bims-mesote Biomed News
on Mesothelioma
Issue of 2023–07–23
eight papers selected by
Laura Mannarino, Humanitas Research
  1. Optimal surgery for resectable malignant pleural mesothelioma in the setting of multimodality treatment.
  2. Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy.
  3. Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies.
  4. Leptospermum extract (QV0) suppresses pleural mesothelioma tumor growth in vitro and in vivo by mitochondrial dysfunction associated apoptosis.
  5. CAMK2D: a novel molecular target for BAP1-deficient malignant mesothelioma.
  6. Expression of stathmin in asbestos-like fibers-induced mesothelioma: A preliminary report.
  7. Rethinking continuity in primary care for people with mesothelioma.
  8. Molecular alterations and potential actionable mutations in peritoneal mesothelioma: a scoping review of high-throughput sequencing studies.
  1. Surg Today. 2023 Jul 20.
    Optimal surgery for resectable malignant pleural mesothelioma in the setting of multimodality treatment.
    Nobuyuki Kondo, Seiki Hasegawa.
      The surgical treatment of malignant pleural mesothelioma (MPM) involves procedures to achieve macroscopic complete resection, depending on the patient's condition. We reviewed the evolution of surgical approaches for resectable MPM. Since surgery is no more than a single step in the set of processes in multimodality treatment (MMT), we concluded that these procedures should give precedence to lung preservation and minimize resection whenever possible. Postoperative quality of life must be prioritized when the patient can receive appropriate adjuvant therapy.
    Keywords:  Macroscopic complete resection; Malignant pleural mesothelioma; Multimodality treatment; Surgery
    DOI:  https://doi.org/10.1007/s00595-023-02723-8
  2. Mol Cancer. 2023 Jul 17. 22(1): 114
    Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy.
    F Torricelli, B Donati, F Reggiani, V Manicardi, S Piana, R Valli, F Lococo, Alessia Ciarrocchi.
       BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients' management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place.
    METHODS: We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis.
    RESULTS: Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability.
    CONCLUSIONS: Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease.
    Keywords:  Cancer heterogeneity; Epithelial mesenchymal transition; Inflammation; Malignant pleural mesothelioma; Tumor associated Macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-023-01816-9
  3. Front Oncol. 2023 ;13 1204722
    Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies.
    Ram Kumar Sahu, Sakina Ruhi, Ashok Kumar Jeppu, Husni Ahmed Al-Goshae, Ayesha Syed, Sanjay Nagdev, Retno Widyowati, Wiwied Ekasari, Jiyauddin Khan, Bedanta Bhattacharjee, Manoj Goyal, Sankha Bhattacharya, Rajendra K Jangde.
      The pathetic malignant mesothelioma (MM) is a extremely uncommon and confrontational tumor that evolves in the mesothelium layer of the pleural cavities (inner lining- visceral pleura and outer lining- parietal pleura), peritoneum, pericardium, and tunica vaginalis and is highly resistant to standard treatments. In mesothelioma, the predominant pattern of lesions is a loss of genes that limit tumour growth. Despite the worldwide ban on the manufacture and supply of asbestos, the prevalence of mesothelioma continues to increase. Mesothelioma presents and behaves in a variety of ways, making diagnosis challenging. Most treatments available today for MM are ineffective, and the median life expectancy is between 10 and 12 months. However, in recent years, considerable progress has already been made in understanding the genetics and molecular pathophysiology of mesothelioma by addressing hippo signaling pathway. The development and progression of MM are related to many important genetic alterations. This is related to NF2 and/or LATS2 mutations that activate the transcriptional coactivator YAP. The X-rays, CT scans, MRIs, and PET scans are used to diagnose the MM. The MM are treated with surgery, chemotherapy, first-line combination chemotherapy, second-line treatment, radiation therapy, adoptive T-cell treatment, targeted therapy, and cancer vaccines. Recent clinical trials investigating the function of surgery have led to the development of innovative approaches to the treatment of associated pleural effusions as well as the introduction of targeted medications. An interdisciplinary collaborative approach is needed for the effective care of persons who have mesothelioma because of the rising intricacy of mesothelioma treatment. This article highlights the key findings in the molecular pathogenesis of mesothelioma, diagnosis with special emphasis on the management of mesothelioma.
    Keywords:  SV40; asbestos; biomarkers; hippo signaling pathway; mesothelioma
    DOI:  https://doi.org/10.3389/fonc.2023.1204722
  4. Front Oncol. 2023 ;13 1162027
    Leptospermum extract (QV0) suppresses pleural mesothelioma tumor growth in vitro and in vivo by mitochondrial dysfunction associated apoptosis.
