legacy asbestos.

Exploring solid-phase proximity ligation assay for survivin detection in urine.

Urine-based biomarkers are a rational and promising approach for the detection of bladder cancer due to the proximity of urine to the location of the tumor site and the non-invasive nature of its sampling. A well-known and highly investigated biomarker for bladder cancer is survivin. For detection of very small amounts of urinary survivin protein a highly sensitive assay was developed. The assay is based on the immuno-PCR technology, more precisely a solid-phase proximity ligation assay (spPLA). The limit of detection for the survivin spPLA was 1.45 pg/mL, resulting in an improvement of the limit of detection by a factor of approximately 23 compared to the previously in-house developed survivin ELISA. A key step in development was the initial isolation of survivin by a molecular fishing rod based on magnetic beads. Interfering matrix compounds pose a special challenge for further analytical application, but can be overcome by this isolation step. The assay is designed to work with only 500 µL of voided urine. The survivin spPLA showed a sensitivity of 30% and specificity of 89% for bladder cancer detection in this study of 110 bladder cancer cases and 133 clinical controls. Moreover, the results demonstrated again that survivin is a useful complementary marker in combination with UBC® Rapid by increasing the overall sensitivity to 70% with a specificity of 86%. Although the performance for detection of bladder cancer was rather low, the herein developed assay might serve as a new tool for survivin biomarker research in diverse human fluids, even if the biological matrix is complex or survivin is only present in small amounts.

Blood-based detection of lung cancer using cysteine-rich angiogenic inducer 61 (CYR61) as a circulating protein biomarker: a pilot study.

Lung cancer is the most often diagnosed cancer and the main cause of cancer deaths in the world compared with other tumor entities. To date, the only screening method for high-risk lung cancer patients is low-dosed computed tomography which still suffers from high false-positive rates and overdiagnosis. Therefore, there is an obvious need to identify biomarkers for the detection of lung cancer that could be used to guide the use of low-dosed computed tomography or other imaging procedures. We aimed to assess the performance of the protein cysteine-rich angiogenic inducer 61 (CYR61) as a circulating biomarker for the detection of lung cancer. CYR61 concentrations in plasma were significantly elevated in 87 lung cancer patients (13.7 ± 18.6 ng·mL-1 ) compared with 150 healthy controls (0.29 ± 0.22 ng·mL-1 ). Subset analysis stratified by sex revealed increased CYR61 concentrations for adenocarcinoma and squamous cell carcinoma in men compared with women. For male lung cancer patients versus male healthy controls, the sensitivity was 84% at a specificity of 100%, whereas for females, the sensitivity was 27% at a specificity of 99%. The determination of circulating CYR61 protein in plasma might improve the detection of lung cancer in men. The findings of this pilot study support further verification of CYR61 as a biomarker for lung cancer detection in men. Additionally, CYR61 is significantly elevated in women but sensitivity and specificity for CYR61 are too low for the improvement of the detection of lung cancer in women.

Application of two job indices for general occupational demands in a pooled analysis of case-control studies on lung cancer.

OBJECTIVES: We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer. METHODS: In 13 case-control studies on lung cancer, as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands - each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman's Standard International Occupational Prestige Scale) were affected by adjustment for the job indices. RESULTS: In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men [PHI 1.74 (95% CI 1.56-1.93), PSI 1.33 (95% CI 1.17-1.51)] and women [PHI 1.62 (95% CI 1.24-2.11), PSI 1.31 (95% CI 1.09-1.56)]. OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI [low versus high prestige OR from 1.44 (95% CI 1.32-1.58) to 1.30 (95% CI 1.17-1.45)], but not PSI. CONCLUSIONS: Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer.

Re-evaluation of potential predictors of calretinin and mesothelin in a population-based cohort study using assays for the routine application in clinical medicine.

OBJECTIVES: Calretinin and mesothelin are molecular markers for the detection of malignant mesothelioma at early stages. Our objective was the re-evaluation of factors influencing calretinin and mesothelin concentrations in plasma of cancer-free men in order to minimise false-positive tests when using commercial assays approved for clinical diagnostics. SETTING: This re-evaluation used data and archived blood samples of the population-based Heinz Nixdorf Recall Study (HNRS) collected from 2011 to 2014. PARTICIPANTS: The present analysis comprised of 569 cancer-free men at the time of blood sampling (median age 70 years) from HNRS. PRIMARY AND SECONDARY OUTCOMES: Mesothelin plasma concentration was determined using ELISA and CLEIA (chemiluminescent enzyme immunoassay). Calretinin plasma concentration was assessed using ELISA. RESULTS: Compared with the previous determination of concentrations, we detected less false-positive tests using the commercial assays. In this analysis, we found nine false-positive calretinin tests using the ELISA (specificity 98.4%, 95% CI 97.0% to 99.2%) and 24 false-positive mesothelin tests using both ELISA and CLEIA (specificity 95.8%, 95% CI 93.8% to 97.2%). We confirmed renal dysfunction as major predictor of elevated marker concentrations. Mesothelin was additionally affected by bronchitis. Furthermore, elevated inflammation values and hypertension only affected the mesothelin concentration determined by ELISA. CONCLUSIONS: The newly available assays of calretinin and mesothelin approved for clinical diagnostics showed high specificities in the population-based cohort of elderly men without a malignant disease. The current evaluation provides a basis to consider influencing factors in order to further improve the diagnostic procedure.

