bims-mesote Biomed News
on Mesothelioma
Issue of 2023–12–03
eight papers selected by
Laura Mannarino, Humanitas Research
  1. Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths.
  2. Brief Report: Real-world toxicity and survival of combination immunotherapy in pleural mesothelioma - RIOMeso.
  3. Sarcomatoid mesothelioma diagnosed in a patient with mesothelioma in situ: a case report on morphologic differences after 9-month interval with details analysis of cytology in early-stage mesothelioma.
  4. The association of genetic factors with serum calretinin levels in asbestos-related diseases.
  5. Genomic profiling of tissue and blood predicts survival outcomes in patients with resected pleural mesothelioma.
  6. A postmortem case control study of asbestos burden in lungs of malignant mesothelioma cases.
  7. Long Non-coding RNA LINC00152 Requires EZH2 to Promote Mesothelioma Cell Proliferation, Migration, and Invasion.
  8. FFPE Proteomics of Malignant Mesothelioma and New Candidate Biomarkers Thioredoxin and Superoxide Dismutase 2 for Immunohistochemistry.
  1. Curr Oncol Rep. 2023 Nov 28.
    Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths.
    Alistair Nash, Jenette Creaney.
       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.
    Keywords:  Genetics; Mesothelioma; Oncogenesis; Sequencing
    DOI:  https://doi.org/10.1007/s11912-023-01479-1
  2. J Thorac Oncol. 2023 Nov 15. pii: S1556-0864(23)02370-5. [Epub ahead of print]
    Brief Report: Real-world toxicity and survival of combination immunotherapy in pleural mesothelioma - RIOMeso.
    N McNamee, C Harvey, L Gray, T Khoo, L Lingam, B Zhang, U Nindra, P Y Yip, A Pal, T Clay, S Arulananda, M Itchins, N Pavlakis, S Kao, S Bowyer, V Chin, L Warburton, I Pires da Silva, T John, B Solomon, M Alexander, A Nagrial.
       BACKGROUND: Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-yr overall survival (OS) of 10%. First line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate743 (CM743) trial, with supportive data from the later line single arm MAPS2 trial. RIOMeso examines survival and toxicity of this regimen in real-world practice.
    METHODS: Demographic and clinicopathological data of Australian patients treated with ipilimumab and nivolumab in first and subsequent line settings for pleural mesothelioma was collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log rank test. Toxicity was investigator-assessed using CTCAE v5.0.
    RESULTS: 119 patients were identified from 11 centres. The median age was 72, 83% were male, 92% were ECOG ≤1, 50% were past or current smokers and 78% had known asbestos exposure. 50% were epithelioid, 19% sarcomatoid, 14% biphasic and 17% unavailable. Ipilimumab and nivolumab was used first line in 75% of patients. Median OS (mOS) was 14.5 months (95%CI 13.0-NA) for the entire cohort. For patients treated first line, mOS was 14.5 months (95%CI 12.5-NA) and in second or later line patients was 15.4 months (95%CI 11.2-NA). There was no statistically significant difference in mOS for epithelioid histology compared to non-epithelioid (19.1 months [95%CI 15.4-NA] vs 13.0 months [95%CI 9.7-NA] respectively, P=0.064). 24% of patients had a CTCAE grade ≥ 3 adverse event, including 3 treatment-related deaths. Colitis was the most frequent adverse event.
    CONCLUSION: Combination immunotherapy in real-world practice has poorer survival outcomes and appears more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma.
    Keywords:  Pleural mesothelioma; immunotherapy; real-world
    DOI:  https://doi.org/10.1016/j.jtho.2023.11.014
  3. Diagn Pathol. 2023 Nov 28. 18(1): 126
    Sarcomatoid mesothelioma diagnosed in a patient with mesothelioma in situ: a case report on morphologic differences after 9-month interval with details analysis of cytology in early-stage mesothelioma.
    Miho Yoshida, Naoe Jimbo, Ryuko Tsukamoto, Tomoo Itoh, Kunimitsu Kawahara, Suguru Mitsui, Yugo Tanaka, Yoshimasa Maniwa.
