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Molecular Carcinogenesis Dec 2023Malignant pleural mesothelioma (MPM), mainly caused by asbestos exposure, has a poor prognosis and lacks effective treatment compared with other cancer types. The...
Malignant pleural mesothelioma (MPM), mainly caused by asbestos exposure, has a poor prognosis and lacks effective treatment compared with other cancer types. The intracellular transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed and hyperactivated in most human cancers. In this study, the role of STAT3 in murine MPM was examined. Inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway with the selective inhibitor JSI-124 has an antitumor effect in murine MPM. Specifically, we demonstrated that JSI-124 inhibits murine MPM cell growth and induces apoptotic and autophagic cell death. Exposure of RN5 and AB12 cells to JSI-124 resulted in apoptosis via the Bcl-2 family of proteins. JSI-124 triggered autophagosome formation, accumulation, and conversion of LC3I to LC3II. Autophagy inhibitors, Chloroquine (CQ) and Bafilomycin A1 (Baf-A1), inhibited autophagy and sensitized RN5 and AB12 cells to JSI-124-induced apoptosis. Our data indicate that JSI-124 is a promising therapeutic agent for MPM treatment.
Topics: Humans; Animals; Mice; Mesothelioma, Malignant; Cell Line, Tumor; Cell Proliferation; Apoptosis; Autophagy
PubMed: 37642305
DOI: 10.1002/mc.23623 -
American Journal of Industrial Medicine Jan 2024Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers.
BACKGROUND
Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers.
METHODS
Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period.
RESULTS
The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter.
CONCLUSIONS
Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.
Topics: Male; Humans; Female; Cause of Death; Mesothelioma; Cohort Studies; Occupational Exposure; Occupational Diseases; Construction Materials; Asbestos; Pleural Neoplasms; Peritoneal Neoplasms; Ovarian Neoplasms; Italy; Lung Neoplasms
PubMed: 37855384
DOI: 10.1002/ajim.23546 -
Molecular Oncology Apr 2024Mesothelioma is a type of late-onset cancer that develops in cells covering the outer surface of organs. Although it can affect the peritoneum, heart, or testicles, it... (Review)
Review
Mesothelioma is a type of late-onset cancer that develops in cells covering the outer surface of organs. Although it can affect the peritoneum, heart, or testicles, it mainly targets the lining of the lungs, making pleural mesothelioma (PMe) the most common and widely studied mesothelioma type. PMe is caused by exposure to fibres of asbestos, which when inhaled leads to inflammation and scarring of the pleura. Despite the ban on asbestos by most Western countries, the incidence of PMe is on the rise, also facilitated by a lack of specific symptomatology and diagnostic methods. Therapeutic options are also limited to mainly palliative care, making this disease untreatable. Here we present an overview of biological aspects underlying PMe by listing genetic and molecular mechanisms behind its onset, aggressive nature, and fast-paced progression. To this end, we report on the role of deubiquitinase BRCA1-associated protein-1 (BAP1), a tumour suppressor gene with a widely acknowledged role in the corrupted signalling and metabolism of PMe. This review aims to enhance our understanding of this devastating malignancy and propel efforts for its investigation.
Topics: Humans; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms; Asbestos; Lung Neoplasms
PubMed: 38459714
DOI: 10.1002/1878-0261.13591 -
Discovery Medicine Oct 2023It is a significant challenge to identify pleural effusion (PE) through differential diagnosis in clinical settings. The present study endeavors to devise a strategy to...
BACKGROUND
It is a significant challenge to identify pleural effusion (PE) through differential diagnosis in clinical settings. The present study endeavors to devise a strategy to differentiate between malignant pleural effusion (MPE) and benign pleural effusion (BPE) by detecting gene methylation.
METHODS
This study recruited 214 patients with PE, among which 104 patients were identified with MPE, while the remaining 110 patients were categorized as having BPE. The methylation levels of short stature homeobox 2 () and RAS association domain family 1, isoform A () genes were analyzed through methylation-specific polymerase chain reaction (MS-PCR).
RESULTS
The methylation status of either or genes was significantly elevated in MPE compared to BPE. The sensitivity and specificity of and methylation in diagnosing PE were 66.3% and 90.9%, respectively. The sensitivity of the combined methylation detection intended to diagnose pulmonary MPE was 73.5% and 52.8% in non-pulmonary MPE ( < 0.05), suggesting that combined detection of and methylation had high diagnostic value for lung cancer. In comparison to the results of cytology and DNA ploidy detection, methylation detection demonstrated a superior diagnostic efficiency in the diagnosis of lung cancer ( < 0.05). Additionally, the combined detection of and methylation was more potent in diagnosing BPE and MPE ( < 0.05), while compensating for the limitations of cytology and DNA ploidy detection.
CONCLUSIONS
The detection of and methylation can effectively differentiate between BPE and MPE, especially in diagnosing pulmonary MPE.
