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Background Malignant pleural mesothelioma (MPM) is a rare disease with a relatively short overall survival (OS). Metalloproteinases (MMPs) have a vast biological effect on tumor progression, invasion, metastasis formation, and apoptosis. MMP expression was previously associated with survival in MPM. Our aim was to evaluate if genetic variability of MMP genes could also serve as a prognostic biomarker in MPM. Methods We genotyped 199 MPM patients for ten polymorphisms: rs243865, rs243849 and rs7201, in MMP2; rs17576, rs17577, rs20544, and rs2250889 in MMP9; and rs1042703, rs1042704, and rs743257 in MMP14. We determined the influence on survival using Cox regression. Results Carriers of polymorphic MMP9 rs2250889 allele had shorter time to progression (TTP) (6.07 versus 10.03 months, HR = 2.45, 95% CI = 1.45–4.14, p = 0.001) and OS (9.23 versus 19.2 months, HR = 2.39, 95% CI = 1.37–4.18, p = 0.002). In contrast, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP (10.93 versus 9.40 months, HR = 0.57, 95% CI = 0.38–0.86 p = 0.007) and OS (20.67 versus 13.50 months, HR = 0.56, 95% CI = 0.37–0.85, p = 0.007). MMP14 rs1042703 was associated with nominally shorter TTP (8.7 versus 9.27 months, HR = 2.09, 95% CI = 1.06–4.12, p = 0.032). Conclusions Selected MMP SNPs were associated with survival and could be used as potential genetic biomarkers in MPM.

Mesothelioma is a rare tumor, frequently associated with asbestos exposure, arising from pleura and peritoneum. Traditionally, diagnosis and treatment have been difficult in a clinical setting. The treatment is based on a trimodal approach involving surgery, chemotherapy, and radiotherapy. The introduction of chemotherapy improved the overall survival. However, the regimen of pemetrexed/cisplatin doublet has not been changed as a standard treatment since 2004. Novel combinations of ipilimumab and nivolumab have only been approved for clinical use in late 2020. The aim of this review was to systematically summarize findings on novel treatment options in mesothelioma. We searched available medical databases online, such as PubMed and Clinicaltrials.gov, to systematically review the literature on novel approaches in immunotherapy, vaccines, and Chimeric Antigen Receptor (CAR)-T cell therapy in mesothelioma. We manually screened 1127 articles on PubMed and 450 trials on ClinicalTrials.gov, and 24 papers and 12 clinical trials published in the last ten years were included in this review. Immunotherapy that was swiftly introduced to treat other thoracic malignancies was slow to reach desirable survival endpoints in mesothelioma, possibly due to limited patient numbers. Novel treatment approaches, such as CAR-T cell therapy, are being investigated. As the incidence of mesothelioma is still rising globally, novel treatment options based on a better understanding of the tumor microenvironment and the genetic drivers that modulate it are needed to support future precision-based therapies.

PD-L1 expression of 5%. All six patients had subjective clinical response with improved PS. Two patients had G2 fatigue, one patient had G1 depression. Five patients are still on treatment.Conclusion: Nivolumab is a safe and effective treatment option for advanced MPM patients with poor PS. Although tumor PD-L1 overexpression is related to treatment response, subjective clinical response is observed in advanced MPM patients regardless of tumor PD-L1 status. Our experience of nivolumab in advanced MPM patients with poor PS outside of clinical trials provides additional data to ongoing clinical trials.

BackgroundMalignant mesothelioma (MM) is a rare disease, linked to asbestos exposure in more than 80% of the cases. Matrix metalloproteinases (MMPs) have been identified as modulators of the tumour microenvironment and carcinogenesis. Polymorphisms of selected MMPs have been studied as potential biomarkers of time to progression (TTP) and overall survival (OS) in MM. The aim of our study was to investigate selected MMP polymorphisms as baseline risk predictors in MM development in combination with other well known risk factors, such as asbestos exposure.Patients and methodsThe study included 236 patients and 161 healthy blood donors as the control group. Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In statistical analyses continuous variables were described using median and range (25%–75%), while frequencies were used to describe categorical variables. Deviation from the Hardy-Weinberg equilibrium (HWE) was assessed using the standard chi-square test. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs).ResultsCarriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44–1.00; P = 0.050). The association was more pronounced in patients with known asbestos exposure: carriers of at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35–0.86; P = 0.009). None of the other tested polymorphisms showed association with the risk of malignant pleural mesothelioma.ConclusionsThe MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development. This finding is even more evident in patients exposed to asbestos, implying a strong gene-environment interaction.

Background. Malignant mesothelioma (MM) is a rare, but fatal disease with few treatment options. The diagnosis and treatment response are challenging in MM. Therefore, the search for novel diagnostic and prognostic biomarkers is ongoing. The aim of our study was to investigate matrix metalloproteinase 9 (MMP9) as a potential serum biomarker of treatment response and survival in MM. We also investigated the influence of genetic polymorphisms on MMP9 serum levels. Methods. We included 110 patients with MM that have been previously genotyped for common MMP9 polymorphisms. Serum samples were collected before treatment, at the end of chemotherapy, and at the time of progression. MMP9 serum levels were measured using enzyme-linked immunosorbent assay kits. The role of serum MMP9 and MMP9 polymorphisms in treatment response was determined using the nonparametric tests and logistic or Cox regression. Results. Median serum MMP9 was 706.7 (499.6-1224.9) ng/ml before treatment, 440.5 (255.9-685.2) ng/ml after chemotherapy, and 502.8 (307.2-851.4) ng/ml at disease progression. After chemotherapy, 87 (79.8%) patients had lower serum MMP9, with the median change of -286.3 (-607.3 to -70.2) ng/ml (P<0.001). At disease progression, 47 (65.3%) patients had lower serum MMP9 compared to pretreatment values, with the median change of -163.7 (-466.6 to 108.6) ng/ml (P=0.001). Patients with higher performance status had higher serum MMP9 before treatment (P=0.010). Among investigated polymorphisms, only rs17576 was associated with serum MMP9 levels before treatment (P=0.041). Conclusion. Median serum MMP9 levels differed significantly before and after treatment of MM, but failed to reach significance as a standalone biomarker. The contribution of MMP9 serum levels and MMP9 polymorphisms to a composite diagnostic and prognostic biomarker should be further tested.

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.

Patients and methods. The study included 236 patients and 161 healthy blood donors as the control group. Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In statistical analyses continuous variables were described using median and range (25%-75%), while frequencies were used to describe categorical variables. Deviation from the Hardy-Weinberg equilibrium (HWE) was assessed using the standard chi-square test. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs).Results. Carriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44-1.00; P = 0.050). The association was more pronounced in patients with known asbestos exposure: carriers of at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35-0.86; P = 0.009).None of the other tested polymorphisms showed association with the risk of malignant pleural mesothelioma.Conclusions. The MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development. This finding is even more evident in patients exposed to asbestos, implying a strong gene-environment interaction.