bims-mesote Biomed News
on Mesothelioma
Issue of 2021–07–18
nine papers selected by
Laura Mannarino, Humanitas Research
  1. Squamous differentiation in surgically resected malignant pleural mesothelioma with neoadjuvant chemotherapy.
  2. Diagnostic Utility of BAP1, EZH2 and Survivin in Differentiating Pleural Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia: Immunohistochemical Study.
  3. Recent Patent based perspective on diagnostic and therapeutic interventions in Malignant Mesothelioma: Is Drug Repositioning knocking the door?
  4. Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma.
  5. Mesothelioma Risk Score: A New Prognostic Pretreatment, Clinical-Molecular Algorithm for Malignant Pleural Mesothelioma.
  6. Independent lung ventilation using a piston-driven anesthesia machine to ventilate the affected lung during resection of the visceral pleura for malignant pleural mesothelioma: A case series.
  7. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab.
  8. Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.
  9. Repositioning PARP inhibitors in the treatment of thoracic malignancies.
  1. Pathol Int. 2021 Jul 13.
    Squamous differentiation in surgically resected malignant pleural mesothelioma with neoadjuvant chemotherapy.
    Masaya Yotsukura, Noriko Motoi, Akihiko Yoshida, Yukihiro Yoshida, Kazuo Nakagawa, Shun-Ichi Watanabe.
      We describe a rare case of malignant pleural mesothelioma (MPM) that developed squamous differentiation. MPM can present various patterns of histology, but squamous differentiation has not been reported in any surgically resected cases to date. The patient was a 50-year-old female without smoking habit who had right MPM and underwent pleurectomy/decortication after chemotherapy. Pathological examination of the surgical specimen found that the MPM contained squamous cancer cells with apparent keratinization close to the tubulopapillary epithelioid tumor cells. Squamous differentiation was recognized close to the mesothelial proliferation, and the topographical origin of the tumor could not be recognized in the lung. The tubulopapillary tumor cells were positive for cytokeratin 5/6, Wilms tumor-1, and calretinin, and negative for thyroid transcription factor-1 (TTF-1), claudin-4, and p40. Squamous cells were positive for cytokeratin 5/6 and p40, and negative for Wilms tumor-1, calretinin, and TTF-1. Loss of BRCA1 associated protein-1 (BAP1) was observed in both the tubulopapillary and squamous tumor cells. Based on the loss of BAP1 and no history of smoking, we diagnosed this case as a rare differentiation of biphasic-type MPM into squamous cell carcinoma.
    Keywords:  immunohistochemistry; mesothelioma; squamous cell; surgical treatment
    DOI:  https://doi.org/10.1111/pin.13143
  2. Pathol Oncol Res. 2021 ;27 600073
    Diagnostic Utility of BAP1, EZH2 and Survivin in Differentiating Pleural Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia: Immunohistochemical Study.
    Sarah Adel Hakim, Hoda Hassan Abou Gabal.
      Background: Epithelioid mesothelioma (EM) is the commonest subtype of malignant pleural mesothelioma. Its histopathological discrimination from reactive mesothelial hyperplasia (RMH) could be challenging. Thus, an immunohistochemical panel is mandatory for better discrimination. BAP1 is a newly identified diagnostic marker whose loss is specific to malignant mesothelioma. EZH2 overexpression is reported in different cancers, but its relation to BAP1 in malignant mesothelioma has not been fully understood. Survivin expression is said to be significantly higher in EM than in non-neoplastic pleural tissue, but its diagnostic utility as an immunohistochemical marker has not been thoroughly investigated in this field. To the best of our knowledge, no previous studies have been conducted to assess the diagnostic accuracy of the combined use of these three nuclear markers (BAP1, EZH2 and Survivin) in discriminating pleural EM from RMH. Methods: This retrospective study includes two groups: 81 cases of pleural EM and 67 cases of RMH, retrieved from the archives of Pathology Department of Ain Shams University Hospitals and Ain-Shams University Specialized Hospital during the period from January 2016 to December 2019. An immunohistochemical study was performed using BAP1, EZH2 and Survivin antibodies. Results: There were highly statistically significant relations between study groups as regards the studied markers (p = 0.001 for each). The specificity was 100% for all combinations of immunohistochemical markers. Sensitivity of any combination of the immunohistochemical markers used in this study was found to be higher than the sensitivity of any of these markers used individually. The combination of all three markers showed the highest diagnostic accuracy (95.9%) and the highest sensitivity (92.6%). However, the combination of Survivin and EZH2 yielded the same diagnostic accuracy and sensitivity. Conclusion: Adding EZH2, Survivin and BAP1 to the diagnostic IHC panel for differentiating pleural EM and RMH could enhance diagnostic sensitivity. Moreover, Survivin is a potentially promising marker in this context, especially when combined with EZH2.
