bims-mesote Biomed News
on Mesothelioma
Issue of 2023–10–29
seven papers selected by
Laura Mannarino, Humanitas Research
  1. Deletions of CDKN2A and MTAP Detected by Copy-Number Variation Array Are Associated with Loss of p16 and MTAP Protein in Pleural Mesothelioma.
  2. Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma.
  3. Evening Primrose Extract Modulates TYMS Expression via SP1 Transcription Factor in Malignant Pleural Mesothelioma.
  4. PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma.
  5. Updates on grading mesothelioma.
  6. Quality of life in patients with PICC diagnosed with mesothelioma: Results of a multicenter epidemiological survey (LifePICC).
  7. MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma.
  1. Cancers (Basel). 2023 Oct 13. pii: 4978. [Epub ahead of print]15(20):
    Deletions of CDKN2A and MTAP Detected by Copy-Number Variation Array Are Associated with Loss of p16 and MTAP Protein in Pleural Mesothelioma.
    Bart Vrugt, Michaela B Kirschner, Mayura Meerang, Kathrin Oehl, Ulrich Wagner, Alex Soltermann, Holger Moch, Isabelle Opitz, Peter J Wild.
      CDKN2A deletion is a common alteration in pleural mesothelioma (PM) and frequently associated with co-deletion of MTAP. Since the standard detection method for CDKN2A deletion and FISH analysis is relatively expensive, we here investigated the suitability of inexpensive p16 and MTAP IHC by comparing concordance between IHC and OncoScan CNV arrays on samples from 52 PM patients. Concordance was determined using Cohen's kappa statistics. Loss of CDKN2A was associated with co-deletion of MTAP in 71% of cases. CDKN2A-MTAP copy-number normal cases were also IHC positive in 93% of cases for p16 and 100% for MTAP, while homozygous deletion of CDKN2A-MTAP was always associated with negative IHC for both proteins. In cases with heterozygous CDKN2A-MTAP loss, IHC expression of p16 and MTAP was negative in 100% and 71%, respectively. MTAP and p16 IHC showed high sensitivity (MTAP 86.5%, p16 100%) and specificity (MTAP 100%, p16 93.3%) for the detection of any gene loss. Loss of MTAP expression occurred exclusively in conjunction with loss of p16 labeling. Both p16 and MTAP IHC showed high concordance with Oncoscan CNV arrays (kappa = 0.952, p < 0.0001, and kappa = 0.787, p < 0.0001 respectively). We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM.
    Keywords:  CDKN2A; MTAP; copy-number array; diagnostics; immunohistochemistry; molecular pathology; p16; pleural mesothelioma
    DOI:  https://doi.org/10.3390/cancers15204978
  2. J Transl Med. 2023 10 25. 21(1): 749
    Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma.
    Michele Carbone, Michael Minaai, Yasutaka Takinishi, Ian Pagano, Haining Yang.
      Mesothelioma is a cancer typically caused by asbestos. Mechanistically, asbestos carcinogenesis has been linked to the asbestos-induced release of HMGB1 from the nucleus to the cytoplasm, where HMGB1 promotes autophagy and cell survival, and to the extracellular space where HMGB1 promotes chronic inflammation and mesothelioma growth. Targeting HMGB1 inhibited asbestos carcinogenesis and the growth of mesothelioma. It is hoped that targeting HMGB1 will be a novel therapeutic strategy that benefits mesothelioma patients. Severe restrictions and/or a complete ban on the use of asbestos were introduced in the 80 and early 90s in the Western world. These measures have proven effective as the incidence of mesothelioma/per 100,000 persons is decreasing in these countries. However, the overall number of mesotheliomas in the Western world has not significantly decreased. There are several reasons for that which are discussed here: (1) the presence of asbestos in old constructions; (2) the development of rural areas containing asbestos or other carcinogenic mineral fibers in the terrain; (3) the discovery of an increasing fraction of mesotheliomas caused by germline genetic mutations of BAP1 and other tumor suppressor genes; (4) mesotheliomas caused by radiation therapy; (5) the overall increase in the population and of the fraction of older people who are much more susceptible to develop all types of cancers, including mesothelioma. In summary, the epidemiology of mesothelioma is changing, the ban on asbestos worked, there are opportunities to help mesothelioma patients especially those who develop in a background of germline mutations and there is the opportunity to prevent a mesothelioma epidemic in the developing world, where the use of asbestos is increasing exponentially. We hope that restrictive measures similar to those introduced in the Western world will soon be introduced in developing countries to prevent a mesothelioma epidemic.
