bims-mesote Biomed News
on Mesothelioma
Issue of 2023–12–24
eleven papers selected by
Laura Mannarino, Humanitas Research
  1. Mesothelin methylation, soluble mesothelin related protein levels and inflammation profiling in workers chronically exposed to naturally occurring asbestos fibers.
  2. Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy.
  3. Malignant pleural mesothelioma mimics thoracic empyema: A case report.
  4. The Current Treatment Landscape of Malignant Pleural Mesothelioma and Future Directions.
  5. Clinical outcomes of stereotactic body radiation therapy for malignant pleural mesothelioma.
  6. PD-L1 expression complements CALGB prognostic scoring system in malignant pleural mesothelioma.
  7. Efficacy and safety profile of combining antiangiogenic agents with chemotherapy in patients with advanced malignant pleural mesothelioma: A systematic review and meta-analysis of randomized controlled trials.
  8. Niraparib plus Dostarlimab in Pleural Mesothelioma or Non-Small Cell Lung Cancer harboring HRR mutations: interim results of the UNITO-001 phase 2 prospective trial.
  9. Clinical Next Generation Sequencing Application in Mesothelioma: Finding a Golden Needle in the Haystack.
  10. Nivolumab and ipilimumab in the real-world setting in patients with mesothelioma.
  11. Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma.
  1. Transl Oncol. 2023 Dec 21. pii: S1936-5233(23)00258-9. [Epub ahead of print]40 101872
    Mesothelin methylation, soluble mesothelin related protein levels and inflammation profiling in workers chronically exposed to naturally occurring asbestos fibers.
    Caterina Ledda, Carla Loreto, Claudia Lombardo, Venera Cardile, Venerando Rapisarda.
      Exposure to asbestiform fibers, including chrysotile and amphibole, is carcinogenic, causing malignant pleural mesothelioma (MPM) when inhaled. Some populations globally face Naturally Occurring Asbestos (NOA) exposure, leading to MPM cases like in Biancavilla, Italy, from Fluoro-edenite (FE) contamination. Studies show NOA exposure causes epigenetic changes, focusing on mesothelin methylation, an MPM marker, and altered inflammation, emphasizing the health risks of FE and asbestos. This research, conducted from February 2022 to October 2022, studied 125 construction workers from Biancavilla and 125 controls from 40 km away without Biancavilla work history. With at least ten years in construction and no respiratory conditions, participants underwent medical assessments and gave blood samples for analysis, including inflammation markers, mesothelin methylation, and soluble mesothelin-related protein levels. The results showed similar demographics but differing inflammation and methylation levels in exposed workers, suggesting long-term cellular changes. Pearson correlation showed intricate biomarker relationships. Significant inflammatory differences were found between FE exposed and non-exposed workers, indicating potential health impacts from FE. This raises concerns for communities like Biancavilla, emphasizing the importance of extensive epigenetic research for public health.
    Keywords:  Asbestiform fibers; Biancavilla; Epigenetic; Fluoro-edenite; Inflammation; Malignant pleural mesothelioma; Mesothelin; Methylation; Naturally occurring asbestos; Soluble mesothelin related protein
    DOI:  https://doi.org/10.1016/j.tranon.2023.101872
  2. Cancers (Basel). 2023 Dec 10. pii: 5787. [Epub ahead of print]15(24):
    Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy.
    Susana Cedres, Augusto Valdivia, Patricia Iranzo, Ana Callejo, Nuria Pardo, Alejandro Navarro, Alex Martinez-Marti, Juan David Assaf-Pastrana, Enriqueta Felip, Pilar Garrido.