       BACKGROUND: Overlapping morphological features of mesothelial cells have been rendered it difficult to distinguish between reactive and malignant conditions. The development of methods based on detecting genomic abnormalities using immunohistochemistry and fluorescence in situ hybridization have contributed markedly to solving this problem. It is important to identify bland mesothelioma cells on cytological screening, perform efficient genomic-based testing, and diagnose mesothelioma, because the first clinical manifestation of pleural mesothelioma is pleural effusion, which is the first sample available for pathological diagnosis. However, certain diagnostic aspects remain challenging even for experts.
    CASE PRESENTATION: This report describes a case of a 72-year-old man with a history of asbestos exposure who presented with pleural effusion as the first symptom and was eventually diagnosed as mesothelioma. Mesothelioma was suspected owing to prominent cell-in-cell engulfment in mesothelial cells on the first cytological sample, and the diagnosis of mesothelioma in situ was confirmed by histology. Unexpectedly, sarcomatoid morphology of mesothelioma was found in the second pathology samples 9 months after the first pathological examination. Both the mesothelioma in situ and invasive lesion showed immunohistochemical loss of methylthioadenosine phosphorylase (MTAP) and homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) on fluorescence in situ hybridization. The patient received medication therapy but died of disease progression 12 months after the diagnosis of the sarcomatoid morphology of mesothelioma.
    CONCLUSION: Our case suggests that cell-in-cell engulfment can be conspicuous in early-stage mesothelioma with inconspicuous nuclear atypia and few multinucleated cells. In addition, the presence of MTAP loss and CDKN2A homozygous deletion are suspected to be involved in early formation to invasive lesions and/or sarcomatoid morphology. We believe that it is important to consider genetic abnormalities when deciding on individual patient management. Furthermore, cases of mesothelioma, even those of an in situ lesion, with MTAP loss and/or CDKN2A deletion should be carefully followed up or subjected to early treatment.
    Keywords:  CDKN2A; Cell-in-cell engulfment; MTAP; Mesothelioma in situ; Sarcomatoid mesothelioma
    DOI:  https://doi.org/10.1186/s13000-023-01416-7
  4. Radiol Oncol. 2023 Dec 01. 57(4): 473-486
    The association of genetic factors with serum calretinin levels in asbestos-related diseases.
    Cita Zupanc, Alenka Franko, Danijela Strbac, Viljem Kovac, Vita Dolzan, Katja Goricar.
       BACKGROUND: Asbestos exposure is associated with different asbestos-related diseases, including malignant mesothelioma (MM). MM diagnosis is confirmed with immunohistochemical analysis of several markers, including calretinin. Increased circulating calretinin was also observed in MM. The aim of the study was to determine if CALB2 polymorphisms or polymorphisms in genes that can regulate calretinin expression are associated with serum calretinin levels or MM susceptibility.
    SUBJECTS AND METHODS: The study included 288 MM patients and 616 occupationally asbestos-exposed subjects without MM (153 with asbestosis, 380 with pleural plaques and 83 without asbestos-related disease). Subjects were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1 and SEPTIN7 genes using competitive allele-specific polymerase chain reaction (PCR). Serum calretinin was determined with ELISA in 545 subjects. Nonparametric tests, logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis.
    RESULTS: Carriers of at least one polymorphic CALB2 rs889704 allele had lower calretinin levels (P = 0.036). Carriers of two polymorphic MIR335 rs3807348 alleles had higher calretinin (P = 0.027), while carriers of at least one polymorphic NRF1 rs13241028 allele had lower calretinin levels (P = 0.034) in subjects without MM. Carriers of two polymorphic E2F2 rs2075995 alleles were less likely to develop MM (odds ratio [OR] = 0.64, 95% confidence interval [CI] = 0.43-0.96, P = 0.032), but the association was no longer significant after adjustment for age (P = 0.093). Optimal serum calretinin cut-off values differentiating MM patients from other subjects differed according to CALB2, NRF1, E2F2, and MIR335 genotypes.