    DOI:  https://doi.org/10.1186/s12967-023-04614-5
  3. Cancers (Basel). 2023 Oct 16. pii: 5003. [Epub ahead of print]15(20):
    Evening Primrose Extract Modulates TYMS Expression via SP1 Transcription Factor in Malignant Pleural Mesothelioma.
    Małgorzata Chmielewska-Kassassir, Katarzyna Sobierajska, Wojciech M Ciszewski, Jakub Kryczka, Andrzej Zieleniak, Lucyna A Wozniak.
       PURPOSE: To determine the mechanism of EPE in downregulating TYMS in MPM cancer.
    METHODS: The TYMS mRNA expression with epithelial-to-mesenchymal transition biomarkers and nuclear factor SP1 was assessed using the GEO database in a data set of MPM patients (GSE51024). Invasive MPM cell lines were in vitro models for the investigation of TYMS expression after EPE treatment. The tyms promoter SP1 binding sequences were determined using Genomatix v 3.4 software Electrophoretic mobility shift and dual-luciferase reporter assays revealed specific SP1 motifs in the interaction of EPE and reference compounds. Chromatin immunoprecipitation and Re-ChIP were used for the co-occupancy study.
    RESULTS: In MPM patients, a positive correlation of overexpressed TYMS with mesenchymal TWIST1, FN1 and N-cadherin was observed. EPE and its major components, gallic and ellagic acid (GA and EA, respectively), downregulated TYMS in invasive MPM cells by interacting with particular SP1 motifs on the tyms promoter. The luciferase constructs confirmed the occupation of two SP1 regulatory regions critical for the promotion of TYMS expression. Both EPE and reference standards influenced SP1 translocation into the nucleus.
    CONCLUSION: EPE components reduced TYMS expression by occupation of SP1 motifs on the tyms promoter and reversed the EMT phenotype of invasive MPM cells. Further in-depth analysis of the molecular docking of polyphenol compounds with SP1 regulatory motifs is required.
    Keywords:  epithelial-to-mesenchymal transition; evening primrose extract; malignant pleural mesothelioma; specificity protein 1 nuclear factor; thymidylate synthase
    DOI:  https://doi.org/10.3390/cancers15205003
  4. J Immunother Cancer. 2023 Oct;pii: e007585. [Epub ahead of print]11(10):
    PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma.
    Krisztian Homicsko, Panagiota Zygoura, Maxim Norkin, Stephanie Tissot, Nicholas Shakarishvili, Sanjay Popat, Alessandra Curioni-Fontecedro, Mary O'Brien, Anthony Pope, Riyaz Shah, Patricia Fisher, James Spicer, Amy Roy, David Gilligan, Sylvie Rusakiewicz, Ekaterina Fortis, Nesa Marti, Roswitha Kammler, Stephen P Finn, Georges Coukos, Urania Dafni, Solange Peters, Rolf A Stahel.
       BACKGROUND: Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better.
    METHODS: We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals.
    RESULTS: We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy.
    CONCLUSION: We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade.
    Keywords:  CD8-positive T-lymphocytes; biomarkers, tumor; immunotherapy; macrophages; programmed cell death 1 receptor
    DOI:  https://doi.org/10.1136/jitc-2023-007585
  5. Histopathology. 2023 Oct 23.
    Updates on grading mesothelioma.
    Jefree J Schulte, Aliya N Husain.