Sensitive Blood-Based Detection of Asbestos-Associated Diseases Using Cysteine-Rich Angiogenic Inducer 61 as Circulating Protein Biomarker.

BACKGROUND: Detection of asbestos-associated diseases like asbestosis or mesothelioma is still challenging. We sought to improve the diagnosis of benign asbestos-associated disease (BAAD) by detection of the protein cysteine-rich angiogenic inducer 61 (Cyr61) in human plasma. METHODS: Plasma Cyr61 was quantified using an enzyme-linked immunosorbent assay. Plasma samples from males diagnosed with BAAD, but without a malignant disease (n = 101), and malignant mesothelioma (n = 21; 15 males, 6 females), as well as nonasbestos-exposed healthy control participants (n = 150; 58 males, 92 females) were analyzed. Clinical sensitivity and specificity of Cyr61 were determined by receiver operating characteristic analysis. RESULTS: The median plasma Cyr61 concentration for healthy control participants was 0.27 ng/mL. Cytoplasmic Cyr61 in peripheral blood mononuclear cells from healthy control participants was evenly distributed, as detected by immunofluorescent staining. The increase in plasma Cyr61 concentrations in the BAAD study group was statistically significant compared to the healthy control participants (P < 0.0001). For the detection of BAAD vs male healthy control participants, clinical sensitivity was 88% and clinical specificity 95% with an area under the curve of 0.924 at maximal Youden Index. For a predefined clinical specificity of 100%, the clinical sensitivity was 76%. For male mesothelioma patients vs male healthy control participants, the clinical sensitivity at maximal Youden Index was 95% with a clinical specificity of 100% (area under the curve, 0.997) and for a predefined clinical specificity of 100%, the clinical sensitivity was 93%. CONCLUSIONS: In our study, plasma Cyr61 protein concentrations showed to be a new biomarker for asbestos-associated diseases like BAAD and mesothelioma in men, which deserves further investigation in large-scale cohort studies.

Digital PCR for the Analysis of MYC Copy Number Variation in Lung Cancer.

BACKGROUND: MYC (v-myc avian myelocytomatosis viral oncogene homolog) is one of the most frequently amplified genes in lung tumors. For the analysis of gene copy number variations, dPCR (digital PCR) is an appropriate tool. The aim of our study was the assessment of dPCR for the detection of MYC copy number variations (CNV) in lung tissue considering clinicopathological parameters. Material and Methods. MYC status was analyzed with dPCR as well as qPCR (quantitative PCR) using gDNA (genomic DNA) from tumor and adjacent nontumor tissue samples of lung cancer patients. The performance of MYC was estimated based on the AUC (area under curve). RESULTS: The results of the MYC amplification correlated significantly between dPCR and qPCR (r S = 0.81, P < 0.0001). The MYC copy number revealed by dPCR showed statistically significant differences between tumor and adjacent nontumor tissues. For discrimination, a sensitivity of 43% and a specificity of 99% were calculated, representing 55 true-positive and one false-positive tests. No statistically significant differences could be observed for age, sex, and smoking status or the clinicopathological parameters (histological subtype, grade, and stage). CONCLUSION: The results of the study show that dPCR is an accurate and reliable method for the determination of MYC copy numbers. The application is characterized by high specificity and moderate sensitivity. MYC amplification is a common event in lung cancer patients, and it is indicated that the determination of the MYC status might be useful in clinical diagnostics.

Exposure to welding fumes suppresses the activity of T-helper cells.

Welders have an increased susceptibility to airway infections with non-typeable Haemophilus influenzae (NTHi), which implicates immune defects and might promote pneumonia and chronic obstructive pulmonary disease (COPD). We hypothesized that welding-fume exposure suppresses Th1-lymphocyte activity. Non-effector CD4+ T-cells from blood of 45 welders (n = 23 gas metal arc welders, GMAW; n = 16 tungsten inert gas welders, TIG; n = 6 others) and 25 non-welders were ex vivo activated towards Th1 via polyclonal T-cell receptor stimulation and IL-12 (first activation step) and then stimulated with NTHi extract or lipopolysaccharide (LPS) (second activation step). IFNγ and IL-2 were measured by ELISA. In the first activation step, IFNγ was reduced in welders compared to non-welders and in the GMAW welders with higher concentrations of respirable particles compared to the lower exposed TIG welders. IFNγ was not influenced by tobacco smoking and correlated negatively with welding-fume exposure, respirable manganese, and iron. In the second activation step, NTHi and LPS induced additional IFNγ, which was reduced in current smokers compared to never smokers in welders as well as in non-welders. Analyzing both activation steps together, IFNγ production was lowest in smoking welders and highest in never smoking non-welders. IL-2 was not associated with any of these parameters. Welding-fume exposure might suppress Th1-based immune responses due to effects of particulate matter, which mainly consists of iron and manganese. For responses to NTHi this is strongest in smoking welders because welding fume suppresses T-cell activation towards Th1 and cigarette smoke suppresses the subsequent Th1-response to NTHi via LPS. Both effects are independent from IL-2-regulated T-cell proliferation. This might explain the increased susceptibility to infections and might promote COPD development.

