bims-mesote Biomed News
on Mesothelioma
Issue of 2024‒07‒07
seven papers selected by
Laura Mannarino, Humanitas Research
  1. Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling.
  2. Comparative analysis of genetic variants in pleural fluids and solid tissue biopsies of pleural mesothelioma patients: Implications for molecular heterogeneity assessment.
  3. Clinical investigation of former workers exposed to asbestos: the health surveillance experience of an Italian University Hospital.
  4. Thoracic SMARCA4-Deficient Undifferentiated Tumor Mimicking Malignant Pleural Mesothelioma on FDG PET/CT.
  5. Single cell view of tumor microenvironment gradients in pleural mesothelioma.
  6. Adverse Prognostic Impact of Transitional and Pleomorphic Patterns in Pleural Nonepithelioid Mesothelioma: Insights From Comprehensive Analysis and Reticulin Stain.
  7. Fibroblast Activation Protein-Directed Imaging Outperforms 18F-FDG PET/CT in Malignant Mesothelioma: A Prospective, Single-Center, Observational Trial.
  1. Cancer Cell Int. 2024 Jun 29. 24(1): 226
    Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling.
    Irene Dell'Anno, Federica Morani, Simone Patergnani, Antonio Daga, Paolo Pinton, Carlotta Giorgi, Luciano Mutti, Federica Gemignani, Stefano Landi.
      BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model.METHODS: In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves.
    RESULTS: After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca2+ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076).
    CONCLUSIONS: Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.
    Keywords:  Malignant pleural mesothelioma; Mitochondrial uncouplers; NOD-SCID; Thonzonium bromide
    DOI:  https://doi.org/10.1186/s12935-024-03400-7
  2. Heliyon. 2024 Jun 15. 10(11): e32152
    Comparative analysis of genetic variants in pleural fluids and solid tissue biopsies of pleural mesothelioma patients: Implications for molecular heterogeneity assessment.
    Roberto Silvestri, Filomena Rea, Marianna Vitiello, Gabriele Moretti, Vittorio Aprile, Marco Lucchi, Paolo Aretini, Chiara Maria Mazzanti, Stefano Landi, Federica Gemignani.
      Objectives: This study aims to determine whether the sequencing of DNA extracted from pleural fluids (PFs) of Pleural Mesothelioma (PM) patients accurately represents the genetic information obtained from the solid tissue counterpart biopsies with particular attention to the identification of single nucleotide variants (SNVs).Materials and methods: Single pleural biopsy, PFs, and blood were collected from PM patients. DNA was extracted from these samples and then subjected to Whole-Exome Sequencing.
    Results: A higher number of SNVs was identified in PFs than in solid tissue biopsies (STBs). Most SNVs were detected in PFs samples but not in STBs samples, while only a few SNVs were detected in STBs samples but not in PFs samples.
    Conclusion: The current findings support the notion that PFs might offer a more robust depiction of cancer's molecular diversity. Nonetheless, the current outcomes challenge the assertion that liquid biopsies can encompass the entirety of intra-patient variations. Indeed, a subset of potential cancer-driver SNVs was exclusively identified in STBs. However, relying solely on STBs would have precluded the detection of significant SNVs that were exclusively present in PFs. This implies that while PFs serve as a valuable complement to STBs, they do not supplant them.
    Keywords:  Cancer-specific mutations; Liquid biopsies; Pleural mesothelioma; Tumour heterogeneity; Whole-exome sequencing
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e32152
  3. Front Public Health. 2024 ;12 1411910
    Clinical investigation of former workers exposed to asbestos: the health surveillance experience of an Italian University Hospital.
    Luigi De Maria, Floriana Pentimone, Domenica Cavone, Antonio Caputi, Stefania Sponselli, Francesco Fragassi, Francesco Dicataldo, Vito Luisi, Giuseppe Delvecchio, Gianmarco Giannelli, Francesco Cafaro, Stefano Sole, Claudia Ronghi, Silvia Zagaria, Giuseppe Loiacono, Gianfranco Sifanno, Giovanni Maria Ferri, Luigi Vimercati.
