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PeerJ 2023Malignant mesothelioma (MM) is a cancer caused mainly by asbestos exposure, and is aggressive and incurable. This study aimed to identify differential metabolites and...
BACKGROUND
Malignant mesothelioma (MM) is a cancer caused mainly by asbestos exposure, and is aggressive and incurable. This study aimed to identify differential metabolites and metabolic pathways involved in the pathogenesis and diagnosis of malignant mesothelioma.
METHODS
By using gas chromatography-mass spectrometry (GC-MS), this study examined the plasma metabolic profile of human malignant mesothelioma. We performed univariate and multivariate analyses and pathway analyses to identify differential metabolites, enriched metabolism pathways, and potential metabolic targets. The area under the receiver-operating curve (AUC) criterion was used to identify possible plasma biomarkers.
RESULTS
Using samples from MM ( = 19) and healthy control ( = 22) participants, 20 metabolites were annotated. Seven metabolic pathways were disrupted, involving alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; arginine and proline metabolism; butanoate and histidine metabolism; beta-alanine metabolism; and pentose phosphate metabolic pathway. The AUC was used to identify potential biomarkers. Using a threshold of AUC = 0.9, five metabolites were identified, including xanthurenic acid, (s)-3,4-hydroxybutyric acid, D-arabinose, gluconic acid, and beta-d-glucopyranuronic acid.
CONCLUSIONS
To the best of our knowledge, this is the first report of a plasma metabolomics analysis using GC-MS analyses of Asian MM patients. Our identification of these metabolic abnormalities is critical for identifying plasma biomarkers in patients with MM. However, additional research using a larger population is needed to validate our findings.
Topics: Humans; Mesothelioma, Malignant; Gas Chromatography-Mass Spectrometry; Metabolomics; Aggression; Alanine
PubMed: 37220527
DOI: 10.7717/peerj.15302 -
International Journal of Molecular... Nov 2021Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach.... (Review)
Review
Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.
Topics: Biomarkers, Tumor; Epithelial-Mesenchymal Transition; Humans; Mesothelioma, Malignant; MicroRNAs; Neoplasm Metastasis; Neoplasm Proteins; Pleural Neoplasms; RNA, Neoplasm; Transforming Growth Factor beta
PubMed: 34830097
DOI: 10.3390/ijms222212216 -
International Journal of Molecular... Dec 2022Malignant mesothelioma (MM) is a devastating cancer of mesothelial cells, caused by asbestos exposure. Limited knowledge regarding the detection of asbestos exposure and... (Review)
Review
Malignant mesothelioma (MM) is a devastating cancer of mesothelial cells, caused by asbestos exposure. Limited knowledge regarding the detection of asbestos exposure and the early diagnosis of MM, as well as a lack of successful treatment options for this deadly cancer, project an immediate need to understand the mechanism(s) of MM development. With the recent discovery of nano-vesicles, namely exosomes, and their enormous potential to contain signature molecules representative of different diseases, as well as to communicate with distant targets, we were encouraged to explore their role(s) in MM biology. In this review, we summarize what we know so far about exosomes and MM based on our own studies and on published literature from other groups in the field. We expect that the information contained in this review will help advance the field of MM forward by revealing the mechanisms of MM development and survival. Based on this knowledge, future therapeutic strategies for MM can potentially be developed. We also hope that the outcome of our studies presented here may help in the detection of MM.
Topics: Humans; Mesothelioma, Malignant; Mesothelioma; Lung Neoplasms; Asbestos; Exosomes
PubMed: 36499762
DOI: 10.3390/ijms232315438 -
Cancer Treatment and Research... 2020Malignant pleural mesothelioma (MPM) is a rare malignancy with a poor prognosis. While treatment with a platinum-based chemotherapy is the standard of care, many...
INTRODUCTION
Malignant pleural mesothelioma (MPM) is a rare malignancy with a poor prognosis. While treatment with a platinum-based chemotherapy is the standard of care, many patients have rapid progression of disease with a median overall survival of ~12 months. Limited data exist about the genomic alterations associated with MPM and their clinical implications.
METHODS
We report genomic alterations and clinical data for 17 patients with MPM who had next generation sequencing performed. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier method.
RESULTS
Median age at diagnosis was 70 years (range 55-85), and 47% of the patients were male. The most common genomic alterations in the 17 patients were NF2 (53%), BAP1 (41%), CDKN2A (41%) and TP53 (29%). The median OS was 10.8 months. When stratified by mutational status, patients had better median OS if they had a BAP1 alteration compared to TP53 alteration (median OS 14.5 vs 7.2 months). Median PFS with first-line chemotherapy was 7 months (SD ± 3.3). However, patients with TP53 mutations had worse PFS with chemotherapy with median of only 3.9 months. Tumor mutation burden (TMB) was available for 12 patients and all had low TMB (range 1 to 8.1 mutation/Mb). Median PFS with immunotherapy was poor with at 1.5 months (SD ±0.4) and there was no significant difference in PFS with immunotherapy based on molecular profile.