    CONCLUSIONS: The results of presented study suggest that genetic variability could influence serum calretinin levels. These findings could contribute to a better understanding of calretinin regulation and potentially to earlier MM diagnosis.
    Keywords:  CALB2; asbestos-related disease; calretinin; malignant mesothelioma; polymorphism
    DOI:  https://doi.org/10.2478/raon-2023-0061
  5. Eur J Cancer. 2023 Nov 20. pii: S0959-8049(23)00759-1. [Epub ahead of print]196 113457
    Genomic profiling of tissue and blood predicts survival outcomes in patients with resected pleural mesothelioma.
    Diego de Miguel-Perez, Edward M Pickering, Umberto Malapelle, William Grier, Francesco Pepe, Pasquale Pisapia, Gianluca Russo, Joseph A Pinto, Alessandro Russo, Giancarlo Troncone, Melissa J Culligan, Katherine A Scilla, Ranee Mehra, Pranshu Mohindra, Oscar Arrieta, Andres F Cardona, Marzia Del Re, Ashutosh Sachdeva, Fred R Hirsch, Andrea Wolf, Joseph S Friedberg, Christian Rolfo.
       PURPOSE: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM.
    EXPERIMENTAL DESIGN: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico.
    RESULTS: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations.
    CONCLUSIONS: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM.
    Keywords:  Blood mutations; Prognostic biomarkers; Resected pleural mesothelioma; Tissue mutations
    DOI:  https://doi.org/10.1016/j.ejca.2023.113457
  6. J Transl Med. 2023 Dec 02. 21(1): 875
    A postmortem case control study of asbestos burden in lungs of malignant mesothelioma cases.
    S D Visonà, B Bertoglio, C Favaron, S Capella, E Belluso, C Colosio, S Villani, T Ivic-Pavlicic, E Taioli.
       BACKGROUND: Asbestos lung content is regarded as the most reliable tool for causal attribution of malignant mesothelioma (MM) to previous asbestos exposures. However, there is a lack of studies on asbestos burden in lungs of MM patients in comparison with healthy individuals. This study aims to provide such a comparison, investigating, as well, differences in asbestos lung burden with sex and time trends.
    METHODS: Asbestos lung content has been assessed on formalin-fixed lung fragments using scanning electron microscopy coupled with energy dispersion spectroscopy (SEM-EDS) on individuals deceased from MM (cases) and healthy subjects without any lung disease who died from violent causes (controls) between 2005 and 2023.
    RESULTS: Asbestos and asbestos bodies (ABs) were found, respectively, in 73.7% and 43.2% of cases and in 28 and 22% of controls; in MM cases the most represented asbestos types were crocidolite and amosite, whereas in controls it was tremolite-actinolite asbestos. The concentration of both asbestos fibers and ABs was statistically significantly higher in MM cases compared to controls. The mean asbestos fibers width was also significantly higher in cases than controls. Males and females with MM showed similar asbestos and ABs concentrations, but females had higher concentrations of chrysotile, and significantly lower fibers width compared to males. Time trends show that MM lung asbestos concentrations decreased starting in 2011.
    DISCUSSION: The results suggest a correlation between asbestos burden in lungs and MM risk. The different concentration of chrysotile, as well as the different width of asbestos fibers in MM males and females might reflect a sex difference in response of the lung microenvironment to inhaled asbestos. Finally, this study provides the first pathological evidence of the effect of the ban of asbestos use, demonstrating a significant decrease of asbestos lung content after 2011.
    Keywords:  Amphiboles; Asbestos; Autopsy; Chrysotile; Epidemiology; Malignant mesothelioma; SEM–EDS
    DOI:  https://doi.org/10.1186/s12967-023-04761-9
  7. Anticancer Res. 2023 Dec;43(12): 5367-5376
    Long Non-coding RNA LINC00152 Requires EZH2 to Promote Mesothelioma Cell Proliferation, Migration, and Invasion.
