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Background: Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling., Methods: 44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Germline variants were selected according to association with inherited cancer using a 168-gene in silico panel, and variants classified according to ACMG/AMP classification as pathogenic (class 5) or likely pathogenic (class 4)., Results: In total, 16 patients (36%) were found to carry pathogenic or likely pathogenic variants in 13 cancer associated genes (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The germline PVs occurred in DNA repair pathways, including homologous recombination repair (HRR) (75%), nucleotide excision repair (6%), cell cycle regulatory (7%), base excision repair (6%), and hypoxic pathway (6%). Five (31%) patients with a germline PV had a first or second degree relative with mesothelioma compared to none for patients without a germline PV. Previously undiagnosed BRCA2 germline PVs were identified in two patients. Potential actionable targets based on the germline PVs were found in four patients (9%)., Conclusion: This study revealed a high frequency of germline PVs in patients with mesothelioma. Furthermore, we identified germline PVs in two genes (NBN & RAD51B) not previously associated with mesothelioma. The data support germline testing in mesothelioma and provide a rationale for additional investigation of the HRR pathway as a potential actionable target., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background/aim: We recently reported that miR-126 is down-regulated in malignant pleural mesothelioma (MPM) and can be combined into a 4-microRNA-classifier that can accurately diagnose MPM with high sensitivity and specificity. Herein we analyzed the epigenetic regulation of miR-126 and its host gene EGF-like domain, multiple 7 (EGFL7)., Materials and Methods: Resected formalin-fixed paraffin-embedded MPM tissues from 29 patients, 14 patient-matched non-neoplastic pleura (NNP) specimens, 5 MPM diagnostic biopsies (DB), and 5 samples of pneumothorax-induced benign reactive mesothelial proliferation (PTHX) were analyzed. miR-126 and EGFL7 mRNA were quantified by RT-qPCR. CpG-islands' methylation in the EGFL7 promoter was analyzed using methylation-specific PCR and in the MIR126-containing intron 7 was quantified by pyrosequencing., Results: Relative to NNP, EGFL7 was under-expressed more than 4-fold in MPM (p<0.001). EGFL7 mRNA and miR-126 levels correlated in MPM (p<0.01) and NNP (p<0.001). The EGFL7 promoter region was hypermethylated in 69% of MPM and 80% of DB samples, but not in NNP and PTHX samples. EGFL7 promoter hypermethylation was associated with epithelioid histology (p<0.05) and reduced patient-survival (p<0.05)., Conclusion: In MPM, DNA-hypermethylation down-regulates miR-126 and its host gene EGFL7, therefore is a poor prognostic factor, and may represent a future therapeutic target for de-methylating strategies re-establishing EGFL7 and miR-126 expression., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Malignant pleural mesothelioma (MPM) is difficult to distinguish from reactive mesothelial proliferations (RMPs). It is uncertain whether miRNAs are useful biomarkers for differentiating MPM from RMPs. Thus, we screened with a quantitative RT-PCR (RT-qPCR)-based platform the expression of 742 miRNAs in formalin-fixed, paraffin-embedded, preoperative diagnostic biopsy samples, surgically resected MPM specimens previously treated with chemotherapy, and corresponding non-neoplastic pleura (NNP), from five patients. miR-126, miR-143, miR-145, and miR-652 were significantly down-regulated (≥twofold) in resected MPM and/or chemotherapy-naïve diagnostic tumor biopsy samples. The miRNA expression pattern was validated by RT-qPCR in a cohort of 40 independent MPMs. By performing binary logistic regression on the RT-qPCR data for the four miRNAs, the established four-miRNA classifier differentiated MPM from NNP with high sensitivity and specificity (area under the curve, 0.96; 95% CI, 0.92-1.00). The classifier's optimal logit(P) value of 0.62 separated NNP and MPM samples with a sensitivity of 0.95 (95% CI, 0.89-1.00), a specificity of 0.93 (95% CI, 0.87-0.99), and an overall accuracy of 0.94 (95% CI, 0.88-1.00). The level of miR-126 in MPM was inversely correlated with that of the known target, the large neutral amino acid transporter, small subunit 1 (r = -0.38; 95% CI, -0.63 to -0.06). Overall, these results indicate that these four miRNAs may be suitable biomarkers for distinguishing MPM from RMPs., (Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The combination of chemotherapy, surgery, and radiotherapy has improved the prognosis for patients with malignant pleural mesothelioma (MPM). Intensity-modulated radiotherapy (IMRT) has allowed for an increase in dose to the pleural cavity and a reduction in radiation doses to organs at risk. The present study reports and analyses the incidence of fatal pulmonary toxicity in patients treated at Rigshospitalet, Copenhagen., Materials and Methods: Twenty-six patients were treated with induction chemotherapy followed by extrapleural pneumonectomy and IMRT between April 2003 and April 2006. The entire preoperative pleural surface area was treated to 50 Gy and areas with residual disease or close surgical margins were treated to 60 Gy in 30 fractions., Results: The main toxicities were nausea, vomiting, esophagitis, dyspnea, and thrombocytopenia. One patient died from an intracranial hemorrhage during severe thrombocytopenia. Four patients (15%) experienced grade 5 lung toxicity, i.e. pneumonitis 19-40 days after the completion of radiotherapy. Patients with pneumonitis had a significantly larger lung volume fraction receiving 10 Gy or more (V10) (median: 60.3%, range 56.4-83.2%) compared to patients without pneumonitis (median: 52.6%, range: 25.6-80.3%) (p=0.02). Mean lung dose (MLD) was also significantly higher in patients who developed pneumonitis (median 13.9 Gy, range: 13.6-14.2 Gy) than in patients who did not (median=12.4 Gy, range: 8.4-15.4 Gy) (p=0.04)., Conclusions: Significant differences in MLD and V10 for patients with fatal pulmonary toxicity compared to patients without fatal lung toxicity have been demonstrated. Based on the presented data local lung dose constraints have been modified in order to avoid unacceptable toxicity.