CONCLUSION
Our study has identified that TP53 confers worse survival and response to platinum chemotherapy compared to BAP1. Overall PDL1 expression and TMB is low in patients with MPM resulting in limited benefit from single agent PD-1/PD-L1 agent.
Topics: Aged; Aged, 80 and over; Female; Genomics; Humans; Male; Mesothelioma, Malignant; Middle Aged; Pleural Neoplasms; Treatment Outcome
PubMed: 33166854
DOI: 10.1016/j.ctarc.2020.100232 -
Journal of Thoracic Oncology : Official... Aug 2022
Topics: Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 35931424
DOI: 10.1016/j.jtho.2022.04.014 -
Proceedings of the National Academy of... Jan 2023is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline mutations often develop mesothelioma, an aggressive malignancy...
is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline mutations and primary cells in which was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline mutations.
Topics: Humans; Heterozygote; Hypoxia-Inducible Factor 1, alpha Subunit; Mesothelioma; Mesothelioma, Malignant; Mutation; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 36656861
DOI: 10.1073/pnas.2217840120 -
Annali Dell'Istituto Superiore Di Sanita 2015Malignant mesothelioma (MM) is rare and difficult to diagnose. Its identification depends upon pathological investigation (cyto-histological assessment and... (Review)
Review
Malignant mesothelioma (MM) is rare and difficult to diagnose. Its identification depends upon pathological investigation (cyto-histological assessment and immunohistochemistry) supported by clinical and radiological evidence. In the last decade, the standardization of diagnostic methods has become a major focus of debate among pathologists and clinicians. This has led to the writing of guidelines and recommendation for the diagnosis to achieve the goal of a standard diagnosis. In this article, a chronological view relating to the pathological diagnosis of MM is presented together with a review of guidelines and recommendations.
Topics: Guidelines as Topic; Humans; Immunohistochemistry; Italy; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 25857384
DOI: 10.4415/ANN_15_01_09 -
BMC Cancer Jun 2022Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes...
Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.
Topics: Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Mesothelioma; Mesothelioma, Malignant; Phosphoproteins; YAP-Signaling Proteins
PubMed: 35689194
DOI: 10.1186/s12885-022-09686-y -
Lung Cancer (Amsterdam, Netherlands) Jan 2024Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the...
OBJECTIVES
Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3-4 treatment related adverse events (TRAE's) and TRAE's led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers.
METHODS
Clinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2-5 TRAE's and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported.
RESULTS
Between January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 - 13.1). Grade 3-4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE's. ORR was 21.7 % (95 % CI 15.7-27.7), median DOR was 5.7 months (IQR 3.2-8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8-63.2). The mPFS was 5.5 months (95 %CI 4.1-6.9), mOS was 14.1 months (95 % CI 11.1-18.2).
CONCLUSIONS
Nivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE's, leading to discontinuation of treatment in 25% of the patients.
Topics: Humans; Nivolumab; Ipilimumab; Mesothelioma, Malignant; Lung Neoplasms; Mesothelioma; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38104353
DOI: 10.1016/j.lungcan.2023.107440 -
Psycho-oncology Oct 2020Despite recent advances in research, malignant mesothelioma remains an incurable and devastating disease, typically bringing shock and emotional distress to patients and... (Review)
Review
OBJECTIVE
Despite recent advances in research, malignant mesothelioma remains an incurable and devastating disease, typically bringing shock and emotional distress to patients and carers. Little research has addressed the psychological impact on either group. This scoping review examines the current state of evidence on the psychological effects of mesothelioma on patients and carers, and identifies areas for further research.
METHODS
We searched PubMed, PsychINFO, CINAHL, the Cochrane Library and Web of Science for English-language peer-reviewed research articles published 1981 to 2019 reporting studies focussing on the psychological effects of mesothelioma on patients and carers. Following data extraction and quality appraisal, reflexive thematic analysis was used to identify themes.
RESULTS
Seventeen articles met the inclusion criteria. Carers' experiences were generally amalgamated with patients'. Three themes were developed. The Passing of Time included the importance of timing of interventions; delays in the medical journey; awareness of different time-phases in mesothelioma; and uncertainty/certainty. Dealing with Difficult Feelings reflected ubiquitous negative emotions, feelings about identity and states of being and associated coping strategies. Craving Good Communication covered issues related to sharing of information and to positive/negative aspects of communication.
CONCLUSIONS
Though limited, the evidence indicates that mesothelioma, with its high symptom-burden, incurability, rarity and asbestos-related causation, leads to complex and inter-relating psychological effects on patients and carers. These effects are both negative and positive. The sparse literature gives a partial picture and demonstrates an urgent need for more nuanced research. Studies exploring the experiences of specific groups are recommended, with particular attention required to carers.
Topics: Adaptation, Psychological; Caregivers; Emotions; Female; Humans; Male; Mental Health; Mesothelioma, Malignant; Palliative Care; Psychological Distress; Quality of Life; Stress, Psychological; Uncertainty
PubMed: 32596966
DOI: 10.1002/pon.5454