      Background: The need for health surveillance of former workers exposed to asbestos was provided by law in Italy after the asbestos ban in 1992.Objectives: We describe the results of the health surveillance of former workers exposed to asbestos, conducted over 27 years, from 1994 to 2020, at the Operative Unit of Occupational Medicine of the University Hospital of Bari.
    Materials and methods: We adopted the health surveillance protocol, which was validated at the national level in 2018.
    Results: A total of 1,405 former workers exposed to asbestos were examined. We proceeded with diagnosing pathologies in 339 cases (24% of the cohort subjected to surveillance), with diagnoses of some cases involving multiple pathologies. Specifically, pleural plaques were diagnosed in 49.2% of the 339 cases, asbestosis in 35.9%, malignant pleural mesothelioma (MPM) in 20.3%, mesothelioma of the vaginal tunic of the testis (MTVT) in 9.1%, lung cancer in 5.8%, and laryngeal cancer in 0.8%.
    Conclusion: Despite the 1992 asbestos ban, asbestos-related diseases remain a serious public health issue. It is important to establish criteria that ensure the health surveillance of formerly exposed workers minimizes costs, reduces the number of invasive examinations, and optimizes achievable results.
    Keywords:  Occupational Medicine; asbestos; asbestosis; formerly exposed workers; health surveillance; mesothelioma
    DOI:  https://doi.org/10.3389/fpubh.2024.1411910
  4. Clin Nucl Med. 2024 Jul 03.
    Thoracic SMARCA4-Deficient Undifferentiated Tumor Mimicking Malignant Pleural Mesothelioma on FDG PET/CT.
    Haibo Wu, Yinting Zhou, Aisheng Dong, Yang Wang, Yan Han.
      ABSTRACT: We describe contrast-enhanced CT and FDG PET/CT findings in a case of thoracic SMARCA4-deficient undifferentiated tumor with extensive pleural involvement and mediastinal lymph node metastases. Contrast-enhanced CT showed multiple enhancing right-sided pleural masses and soft tissue plaques and enlarged mediastinal lymph nodes. The pleural lesions and mediastinal lymph nodes showed intense FDG uptake mimicking malignant pleural mesothelioma with mediastinal lymph node metastases.
    DOI:  https://doi.org/10.1097/RLU.0000000000005358
  5. Cancer Discov. 2024 Jul 05.
    Single cell view of tumor microenvironment gradients in pleural mesothelioma.
    Bruno Giotti, Komal Dolasia, William Zhao, Peiwen Cai, Robert Sweeney, Elliot Merritt, Evgeny Kiner, Grace S Kim, Atharva Bhagwat, Thinh Nguyen, Samarth Hegde, Bailey G Fitzgerald, Sanjana Shroff, Travis Dawson, Monica Garcia-Barros, Jamshid Abdul-Ghafar, Rachel Chen, Sacha Gnjatic, Alan Soto, Rachel Brody, Seunghee Kim-Schulze, Zhihong Chen, Kristin G Beaumont, Miriam Merad, Raja M Flores, Robert P Sebra, Amir Horowitz, Thomas U Marron, Anna Tocheva, Andrea Wolf, Alexander M Tsankov.
      Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0017
  6. Arch Pathol Lab Med. 2024 Jul 02.
    Adverse Prognostic Impact of Transitional and Pleomorphic Patterns in Pleural Nonepithelioid Mesothelioma: Insights From Comprehensive Analysis and Reticulin Stain.
    Francesco Fortarezza, Federica Pezzuto, Sonia Maniglio, Andrea Marzullo, Antonio d'Amati, Domenica Cavone, Daniele Egidio Romano, Floriana Pentimone, Angela De Palma, Giuseppe Marulli, Teresa Lettini, Concetta Caporusso, Marcella Barbarino, Cecilia Salzillo, Andrea Quaranta, Fiorella Calabrese, Gabriella Serio, Luigi Vimercati.
      CONTEXT.—: Mesothelioma subtyping into epithelioid and nonepithelioid categories plays a crucial role in prognosis and treatment selection, with emerging recognition of the impact of various histologic patterns.OBJECTIVE.—: To investigate the prognostic implications of transitional and pleomorphic patterns in sarcomatoid mesothelioma.