Objectives: Extrapleural pneumonectomy (EPP) in MPM may be confined with both morbidity and mortality and careful preoperative staging identifying resectable patients is important. Staging is difficult and the accuracy of preoperative CT scan, 18F-FDG PET/CT scan (PET/CT), and mediastinoscopy is unclear. The objectives were to compare these staging techniques to each other and to surgical-pathological findings., Methods: Patients had epithelial subtype MPM, age

Background: Despite extensive research, the debate continues as to the optimal way of guiding intraoperative and postoperative fluid therapy. In 2009 we changed our institutional guideline for perioperative fluid therapy in patients undergoing extrapleural pneumonectomy (EPP) and implemented the use of central venous oxygen saturation and intended low urine output to guide therapy in the early postoperative period. Here we evaluate the consequences of our changes. Methods: Retrospective, observational study of 30 consecutive patients undergoing EPP; 18 who had surgery before and 12 who had surgery after the changes. Data were collected from patient files and from institutional databases. Outcome measures included: Volumes of administered fluids, fluid balances, length of stays and postoperative complications. Dichotomous variables were compared with Fisher's exact test, whereas continuous variables were compared with Student's unpaired t-test or the Wilcoxon Two-Sample Test depending on the distribution of data. Results: The applied changes significantly reduced the volumes of administered fluids, both in the intraoperative (p = 0.01) and the postoperative period (p = 0.04), without increasing the incidence of postoperative complications. Mean length of stay in the intensive care unit (LOSI) was reduced from three to one day (p = 0.04) after the changes. Conclusion: The use of clinical parameters to balance fluid restriction and a sufficient circulation in patients undergoing EPP was associated with a reduction in mean LOSI without increasing the incidence of postoperative complications. Due to methodological limitations these results are only hypothesis generating. [ABSTRACT FROM AUTHOR]

Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated. [ABSTRACT FROM AUTHOR]

The article presents a study that quantified and compared the expression of miR-17-5p, -30c, -221 and -222 in formalin-fixed paraffin-embedded (FFPE) epithelioid malignant pleural mesothelioma (MPM) and NP tissue-samples collected from 13 patients. The researchers wanted to test whether the microRNA may be useful in differentiating MPM from reactive mesothelial proliferations (RMP) in vivo. They found that chemotherapy did not affect the expression of the microRNA.