    Keywords:  BAP1; EZH2; immunohistochemistry; mesothelioma; reactive mesothelial hyperplasia; survivin
    DOI:  https://doi.org/10.3389/pore.2021.600073
  3. Recent Pat Anticancer Drug Discov. 2021 Jul 11.
    Recent Patent based perspective on diagnostic and therapeutic interventions in Malignant Mesothelioma: Is Drug Repositioning knocking the door?
    Vikas Yadav, Roghaiyeh Safari.
       BACKGROUND: Malignant Mesothelioma (MM), an orphan but aggressive malignancy of the mesothelial membrane, is a fatal tumor. Global epidemic related to malignant pleural mesothelioma is on the rise, so there is a need to explore novel biomarkers and ingenious therapeutic approaches to stalk this silent killer.
    OBJECTIVE: The main aim of the present review is to provide a consolidated overview of the recent active patents related to diagnosis and therapy in MM that will affect its future management.
    METHOD: A search of existing literature was conducted from a PubMed database search. Recent patent information was fetched out from online accessible open-access databases. For related clinical trials, www.clinicaltrial.gov was searched.
    RESULTS: Patent search data showed 72 active patents related to diagnosis and therapy in the field of MM, which we classified into eight broad categories. Of these, a maximum of 17 patents was attributed to immunotherapy, and 13 each were attributed to "Drug Repositioning" and "Biological / synthetic" based candidates. The remaining 17 patents were distributed amongst virotherapy and various miscellaneous categories. A relatively low number of patents accounts for gene signature (7), epigenetics (3), and microRNA (2) based diagnosis and therapy. Furthermore, our clinical trial-based investigation revealed the futuristic impact of listed patents in MM patient management.
    CONCLUSION: This review article has provided an overview of patent-based advancement in MM, which might become the apex in clinical settings in the future. Interestingly, immunotherapy and "drug repositioning" based therapy seems to be the front-runners in the race to provide relief.
    Keywords:  Clinical Trials; Drug Repositioning; Epigenetics; Immunotherapy; Malignant Mesothelioma; MicroRNA; Recent Patent; Virotherapy
    DOI:  https://doi.org/10.2174/1574892816666210712113739
  4. Front Oncol. 2021 ;11 660039
    Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma.
    Stefanie Hiltbrunner, Laura Mannarino, Michaela B Kirschner, Isabelle Opitz, Angelica Rigutto, Alexander Laure, Michela Lia, Paolo Nozza, Antonio Maconi, Sergio Marchini, Maurizio D'Incalci, Alessandra Curioni-Fontecedro, Federica Grosso.
      Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.
    Keywords:  genetic alterations; immunotherapy; mesothelioma; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.660039
  5. J Thorac Oncol. 2021 Jul 06. pii: S1556-0864(21)02255-3. [Epub ahead of print]
    Mesothelioma Risk Score: A New Prognostic Pretreatment, Clinical-Molecular Algorithm for Malignant Pleural Mesothelioma.
    Beow Y Yeap, Assunta De Rienzo, Ritu R Gill, Michela E Oster, Mary N Dao, Nhien T Dao, Rachel D Levy, Kimberly Vermilya, Corinne E Gustafson, Gavin Ovsak, William G Richards, Raphael Bueno.
       BACKGROUND: Prognostic models for malignant pleural mesothelioma (MPM) have been limited to demographics, symptoms, and laboratory values. We hypothesize higher accuracy using both tumor and patient characteristics. The Mesothelioma Prognostic Test (MPT) and molecular subtype based on Claudin-15 to Vimentin (C/V) expression ratio are molecular signatures associated with survival. Tumor volume (TV) has improved performance compared to clinical staging, while neutrophil-to-lymphocyte ratio (NLR) is prognostic for MPM.
    METHODS: Tumor specimens and clinical data were collected prospectively from patients who underwent extra-pleural pneumonectomy (EPP) or pleurectomy and decortication (PD) during 2007-2014. MPT and C/V ratio were determined by RT-qPCR, while TV was assessed from pre-operative scans. Risk groups were derived from combinations of adverse factors based on the Cox model. Predictive accuracy was assessed using Harrell's c-index.
    RESULTS: MPT, molecular subtype, TV, and NLR were independently prognostic in EPP patients (N=191), suggesting equal weighting in a final three-group model (c=0.644). In the PD cohort (N=193), MPT poor risk combined with TV>200 cc was associated with triple the risk compared to other subgroups (hazard ratio=2.94, 95% CI: 1.70-5.09, p<0.001) persisting when adjusted for molecular subtype, NLR, performance status and serum albumin to yield a final three-group model (c=0.641). The EPP and PD models achieved higher accuracy than published models (c<0.584, c<0.575) and pathological staging (c=0.554, c=0.571).