      Mesothelioma is a rare disease with an historically poor prognosis. Over the past decade, a grading system has been developed that is a powerful prognostic tool in epithelioid mesothelioma. Grading of epithelioid mesothelioma is now required or strongly recommended by expert consensus, the College of American Pathologists, the World Health Organization, and the International Mesothelioma Interest Group. The original nuclear grading system for epithelioid mesothelioma, developed in the United States, split epithelioid mesotheliomas into three prognostic groups with marked differences in survival. Now, this three-tiered nuclear grading system has been combined with the presence or absence of necrosis to form the currently recommended two-tiered grading system of low- and high-grade epithelioid mesothelioma. This review will focus on the development of this grading system in mesothelioma, the grading system's shortcomings, and the application of the grading system to cytology specimens and other extra-pleural sites. Lastly, this review will briefly discuss alternative grading systems and future considerations.
    Keywords:  Epithelioid mesothelioma; mesothelioma; nuclear grading
    DOI:  https://doi.org/10.1111/his.15065
  6. J Vasc Access. 2023 Oct 24. 11297298231202046
    Quality of life in patients with PICC diagnosed with mesothelioma: Results of a multicenter epidemiological survey (LifePICC).
    Tatiana Bolgeo, Roberta Di Matteo, Stefania Crivellari, Denise Gatti, Antonella Cassinari, Carmela Riccio, Antonina De Angelis, Sara Delfanti, Elisabetta Ferrero, Claudia Gnani, Giuseppe Riili, Antonio Maconi.
       BACKGROUND: Pleural mesothelioma (PM) is a rare and aggressive cancer. PICC devices are widely used in cancer patients. The aim of the study is to evaluate the quality of life of patients with PICC diagnosed with PM treated at the Hospital of Casale Monferrato and Alessandria (Italy), an area with a high incidence of asbestos-related diseases.
    STUDY DESIGN AND METHODS: Longitudinal prospective observational study with data collection at PICC insertion (T0), after 3 months (T1), 6 months (T2), and 9 months (T3). Participants were aged >18 years, diagnosed with PM, eligible for PICC insertion. Questionnaires used: EORTC QLQ-C30, EORTC QLQ-LC13, and HADS rating scale.
    RESULTS: Twenty-eight patients were enrolled. The mean age was 68.93 years (SD 9.13), mostly male (57.1%). The most frequent cancer stage at diagnosis was III (39.3%), then I (32.1%), and IV (21.4%). 85.7% were treated with chemotherapy, 14.3% also with immunotherapy. 96.4% of patients reported no complications during PICC implantation. The perception of health status and quality of life, measured on a scale of 1-7, was in line with an average score of 5 during the evaluation period. The total anxiety and depression score remained normal for most patients (0-7).
    CONCLUSIONS: The PICC management involved a multidisciplinary team with different skills: study findings revealed the key role that dedicated nurses play in PICC placement and ensuring patient problems are promptly addressed. From our study results, PICC placement does not seem to negatively impact the patient's quality of life.
    Keywords:  Epidemiological survey; PICC; mesothelioma; oncology nursing; quality of life
    DOI:  https://doi.org/10.1177/11297298231202046
  7. Cancers (Basel). 2023 Oct 12. pii: 4962. [Epub ahead of print]15(20):
    MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma.
    Sophia F Magkouta, Photene C Vaitsi, Marianthi P Iliopoulou, Apostolos G Pappas, Chrysavgi N Kosti, Katherina Psarra, Ioannis T Kalomenidis.
       BACKGROUND: MTH1 protects tumor cells and their supporting endothelium from lethal DNA damage triggered by oxidative stress in the tumor microenvironment, thus promoting tumor growth. The impact of MTH1 on the tumor-related immune compartment remains unknown. We hypothesized that MTH1 regulates immune fitness and therefore enhances the activity of currently used immunotherapeutic regimens.
    METHODS: Our hypotheses were validated in two syngeneic murine mesothelioma models using the clinically relevant MTH1 inhibitor, karonudib. We also examined the effect of combined MTH1 and PD-L1 blockade in mesothelioma progression, focusing on the main immune players.
    RESULTS: Karonudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy.
    CONCLUSIONS: Combined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma.
    Keywords:  MTH1; immunotherapy; mesothelioma
    DOI:  https://doi.org/10.3390/cancers15204962
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