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Respirology (Carlton, Vic.) Nov 2020
Topics: Humans; Lung Neoplasms; Pleural Effusion, Malignant
PubMed: 32648365
DOI: 10.1111/resp.13899 -
Frontiers in Immunology 2023
Topics: Humans; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Immunotherapy
PubMed: 37554331
DOI: 10.3389/fimmu.2023.1251384 -
Jornal Brasileiro de Pneumologia :... May 2024
Topics: Humans; Mesothelioma; Lung Neoplasms; Pleural Neoplasms
PubMed: 38808836
DOI: 10.36416/1806-3756/e20240118 -
Current Oncology Reports Dec 2023In this article, we provide a comprehensive analysis of recent progress in the genetic characterisation of pleural mesothelioma, and the translation of these findings to... (Review)
Review
PURPOSE OF REVIEW
In this article, we provide a comprehensive analysis of recent progress in the genetic characterisation of pleural mesothelioma, and the translation of these findings to clinical practice.
RECENT FINDINGS
Advancements in sequencing technology have allowed the identification of driver mutations and improved our understanding of how these mutations may shape the mesothelioma tumour microenvironment. However, the identification of frequently mutated regions including CDKN2A, BAP1 and NF2 have, to date, not yet yielded targeted therapy options that outperform standard chemo- and immunotherapies. Similarly, the association between mutational profile and the immune microenvironment or immunotherapy response is not well characterised. Further research into the link between tumour mutational profile and response to therapy is critical for identifying targetable vulnerabilities and stratifying patients for therapy.
Topics: Humans; Lung Neoplasms; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Genomics; Tumor Microenvironment
PubMed: 38015374
DOI: 10.1007/s11912-023-01479-1 -
Chest Nov 2021Most patients with malignant pleural mesothelioma (MPM) seek treatment with malignant pleural effusion (MPE). In vitro evidence suggests that MPE may not be a simple...
BACKGROUND
Most patients with malignant pleural mesothelioma (MPM) seek treatment with malignant pleural effusion (MPE). In vitro evidence suggests that MPE may not be a simple bystander of malignancy, but rather potentially has biological properties that improve cancer cell survival and promote cancer progression. If this is the case, MPE management may need to shift from current symptomatic strategies to aggressive fluid removal to impact survival.
RESEARCH QUESTION
Is there an association between pleural fluid exposure and survival in MPM?
STUDY DESIGN AND METHODS
Data from 761 patients who received a diagnosis of MPM between 2008 and 2018 were collected from patient medical records in three UK pleural units. Data included factors previously identified as influencing prognosis in MPM. Medical imaging was reviewed for presence, size, and duration of pleural effusion. Time-dependent covariate analysis of pleural fluid exposure and survival (model included weight loss, serum albumin, hemoglobin, MPM subtype, performance status, chemotherapy, and age) and multivariate Cox regression analysis of pleurodesis and survival were conducted.
RESULTS
Median overall survival was 278 days (interquartile range, 127-505 days; 95% CI, 253-301 days). Pleural fluid exposure duration showed no association with survival (hazard ratio, 1.0; 95% CI, 1.0-1.0). Median survival was 473, 378, and 258 days with complete, partial, and no pleurodesis (P = .008).
INTERPRETATION
Pleurodesis success seems to be associated with improved survival; however, it is unclear whether duration of MPM exposure to pleural fluid is associated with survival within the limitations of this retrospective study. Future prospective studies are required to assess this potentially important mechanism.
Topics: Aged; Antineoplastic Agents; Disease Progression; Female; Humans; Male; Mesothelioma, Malignant; Pleural Effusion, Malignant; Pleural Neoplasms; Pleurodesis; Prognosis; Radiography, Thoracic; Retrospective Studies; Survival Analysis; Time-to-Treatment; Ultrasonography; United Kingdom
PubMed: 34119515
DOI: 10.1016/j.chest.2021.05.063 -
PloS One 2021Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease...
Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease is rare but may occur in high-risk settings, often manifesting as a pulmonary infection. To date HCMV has not been investigated in malignant pleural mesothelioma (MPM). In a consecutive case series of 144 MPM patients we evaluated two biomarkers of HCMV: IgG serostatus (defined as positive and negative) and DNAemia (>100 copies/mL of cell free HCMV DNA in serum). Approximately half of the MPM patient population was HCMV IgG seropositive (51%). HCMV DNAemia was highly prevalent (79%) in MPM and independent of IgG serostatus. DNAemia levels consistent with high level current infection (>1000 copies/mL serum) were present in 41% of patients. Neither IgG serostatus nor DNAemia were associated with patient survival. In tissues, we observed that HCMV DNA was present in 48% of tumors (n = 40) and only 29% of normal pleural tissue obtained from individuals without malignancy (n = 21). Our results suggest nearly half of MPM patients have a high level current HCMV infection at the time of treatment and that pleural tissue may be a reservoir for latent HCMV infection. These findings warrant further investigation to determine the full spectrum of pulmonary infections in MPM patients, and whether treatment for high level current HCMV infection may improve patient outcomes.