    Huaikai Shi, Le Zhang, Ta-Kun Yu, Ling Zhuang, Helen Ke, Ben Johnson, Emma Rath, Kenneth Lee, Sonja Klebe, Steven Kao, Karl Lijun Qin, Hong Ngoc Thuy Pham, Quan Vuong, Yuen Yee Cheng.
      Pleural mesothelioma (PM) is a highly aggressive, fast-growing asbestos-induced cancer with limited effective treatments. There has been interest in using naturally occurring anticancer agents derived from plant materials for the treatment of PM. However, it is unclear if an aqueous extract from Leptospermum polygalifolium (QV0) has activity against PM. Here we investigated the anti-cancer properties of QV0 and Defender® (QV0 dietary formula) in vitro and in vivo, respectively. QV0 suppressed the growth of eight PM cell lines in a dose-dependent manner, effective at concentrations as low as 0.02% w/v (equivalent to 0.2 mg/ml). This response was found to be associated with inhibited cell migration, proliferation, and colony formation but without evident cell cycle alteration. We observed mitochondrial dysfunction post-QV0 treatment, as evidenced by significantly decreased basal and maximal oxygen consumption rates. Ten SCID mice were treated with 0.25 mg/g Defender® daily and exhibited reduced tumor size over 30 days, which was associated with an average extension of seven days of mouse life. There was no evidence of liver toxicity or increased blood glucose post-treatment in animals treated with Defender®. Significantly enhanced tumor apoptosis was observed in the Defender®-treated animals, correlating to mitochondrial dysfunction. Lastly, the high levels of polyphenols and antioxidant properties of QV0 and Defender® were detected in HPLC analysis. To the best of our knowledge, this study constitutes the first demonstration of an improved host survival (without adverse effects) response in a QV0-treated PM mouse model, associated with evident inhibition of PM cell growth and mitochondrial dysfunction-related enhancement of tumor apoptosis.
    Keywords:  Leptospermum; anti-cancer (anticancer) drugs; apoptosis; mitochondria dysfunction; pleural mesothelioma
    DOI:  https://doi.org/10.3389/fonc.2023.1162027
  5. Cell Death Discov. 2023 Jul 21. 9(1): 257
    CAMK2D: a novel molecular target for BAP1-deficient malignant mesothelioma.
    Sivasundaram Karnan, Akinobu Ota, Hideki Murakami, Md Lutfur Rahman, Md Wahiduzzaman, Muhammad Nazmul Hasan, Lam Quang Vu, Ichiro Hanamura, Akihito Inoko, Miho Riku, Hideaki Ito, Yoshifumi Kaneko, Toshinori Hyodo, Hiroyuki Konishi, Shinobu Tsuzuki, Yoshitaka Hosokawa.
      Malignant mesothelioma (MMe) is a rare but aggressive malignancy. Although the molecular genetics of MMe is known, including BRCA1-associated protein-1 (BAP1) gene alterations, the prognosis of MMe patients remains poor. Here, we generated BAP1 knockout (BAP1-KO) human mesothelial cell clones to develop molecular-targeted therapeutics based on genetic alterations in MMe. cDNA microarray and quantitative RT-PCR (qRT-PCR) analyses revealed high expression of a calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D) gene in the BAP1-KO cells. CAMK2D was highly expressed in 70% of the human MMe tissues (56/80) and correlated with the loss of BAP1 expression, making it a potential diagnostic and therapeutic target for BAP1-deficient MMe. We screened an anticancer drugs library using BAP1-KO cells and successfully identified a CaMKII inhibitor, KN-93, which displayed a more potent and selective antiproliferative effect against BAP1-deficient cells than cisplatin or pemetrexed. KN-93 significantly suppressed the tumor growth in mice xenografted with BAP1-deficient MMe cells. This study is the first to provide a potential molecular-targeted therapeutic approach for BAP1-deficient MMe.
    DOI:  https://doi.org/10.1038/s41420-023-01552-5
  6. Histol Histopathol. 2023 Jun 30. 18649
    Expression of stathmin in asbestos-like fibers-induced mesothelioma: A preliminary report.
    Claudia Lombardo, Giuseppe Broggi, Ermanno Vitale, Caterina Ledda, Carla Loreto, Serena Matera, Maria Hagnas, Rosario Caltabiano, Veronica Filetti.
       BACKGROUND: Mesothelioma is strongly associated with exposure to asbestos fibers, however, recent studies have also linked exposure to "naturally occurring asbestos" fibers with this disease. Fluoro-edenite, a silicate mineral found in the southeast of Biancavilla (Sicily, Italy), has been identified as a potential risk factor for mesothelioma. Unfortunately, this cancer often has a poor prognosis, and current diagnostic and prognostic biomarkers are inadequate. Histological subtype, gender, and age at diagnosis are the most significant parameters for mesothelioma. Stathmin, a cytosolic protein that regulates cell growth and migration and is overexpressed in many human malignancies, has not yet been linked to mesothelioma survival or clinical-pathological variables.