      Malignant pleural mesothelioma (MPM) is a locally aggressive disease related to asbestos exposure with a median survival for untreated patients of 4-8 months. The combination of chemotherapy based on platinum and antifolate is the standard treatment, and the addition of bevacizumab adds two months to median survival. Recently, in first-line treatment, immunotherapy combining nivolumab with ipilimumab has been shown to be superior to chemotherapy in the CheckMate-743 study in terms of overall survival (18.1 months), leading to its approval by the FDA and EMA. The positive results of this study represent a new standard of treatment for patients with MPM; however, not all patients will benefit from immunotherapy treatment. In an effort to improve the selection of patient candidates for immunotherapy for different tumors, biomarkers that have been associated with a greater possibility of response to treatment have been described. MPM is a type of tumor with low mutational load and neo-antigens, making it a relatively non-immunogenic tumor for T cells and possibly less susceptible to responding to immunotherapy. Different retrospective studies have shown that PD-L1 expression occurs in 20-40% of patients and is associated with a poor prognosis; however, the predictive value of PD-L1 in response to immunotherapy has not been confirmed. The purpose of this work is to review the state of the art of MPM treatment in the year 2023, focusing on the efficacy results of first-line or subsequent immunotherapy studies on patients with MPM and possible chemo-immunotherapy combination strategies. Additionally, potential biomarkers of response to immunotherapy will be reviewed, such as histology, PD-L1, lymphocyte populations, and TMB.
    Keywords:  biomarkers; immunotherapy; malignant pleural mesothelioma
    DOI:  https://doi.org/10.3390/cancers15245787
  3. World J Clin Cases. 2023 Dec 16. 11(35): 8372-8378
    Malignant pleural mesothelioma mimics thoracic empyema: A case report.
    Ya-Hsin Yao, Yen-Shou Kuo.
       BACKGROUND: Thoracic empyema and malignant pleural mesothelioma (MPM) are distinct medical conditions with similar symptoms, including cough, chest pain, and breathing difficulty. We present a rare MPM case mimicking thoracic empyema. Physicians must consider MPM risks for patients exposed to building material who exhibit lobulated pleural effusions, indicating thoracic empyema.
    CASE SUMMARY: A 68-year-old retired male construction worker suffered from shortness of breath and chest tightness over 10 d, particularly during physical activity. A poor appetite and 4 kg weight loss over the past 3 wk were also reported. Chest images and laboratory data concluded a tentative impression of empyema thoracis (right). Video-assisted thoracic surgery with decortication and delobulation (right) was conducted. The pathological report yielded an MPM diagnosis. Refractory pleural bilateral effusions and respiratory failure developed postoperatively, and the patient died three weeks after the operation.
    CONCLUSION: Thoracic empyema and MPM are distinct medical conditions that can present similar symptoms, and video-assisted thoracic surgery facilitates an accurate diagnosis. Empyema-mimicking presentations and postoperative refractory pleural effusion may indicate a poor MPM outcome.
    Keywords:  Case report; Malignant pleural mesothelioma; Thoracic empyema; Video-assisted thoracic surgery
    DOI:  https://doi.org/10.12998/wjcc.v11.i35.8372
  4. Cancers (Basel). 2023 Dec 12. pii: 5808. [Epub ahead of print]15(24):
    The Current Treatment Landscape of Malignant Pleural Mesothelioma and Future Directions.
    Beatriz Bertin, Miguel Zugman, Gustavo Schvartsman.
      The incidence of malignant pleural mesothelioma is expected to increase globally. New treatment options for this malignancy are eagerly awaited to improve the survival and quality of life of patients. The present article highlights the results of recent advances in this field, analyzing data from several relevant trials. The heterogeneous tumor microenvironment and biology, together with the low mutational burden, pose a challenge for treating such tumors. So far, no single biomarker has been soundly correlated with targeted therapy development; thus, combination strategies are often required to improve outcomes. Locally applied vaccines, the expansion of genetically engineered immune cell populations such as T cells, the blockage of immune checkpoints that inhibit anti-tumorigenic responses and chemoimmunotherapy are among the most promising options expected to change the mesothelioma treatment landscape.
    Keywords:  asbestos; cellular therapy; chemotherapy; immunotherapy; mesothelioma; pleura; targeted agents
    DOI:  https://doi.org/10.3390/cancers15245808
  5. Radiother Oncol. 2023 Dec 15. pii: S0167-8140(23)09364-7. [Epub ahead of print]191 110057
    Clinical outcomes of stereotactic body radiation therapy for malignant pleural mesothelioma.