Topics: Humans; Pleural Effusion, Malignant; Methylation; Biomarkers, Tumor; Pleural Effusion; Lung Neoplasms; DNA; Homeodomain Proteins
PubMed: 37811622
DOI: 10.24976/Discov.Med.202335178.79 -
International Journal of Molecular... Sep 2023The sensitivity of pleural fluid (PF) analyses for the diagnosis of malignant pleural effusions (MPEs) is low to moderate. Knowledge about the pathobiology and molecular...
The sensitivity of pleural fluid (PF) analyses for the diagnosis of malignant pleural effusions (MPEs) is low to moderate. Knowledge about the pathobiology and molecular characteristics of this condition is limited. In this study, the crosstalk between stromal cells and tumor cells was investigated in vitro in order to reveal factors that are present in PF which can mediate MPE formation and aid in discriminating between benign and malignant etiologies. Eighteen PF samples, in different proportions, were exposed in vitro to mesothelial MeT-5A cells to determine the biological effects on these cells. Treatment of normal mesothelial MeT-5A cells with malignant PF increased cell viability, proliferation, and migration, and activated different survival-related signaling pathways. We identified differentially expressed miRNAs in PF samples that could be responsible for these changes. Consistently, bioinformatics analysis revealed an enrichment of the discovered miRNAs in migration-related processes. Notably, the abundance of three miRNAs (miR-141-3p, miR-203a-3, and miR-200c-3p) correctly classified MPEs with false-negative cytological examination results, indicating the potential of these molecules for improving diagnosis. Malignant PF produces phenotypic and functional changes in normal mesothelial cells. These changes are partly mediated by certain miRNAs, which, in turn, could serve to differentiate malignant from benign effusions.
Topics: Humans; Pleural Effusion, Malignant; Cell Survival; Computational Biology; Cross Reactions; MicroRNAs
PubMed: 37762343
DOI: 10.3390/ijms241814022 -
Zhonghua Bing Li Xue Za Zhi = Chinese... May 2024
Review
Topics: Humans; Mesothelioma; Mesothelioma, Malignant; Mutation; Precision Medicine
PubMed: 38678339
DOI: 10.3760/cma.j.cn112151-20231016-00267 -
Radiology Feb 2024An 81-year-old man living in South Korea was referred to the pulmonology clinic because of abnormal findings at routine surveillance CT. His past medical history...
An 81-year-old man living in South Korea was referred to the pulmonology clinic because of abnormal findings at routine surveillance CT. His past medical history included right radical nephroureterectomy for ureteral cancer in 2016, transurethral resection of a bladder tumor in 2015, and tuberculous pleurisy in his third decade of life that was complicated by a chronic calcified empyema. He had been doing well clinically until 6 months prior, when he presented to an outside hospital with progressive right-sided chest pain and dyspnea and was found to have active tuberculosis. During that hospitalization, he underwent chest CT and CT-guided biopsy of an incidentally found thoracic lesion, which revealed chronic active inflammation. His symptoms improved after initiation of antituberculous medication, and he was discharged home to complete treatment. Because of interval growth of this lesion noted on a subsequent surveillance CT scan, he was referred to pulmonology for further evaluation. Laboratory tests obtained during his visit revealed mild leukocytosis (1258 cells × 10/L; normal range, 4000-10 000 cells × 10/L) with neutrophilic predominance (82% neutrophils; normal range, 50%-75% neutrophils), and a mildly elevated C-reactive protein level (3.17 mg/dL; normal range, 0-0.5 mg/dL). A sputum culture was negative for tuberculosis. The patient reported mild chest discomfort and dyspnea. Liver MRI was performed to further evaluate an abnormal lesion seen at CT. Given the patient's recent nonspecific biopsy results and tuberculosis treatment, no further work-up was pursued. Contrast-enhanced chest CT was performed 6 months later because the patient developed worsening chest pain and dyspnea. He remained afebrile, with persistent leukocytosis (1485 cells × 10/L) and an elevated C-reactive protein level (3.56 mg/dL). On the basis of the imaging findings, repeat CT-guided biopsy and PET/CT were performed, thereby enabling confirmation of the diagnosis, and appropriate treatment was initiated.
Topics: Male; Humans; Aged, 80 and over; C-Reactive Protein; Leukocytosis; Positron Emission Tomography Computed Tomography; Lymphoma, Large B-Cell, Diffuse; Pleural Neoplasms; Chest Pain; Dyspnea; Image-Guided Biopsy; Tuberculosis; Empyema, Pleural
PubMed: 38411510
DOI: 10.1148/radiol.223090 -
Journal of Cellular and Molecular... Apr 2024The Hippo signalling pathway, a highly conserved signalling cassette, regulates organ size by controlling cell growth, apoptosis and stem cell self-renewal. The... (Review)
Review
The Hippo signalling pathway, a highly conserved signalling cassette, regulates organ size by controlling cell growth, apoptosis and stem cell self-renewal. The tumourigenic potential of this pathway is largely attributed to the activity of YAP/TAZ, which activate the TEAD1-4 transcription factors, leading to the expression of genes involved in cell proliferation and suppression of cell death. Aberrant regulation of the YAP/TAZ-TEAD signalling axis is commonly observed in malignant pleural mesothelioma (MPM), an insidious neoplasm of the pleural tissue that lines the chest cavity and covers the lungs with poor prognosis. Given the limited effectiveness of current treatments, targeting the YAP/TAZ-TEAD signalling cascade has emerged as a promising therapeutic strategy in MPM. Several inhibitors of the YAP/TAZ-TEAD signalling axis are presently undergoing clinical development, with the goal of advancing them to clinical use in the near future.