    CONCLUSION(S): The novel models utilize pre-treatment parameters obtained from minimally invasive biopsy, imaging and blood tests to evaluate the expected outcome of each type of surgery in newly diagnosed patients and improve stratification on clinical trials.
    Keywords:  Mesothelioma; Prediction; RT-qPCR tests; Surgery; Survival
    DOI:  https://doi.org/10.1016/j.jtho.2021.06.014
  6. J Clin Anesth. 2021 Jul 13. pii: S0952-8180(21)00297-X. [Epub ahead of print]75 110456
    Independent lung ventilation using a piston-driven anesthesia machine to ventilate the affected lung during resection of the visceral pleura for malignant pleural mesothelioma: A case series.
    Tatsuya Kida, Teisei Kobashi, Tomohide Takei, Takao Morohoshi, Masakazu Sumitomo.
      
    Keywords:  independent lung ventilation; malignant pleural mesothelioma; piston-driven anesthesia machine; pleurectomy/decortication
    DOI:  https://doi.org/10.1016/j.jclinane.2021.110456
  7. Cancer Discov. 2021 Jul 15. pii: candisc.0407.2021. [Epub ahead of print]
    A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab.
    Prasad S Adusumilli, Marjorie G Zauderer, Isabelle Riviere, Stephen B Solomon, Valerie W Rusch, Roisin E O'Cearbhaill, Amy Zhu, Waseem Cheema, Navin K Chintala, Elizabeth Halton, John Pineda, Rocio Perez-Johnston, Kay See Tan, Bobby Daly, Jose A Araujo Filho, Daniel Ngai, Erin McGee, Alain Vincent, Claudia Diamonte, Jennifer L Sauter, Shanu Modi, Devanjan Sikder, Brigitte Senechal, Xiuyan Wang, William D Travis, Mithat Gonen, Charles M Rudin, Renier J Brentjens, David R Jones, Michel Sadelain.
      Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M-60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T-cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for {greater than or equal to}6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0407
  8. Genome Med. 2021 Jul 14. 13(1): 113
    Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.
    Clément Meiller, François Montagne, Theo Z Hirsch, Stefano Caruso, Julien de Wolf, Quentin Bayard, Jean-Baptiste Assié, Léa Meunier, Yuna Blum, Lisa Quetel, Laure Gibault, Ecaterina Pintilie, Cécile Badoual, Sarah Humez, Françoise Galateau-Sallé, Marie-Christine Copin, Eric Letouzé, Arnaud Scherpereel, Jessica Zucman-Rossi, Françoise Le Pimpec-Barthes, Marie-Claude Jaurand, Didier Jean.
       BACKGROUND: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples.
    METHODS: Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed.
    RESULTS: Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients.
    CONCLUSIONS: This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.
    Keywords:  Clonality; NF2 subclonal mutation; Spatial molecular intra-tumor heterogeneity; Thoracic tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13073-021-00931-w
  9. Cancer Treat Rev. 2021 Jul 07. pii: S0305-7372(21)00104-3. [Epub ahead of print]99 102256
    Repositioning PARP inhibitors in the treatment of thoracic malignancies.
    Francesco Passiglia, Maria Lucia Reale, Valeria Cetoretta, Elena Parlagreco, Francesca Jacobs, Angela Listì, Luisella Righi, Paolo Bironzo, Silvia Novello, Giorgio Vittorio Scagliotti.
      The evaluation of the homologous recombination repair (HRR) status is emerging as a predictive tumor agnostic biomarker for poly (ADP-ribose) polymerase (PARP) inhibition across different tumor types and testing for HRR-signature is currently a developing area with promising therapeutic implications. Treatment with PARP inhibitors (PARPi) either as single agent or in combination with chemotherapy have shown so far limited activity in patients with thoracic malignancies. A deeper understanding of the biological background underlying HRR-deficient tumors, along with the recent advent of new effective targeted and immunotherapeutic agents, prompted the design of a new generation of clinical trials investigating novel PARPi-combinations in patients with lung cancer as well as malignant pleural mesothelioma. In this review we briefly summarize the biological basis of the DNA damage response pathway inhibition and provide an updated and detailed overview of clinical trials testing different PARPi-combinations strategies in patients with thoracic malignancies.
    Keywords:  Homologous recombination repair; Malignant pleural mesothelioma; Non-small cell lung cancer; PARP; Small cell lung cancer
    DOI:  https://doi.org/10.1016/j.ctrv.2021.102256
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