Topics: Aged; Antibodies, Viral; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Disease-Free Survival; Female; Humans; Immunoglobulin G; Male; Mesothelioma, Malignant; Middle Aged; Pleural Neoplasms; Pneumonia, Viral; Retrospective Studies; Survival Rate
PubMed: 34383785
DOI: 10.1371/journal.pone.0254136 -
Nature Genetics Apr 2023Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing...
Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.
Topics: Humans; Mesothelioma, Malignant; Mesothelioma; Multiomics; Pleural Neoplasms; Lung Neoplasms; Biomarkers, Tumor
PubMed: 36928603
DOI: 10.1038/s41588-023-01321-1 -
Modern Pathology : An Official Journal... Feb 2020Localized pleural mesothelioma is a rare solitary circumscribed pleural tumor that is microscopically similar to diffuse malignant pleural mesothelioma. However, the...
Localized pleural mesothelioma is a rare solitary circumscribed pleural tumor that is microscopically similar to diffuse malignant pleural mesothelioma. However, the molecular characteristics and nosologic relationship with its diffuse counterpart remain unknown. In a consecutive cohort of 1110 patients with pleural mesotheliomas diagnosed in 2005-2018, we identified six (0.5%) patients diagnosed with localized pleural mesotheliomas. We gathered clinical history, evaluated the histopathology, and in select cases performed karyotypic analysis and targeted next-generation sequencing. The cohort included three women and three men (median age 63; range 28-76), often presenting incidentally during radiologic evaluation for unrelated conditions. Neoadjuvant chemotherapy was administered in two patients. All tumors (median size 5.0 cm; range 2.7-13.5 cm) demonstrated gross circumscription (with microscopic invasion into lung, soft tissue, and/or rib in four cases), mesothelioma histology (four biphasic and two epithelioid types), and mesothelial immunophenotype. Of four patients with at least 6-month follow-up, three were alive (up to 8.9 years). Genomic characterization identified several subgroups: (1) BAP1 mutations with deletions of CDKN2A and NF2 in two tumors; (2) TRAF7 mutations in two tumors, including one harboring trisomies of chromosomes 3, 5, 7, and X; and (3) genomic near-haploidization, characterized by extensive loss of heterozygosity sparing chromosomes 5 and 7. Localized pleural mesotheliomas appear genetically heterogeneous and include BAP1-mutated, TRAF7-mutated, and near-haploid subgroups. While the BAP1-mutated subgroup is similar to diffuse malignant pleural mesotheliomas, the TRAF7-mutated subgroup overlaps genetically with adenomatoid tumors and well-differentiated papillary mesotheliomas, in which recurrent TRAF7 mutations have been described. Genomic near-haploidization, identified recently in a subset of diffuse malignant pleural mesotheliomas, suggests a novel mechanism in the pathogenesis of both localized pleural mesothelioma and diffuse malignant pleural mesothelioma. Our findings describe distinctive genetic features of localized pleural mesothelioma, with both similarities to and differences from diffuse malignant pleural mesothelioma.
Topics: Adult; Aged; Biomarkers, Tumor; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Deletion; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation; Neurofibromin 2; Phenotype; Pleural Neoplasms; Solitary Fibrous Tumor, Pleural; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 31371807
DOI: 10.1038/s41379-019-0330-9 -
Respirology (Carlton, Vic.) Sep 2020Pleural diseases affect millions of people worldwide. Pleural infection, malignant pleural diseases and pneumothorax are common clinical challenges. A large number of... (Review)
Review
Pleural diseases affect millions of people worldwide. Pleural infection, malignant pleural diseases and pneumothorax are common clinical challenges. A large number of recent clinical trials have provided an evidence-based platform to evaluate conventional and novel methods to drain pleural effusions/air which reduce morbidity and unnecessary interventions. These successes have generated significant enthusiasm and raised the profile of pleural medicine as a new subspecialty. The ultimate goal of pleural research is to prevent/stop development of pleural effusions/pneumothorax. Current research studies mainly focus on the technical aspects of pleural drainage. Significant knowledge gaps exist in many aspects such as understanding of the pathobiology of the underlying pleural diseases, pharmacokinetics of pleural drug delivery, etc. Answers to these important questions are needed to move the field forward. This article collates opinions of leading experts in the field in highlighting major knowledge gaps in common pleural diseases to provoke thinking beyond pleural drainage. Recognizing the key barriers will help prioritize future research in the quest to ultimately cure (rather than just drain) these pleural conditions.
Topics: Biomedical Research; Drainage; Expert Testimony; Humans; Mesothelioma; Pleural Effusion; Pleural Effusion, Malignant; Pleural Neoplasms; Pneumothorax
PubMed: 32613624
DOI: 10.1111/resp.13881 -
Cancer Letters Oct 2023Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of...
Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.
Topics: Cisplatin; Animals; Humans; Pyridines; Benzamides; Cell Line, Tumor; Y-Box-Binding Protein 1; Pleural Neoplasms; Xenograft Model Antitumor Assays; Drug Synergism; Mesothelioma; Mice; Cell Proliferation; Antineoplastic Combined Chemotherapy Protocols; Mice, Nude; Antineoplastic Agents; Acetylation; Female; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 37730104
DOI: 10.1016/j.canlet.2023.216395