Topics: Humans; Mesothelioma, Malignant; Signal Transduction; Transcription Factors; Neoplasms; Hippo Signaling Pathway
PubMed: 38606782
DOI: 10.1111/jcmm.18330 -
Journal of Pediatric Surgery Jun 2024Malignant peritoneal and pleural mesothelioma are rare in young patients, with a paucity of data regarding clinical characteristics and outcomes. We aimed to describe...
PURPOSE
Malignant peritoneal and pleural mesothelioma are rare in young patients, with a paucity of data regarding clinical characteristics and outcomes. We aimed to describe the clinical characteristics, treatment strategies, and outcomes for pediatric and adolescent/young adult (AYA) patients.
METHODS
The National Cancer Database (NCDB) was queried for malignant peritoneal and pleural mesothelioma in pediatric and AYA patients (ages 0-39) from 2004 to 2019. Stratification was performed for pediatric (age 0-21) and young adult (age 22-39) patients. Chi-squared, multivariable cox regression, and Kaplan-Meier analyses were performed.
RESULTS
We identified 570 total patients, 46 pediatric and 524 young adult, with mesothelioma (363 peritoneal and 207 pleural). There were significant differences in sex distribution as patients with peritoneal mesothelioma were more frequently female (63.1%). Patients with peritoneal mesothelioma were more likely to have radical surgery compared to pleural mesothelioma (56.7% v. 24.6%, respectively). A majority of patients with peritoneal and pleural mesothelioma received chemotherapy (66.4% and 61.4%, respectively). For peritoneal mesothelioma, surgical resection was associated with improved overall survival, whereas male sex, neoadjuvant chemotherapy, and radiation were associated with worse overall survival. For pleural mesothelioma, intraoperative chemotherapy was associated with improved overall survival, whereas Black race was associated with worse overall survival. Mean overall survival was greater for patients with peritoneal mesothelioma (125 months) compared to those with pleural mesothelioma (69 months), which remained significant after stratification of pediatric and young adult patients.
CONCLUSION
By analyzing a large cohort of pediatric and AYA mesothelioma, this study highlights clinical, prognostic, and survival differences between peritoneal and pleural disease.
LEVEL OF EVIDENCE
Level III.
TYPE OF STUDY
Retrospective.
Topics: Humans; Adolescent; Peritoneal Neoplasms; Male; Female; Child; Young Adult; Pleural Neoplasms; Databases, Factual; Adult; Child, Preschool; Infant; United States; Mesothelioma, Malignant; Retrospective Studies; Mesothelioma; Infant, Newborn; Kaplan-Meier Estimate
PubMed: 38418273
DOI: 10.1016/j.jpedsurg.2024.02.002 -
Journal of Surgical Oncology Sep 2023Pleural metastasis has extremely poor prognosis. Resection of pleural implants with infusion of intrathoracic hyperthermic chemotherapy may offer a survival advantage in... (Review)
Review
OBJECTIVES
Pleural metastasis has extremely poor prognosis. Resection of pleural implants with infusion of intrathoracic hyperthermic chemotherapy may offer a survival advantage in selected patients. We evaluated the safety and efficacy of hyperthermic intrathoracic extracorporeal chemotherapy (HITEC) in patients who underwent pleurectomy/decortication (P/D) for secondary malignant pleural disease (SPD).
METHODS
A total of 101 patients were evaluated over 72 months, with 35 patients electing to proceed with P/D and 60 minutes of HITEC with cisplatin at 42°C. Inclusion criteria were adults 18-79 years with unilateral pleural dissemination. Exclusion criteria were patients without control of primary site, extrathoracic metastatic disease, significant comorbidities, and a history of adverse reaction to cisplatin.
RESULTS
Median age was 56 years (36-73); 60% were women. SPD was thymoma in 13, breast cancer in 9, lung cancer in 6, colon cancer in 2, renal cell in 2, and esophageal, anal, and thymic cancers in one each. There was no operative mortality. Postoperative complications occurred in 18 patients (51%). No patient developed renal failure. Median follow-up was 24 months (4-60). The overall survival rate was 61%; 17 patients (49%) developed recurrent disease at a median of 12 months (6-36). There were no recurrences after 36 months Eleven patients (31%) died of metastatic disease at a median of 17 months (7-25).
CONCLUSIONS
Surgical cytoreduction of SPD followed by HITEC with cisplatin was well tolerated. No patient developed cisplatin-related toxicities. Long-term follow-up is warranted to determine survival advantage and refinement of inclusion criteria.
Topics: Adult; Humans; Female; Middle Aged; Male; Cisplatin; Combined Modality Therapy; Pleural Neoplasms; Mesothelioma; Thymus Neoplasms; Pleural Diseases; Hyperthermia, Induced
PubMed: 37409778
DOI: 10.1002/jso.27389