    AIM: The aim of this study was to investigate the immunohistochemical expression of stathmin in ten mesothelioma tissue samples with available clinical and follow-up data.
    MATERIAL AND METHODS: Paraffin-embedded tissue samples from ten mesothelioma patients were processed for immunohistochemical analyses to evaluate stathmin expression.
    RESULTS: Our findings suggest that stathmin overexpression is associated with shorter overall survival in patients with mesothelioma. Furthermore, stathmin expression was significantly correlated with the survival time of mesothelioma patients.
    CONCLUSION: Our results suggest that stathmin expression may serve as a potential prognostic biomarker for mesothelioma. This biomarker could be used to promptly identify patients with poor prognosis and to guide clinicians in the selection of treatment options.
    DOI:  https://doi.org/10.14670/HH-18-649
  7. Br J Gen Pract. 2023 Jul;pii: bjgp23X733485. [Epub ahead of print]73(suppl 1):
    Rethinking continuity in primary care for people with mesothelioma.
    Emilie Couchman, Steph Ejegi-Memeh, Sarah Mitchell, Clare Gardiner.
       BACKGROUND: Mesothelioma is a terminal disease linked to asbestos exposure, often with a poor prognosis. Palliative care can be valuable at all stages of the disease trajectory. GPs have a key role in supporting such patients. Continuity is difficult to provide within the current NHS primary care system but is highly valued by patients with mesothelioma.
    AIM: To understand the experiences of continuity in primary care among people with mesothelioma, their close persons, and their healthcare professionals; how they achieve this (or not); and how it affects healthcare service use.
    METHOD: A systematic review of the international literature on continuity in primary care for people with advanced cancer. Realist case studies of patient journeys through the healthcare system (involving longitudinal interviews and observations with people with mesothelioma, their close persons, and their healthcare professionals; and exploration of the organisational context).
    RESULTS: Four themes were developed from the literature: the role of GPs in facilitating continuity; the role of patients and/or close persons in facilitating continuity; changing needs throughout the disease trajectory; and the organisational context in primary care. Preliminary findings from the case study data are presented. The coding framework includes themes relating to the initial programme theories, the Candidacy Framework, components of capacity, researcher reflexivity, and other disease- and service-specific themes.
    CONCLUSION: More research is needed to understand the experiences of continuity in primary care among people with mesothelioma. Specifically, there is an evidence gap regarding understanding their ability to achieve their desired level of continuity within primary care.
    DOI:  https://doi.org/10.3399/bjgp23X733485
  8. ESMO Open. 2023 Jul 13. pii: S2059-7029(23)00835-9. [Epub ahead of print]8(4): 101600
    Molecular alterations and potential actionable mutations in peritoneal mesothelioma: a scoping review of high-throughput sequencing studies.
    M V Dietz, J P van Kooten, M S Paats, J G V J Aerts, C Verhoef, E V E Madsen, H J Dubbink, J H von der Thüsen.
       BACKGROUND: Peritoneal mesothelioma (PeM) is a rare malignancy with a poor prognosis. Currently there is a lack of effective systemic therapies. Due to the rarity of PeM, it is challenging to study new treatment options. Off-label use of targeted drugs could be an effective approach. This scoping review aims to explore the genomic landscape of PeM to identify potential therapeutic targets.
    MATERIALS AND METHODS: A systematic literature search of Embase, Medline, Web of Science, the Cochrane Library, and Google Scholar was carried out up to 1 November 2022. Studies that reported on molecular alterations in PeM detected by high-throughput sequencing techniques were included. Genes that were altered in ≥1% of PeMs were selected for the identification of potential targeted therapies.
    RESULTS: Thirteen articles were included, comprising 824 PeM patients. In total, 142 genes were altered in ≥1% of patients, of which 7 genes were altered in ≥10%. BAP1 was the most commonly altered gene (50%). Other commonly altered genes were NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%), and SETD2 (13%). In total, 17% of PeM patients were carriers of a germline mutation, mainly in BAP1 (7%).
    CONCLUSIONS: This scoping review provides an overview of the mutational landscape of PeM. Germline mutations might be a larger contributor to the incidence of PeM than previously thought. Currently available targeted therapy options are limited, but several targeted agents [such as poly (ADP-ribose) polymerase (PARP), enhancer of zeste homolog 2 (EZH2), and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors] were identified that might provide new targeted therapy options in the future.
    Keywords:  germline mutations; molecular alterations; peritoneal mesothelioma; targeted therapies
    DOI:  https://doi.org/10.1016/j.esmoop.2023.101600
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