    Ihiro Endo, Vishwa Jeet Amatya, Kei Kushitani, Tetsuya Nakagiri, Kohei Aoe, Yukio Takeshima.
       BACKGROUND/AIM: Long non-coding RNAs (lncRNAs) establish gene regulatory networks in different human cancers and are involved in tumorigenesis. lncRNA LINC00152 is over-expressed in several malignant tumors and involved in tumorigenesis; however, its underlying regulatory mechanisms remain unclear. Mesothelioma, a cancer originating from mesothelial cells, is highly aggressive with a poor prognosis. Therefore, identification of new therapeutic targets is necessary for mesothelioma treatment.
    MATERIALS AND METHODS: Here, we conducted bioinformatics analyses of LINC00152 and enhancer of zeste homolog 2 (EZH2) expression levels and their correlation with the prognosis of patients with mesothelioma. Small interfering RNAs targeting LINC00152 and EZH2 were transfected into mesothelioma cell lines to analyze their biological functions and regulatory mechanisms.
    RESULTS: High LINC00152 expression was associated with a poor prognosis of patients with mesothelioma. LINC00152 knockdown inhibited the proliferation, migration, and invasion of mesothelioma cell lines. These results suggest that LINC00152 is a tumor-promoting factor in mesothelioma. EZH2 is highly expressed in mesothelioma and other malignancies. Direct interaction between LINC00152 and EZH2 is associated with cancer development and progression. When EZH2 expression was suppressed, LINC00152 knockdown did not suppress the proliferation, migration, and invasion of mesothelioma cells. Therefore, the tumor-promoting effect of LINC00152 in mesothelioma was dependent on EZH2 expression.
    CONCLUSION: LINC00152 promotes mesothelioma cell proliferation, migration, and invasion in cooperation with EZH2, highlighting its potential as an effective therapeutic target for mesothelioma.
    Keywords:  CYTOR; EZH2; LINC00152; Mesothelioma; cell proliferation; invasion; long non-coding RNA; migration
    DOI:  https://doi.org/10.21873/anticanres.16740
  8. Lab Invest. 2023 Nov 25. pii: S0023-6837(23)00242-8. [Epub ahead of print] 100299
    FFPE Proteomics of Malignant Mesothelioma and New Candidate Biomarkers Thioredoxin and Superoxide Dismutase 2 for Immunohistochemistry.
    Takuya Hiratsuka, Akihiko Yoshizawa, Tatsuya Endo, Takushi Yamamoto, Shinya Toyokuni, Tatsuaki Tsuruyama.
      The pathogenesis of malignant mesothelioma (MM) has been extensively investigated, focusing on stress derived from reactive oxygen species (ROS). We aimed to identify diagnostic biomarkers of MM by analyzing proteins in formalin-fixed paraffin-embedded specimens (FFPE) using liquid chromatography-mass spectrometry. We extracted proteins from FFPE sections of MM tissues (n = 6) and compared their profiles with those of benign mesothelial tissues (n = 5) and alveolar tissue (n = 1). Proteomic data were statistically assessed and profiled using principal component analysis. We were successful in the classification of MM and healthy tissue. The levels of superoxide dismutase 2 (SOD2), an enzyme that converts superoxide anion into oxygen and hydrogen peroxide, and thioredoxin (TXN), which plays a crucial role in reducing disulfide bonds in proteins, primarily contributed to the classification. Other redox-related proteins, such as pyruvate dehydrogenase subunit X, and ceruloplasmin also contributed to the classification. Protein-protein interaction analysis demonstrated that these proteins play essential roles in MM pathogenesis. Immunohistochemistry revealed that TXN levels were significantly lower, whereas SOD2 levels were significantly higher in lung cancer (LC) tissues than in controls. Proteomic profiling suggested that MM tissues experienced increased exposure to H2O2 and other ROS. Combining immunohistochemistry for TXN and SOD2 allows for differentiation among MM, LC, and control tissues; hence, TXN and SOD2 may be promising MM biomarkers and therapeutic targets.
    DOI:  https://doi.org/10.1016/j.labinv.2023.100299
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