    DESIGN.—: A total of 132 mesothelioma cases (87 biphasic, 45 sarcomatoid) were analyzed. Histologic slides were assessed, treatment data collected, and cases categorized into predominant epithelioid or sarcomatoid patterns. The sarcomatoid mesotheliomas were classified into usual, pleomorphic, and transitional patterns, with reticulin staining for the latter. Statistical analysis included Cox regression and Kaplan-Meier methods.
    RESULTS.—: Younger age (P = .02) and receiving therapy (P < .001) correlated with improved survival for both histotypes. Advanced stage was associated with shorter survival in sarcomatoid cases (P = .02). Predominant epithelioid pattern in biphasic cases led to longer survival (P < .001). Transitional and pleomorphic patterns were indicative of worse prognosis, with significantly lower survival in cases with both patterns than with usual sarcomatoid (P = .046). Multivariate analysis identified independent survival factors, including predominant epithelioid component in biphasic mesothelioma (P = .001) and chemotherapy (P < .001).
    CONCLUSIONS.—: Histologic subtyping in mesothelioma plays a pivotal role in prognosis. Transitional and pleomorphic patterns, even in low percentages, indicate poorer outcomes. This study highlights the need for standardized diagnostic support and suggests the potential utility of histochemical staining in identifying more aggressive morphologic aspects. Recognizing the significance of these patterns can guide treatment decisions and patient care strategies.
    DOI:  https://doi.org/10.5858/arpa.2023-0523-OA
  7. J Nucl Med. 2024 Jul 03. pii: jnumed.124.267473. [Epub ahead of print]
    Fibroblast Activation Protein-Directed Imaging Outperforms 18F-FDG PET/CT in Malignant Mesothelioma: A Prospective, Single-Center, Observational Trial.
    Lukas Kessler, Felix Schwaning, Martin Metzenmacher, Kim Pabst, Jens Siveke, Marija Trajkovic-Arsic, Benedikt Schaarschmidt, Marcel Wiesweg, Clemens Aigner, Till Plönes, Kaid Darwiche, Servet Bölükbas, Martin Stuschke, Lale Umutlu, Michael Nader, Dirk Theegarten, Rainer Hamacher, Wilfried E E Eberhardt, Martin Schuler, Ken Herrmann, Wolfgang P Fendler, Hubertus Hautzel.
      The fibroblast activation protein (FAP) is highly expressed in tumor and stromal cells of mesothelioma and thus is an interesting imaging and therapeutic target. Previous data on PET imaging with radiolabeled FAP inhibitors (FAPIs) suggest high potential for superior tumor detection. Here, we report the data of a large malignant pleural mesothelioma cohort within a 68Ga-FAPI46 PET observational trial (NCT04571086). Methods: Of 43 eligible patients with suspected or proven malignant mesothelioma, 41 could be included in the data analysis of the 68Ga-FAPI46 PET observational trial. All patients underwent 68Ga-FAPI46 PET/CT, contrast-enhanced CT, and 18F-FDG PET/CT. The primary study endpoint was the association of 68Ga-FAPI46 PET uptake intensity and histopathologic FAP expression. Furthermore, secondary endpoints were detection rate and sensitivity, specificity, and positive and negative predictive values as compared with 18F-FDG PET/CT. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between 68Ga-FAPI46 SUVmax or SUVpeak and histopathologic FAP expression was significant (SUVmax: r = 0.49, P = 0.037; SUVpeak: r = 0.51, P = 0.030).68Ga-FAPI46 and 18F-FDG showed similar sensitivity by histopathologic validation on a per-patient (100.0% vs. 97.3%) and per region (98.0% vs. 95.9%) basis. Per-region analysis revealed higher 68Ga-FAPI46 than 18F-FDG specificity (81.1% vs. 36.8%) and positive predictive value (87.5% vs. 66.2%). Conclusion: We confirm an association of 68Ga-FAPI46 uptake and histopathologic FAP expression in mesothelioma patients. Additionally, we report high sensitivity and superior specificity and positive predictive value for 68Ga-FAPI46 versus 18F-FDG.
    Keywords:  FAPI; cancer imaging; fibroblast activation protein; mesothelioma; thoracic cancer
    DOI:  https://doi.org/10.2967/jnumed.124.267473
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