Circulating long non-coding RNA GAS5 (growth arrest-specific transcript 5) as a complement marker for the detection of malignant mesothelioma using liquid biopsies.

BACKGROUND: For the detection of malignant mesothelioma additional markers are needed besides the established panel consisting of calretinin and mesothelin. The aim of this study was the identification and verification of long non-coding RNAs (lncRNAs) as complementing circulating markers. METHODS: Candidate lncRNAs were identified in silico using previously published RNA expression profiles and verified using quantitative PCR (qPCR) in mesothelioma cell lines as well as human plasma samples from mesothelioma patients and asbestos-exposed controls. RESULTS: GAS5 (growth arrest-specific transcript 5) as a single marker is marked by a low sensitivity of 14%, but the combination of GAS5 with calretinin and mesothelin increased the panel's sensitivity from 64 to 73% at a predefined specificity of 97%. Circulating GAS5 is not affected by pleurectomy before blood collection, age, or smoking status. CONCLUSIONS: GAS5 is verified as an appropriate circulating marker for the supplement of calretinin and mesothelin to detect malignant mesothelioma. Although the sensitivity of GAS5 is too low for the use as a single marker, the addition of GAS5 as a third marker improves the performance of the established marker panel. The benefit of GAS5 for the detection of malignant mesothelioma at early stages needs to be validated in a prospective study.

Cancer risks of firefighters: a systematic review and meta-analysis of secular trends and region-specific differences.

PURPOSE: The objective of this study was to conduct a systematic review and meta-analysis to evaluate the cancer risks among firefighters in the time course and from different geographical areas. METHOD: A PubMed search was performed to identify cohort studies about cancer risk and firefighting presented with standardized incidence ratios (SIRs) or standardized mortality ratios (SMRs). Using random-effect models, meta-relative risk estimates (mSIRs, mSMRs) and 95% confidence intervals (CI) were assessed. Cohort studies with employment starting before 1950 were classified as "old", studies starting between 1950 and 1970 as "medium", and later studies as "new". RESULTS: The general cancer risk of firefighters was similar to the general population, but mSMR decreased over time (new studies: mSMR = 0.81, 95% CI 0.70-0.92). We observed an increase of mSIR for melanoma of the skin and prostate cancer as well as a decrease of mSIR for stomach cancer with later employment onset. For those cancer sites, we did not observe a secular trend of mSMRs. Regional differences between relative cancer risks were particularly observed for bladder cancer. CONCLUSIONS: Among other things, innovative firefighting techniques and better personal protective equipment have provided a safer and healthier working environment for firefighters over time leading to a reduction of overall cancer incidence and mortality ratios. Increased general preventive medical checkups and possible additional screenings for firefighters might have led to more findings of malignant melanoma of the skin and prostate cancer in the recent past.

Mesothelin, Calretinin, and Megakaryocyte Potentiating Factor as Biomarkers of Malignant Pleural Mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) is a highly lethal cancer caused by exposure to asbestos. Currently, the diagnosis is a challenge, carried out by means of invasive methods of limited sensitivity. This is a case-control study to evaluate the individual and combined performance of minimally invasive biomarkers for the diagnosis of MPM. METHOD: A study of 166 incident cases of MPM and 378 population controls of Mestizo-Mexican ethnicity was conducted. Mesothelin, calretinin, and megakaryocyte potentiating factor (MPF) were quantified in plasma by ELISA. The samples were collected from 2011 to 2016. RESULTS: Based on ROC analysis and a preset specificity of 95%, the combination of the three biomarkers reached an AUC of 0.944 and a sensitivity of 82% in men. In women, an AUC of 0.937 and a sensitivity of 87% were reached. In nonconditional logistic regression models, the adjusted ORs in men were 7.92 (95% CI 3.02-20.78) for mesothelin, 20.44 (95% CI 8.90-46.94) for calretinin, and 4.37 (95% CI 1.60-11.94) for MPF. The ORs for women were 28.89 (95% CI 7.32-113.99), 17.89 (95% CI 3.93-81.49), and 2.77 (95% CI 0.47-16.21), respectively. CONCLUSIONS: To our knowledge, this is the first study evaluating a combination of mesothelin, calretinin, and MPF, and demonstrating a sex effect for calretinin. The biomarker panel showed a good performance in a Mestizo-Mexican population, with high sensitivity and specificity for the diagnosis of MPM.