    Jacob Y Shin, Michael Offin, Charles B Simone, Zhigang Zhang, Annemarie F Shepherd, Abraham J Wu, Narek Shaverdian, Daphna Y Gelblum, Daniel R Gomez, Jennifer L Sauter, Michelle S Ginsberg, Prasad S Adusumilli, Valerie W Rusch, Marjorie G Zauderer, Andreas Rimner.
       BACKGROUND: The objective of this study is to determine the outcomes and toxicities of patients with malignant pleural mesothelioma (MPM) treated with stereotactic body radiotherapy (SBRT).
    MATERIALS AND METHODS: Data were extracted from an institutional tumor registry for patients diagnosed with mesothelioma and treated with SBRT. Kaplan-Meier and Cox regression analyses were employed to determine local control (LC) and overall survival (OS).
    RESULTS: Forty-four patients with 59 total treated tumors from December 2006 to April 2022 were identified. Fifty-one (86.4 %) cases had oligoprogressive disease (five sites or less). The median prescription dose delivered was 3000 cGy in 5 fractions (range: 2700-6000 cGy in 3-8 fractions). Fifty-one (86.4 %) tumors were in the pleura, 4 (6.8 %) spine, 2 (3.4 %) bone, 1 (1.7 %) brain, and 1 (1.7 %) pancreas. The median follow-up from SBRT completion for those alive at last follow-up was 28 months (range: 14-52 months). The most common toxicities were fatigue (50.8 %), nausea (22.0 %), pain flare (15.3 %), esophagitis (6.8 %), dermatitis (6.8 %), and pneumonitis (5.1 %). There were no grade ≥ 3 acute or late toxicities. There were 2 (3.4 %) local failures, one of the pleura and another of the spine. One-year LC was 92.9 % (95 % CI: 74.6-98.2 %) for all lesions and 96.3 % (95 % CI: 76.5-99.5 %) for pleural tumors. One-year LC was 90.9 % (95 % CI: 68.1-97.6 %) for epithelioid tumors and 92.1 % (95 % CI: 72.1-98.0 %) for oligoprogressive tumors. One-year OS from time of SBRT completion was 36.4 % (95 % CI: 22.6-50.3 %). On multivariable analysis, KPS was the lone significant predictor for OS (p = 0.029).
    CONCLUSIONS: Our single-institutional experience on patients with MPM suggests that SBRT is safe with a low toxicity profile and potentially achieve good local control.
    Keywords:  Local control; Oligoprogression; SBRT; Toxicity
    DOI:  https://doi.org/10.1016/j.radonc.2023.110057
  6. Front Oncol. 2023 ;13 1269029
    PD-L1 expression complements CALGB prognostic scoring system in malignant pleural mesothelioma.
    Alejandro Avilés-Salas, Luis Cabrera-Miranda, Norma Hernández-Pedro, Diana Sofía Vargas-Lías, Suraj Samtani, Wendy Muñoz-Montaño, Daniel Motola-Kuba, Luis Corrales-Rodríguez, Claudio Martín, Andrés F Cardona, Cittim B Palomares-Palomares, Oscar Arrieta.
       Background: Programmed death ligand-1 (PD-L1) expression is a predictive biomarker in patients with lung cancer, but its role in malignant pleural mesothelioma (MPM) remains unclear. Evidence suggests that higher PD-L1 expression is correlated with worse survival. CALGB is the main scoring system used to predict the benefit of chemotherapy treatment. This study aimed to determine the prognostic value of PD-L1 expression and its addition to CALGB scoring system in patients with MPM.
    Methods: In this retrospective analysis, we evaluated samples with confirmed locally advanced or metastatic MPM. PD-L1 Tumor Proportional Score (TPS) was determined by immunohistochemistry at diagnosis.
    Results: 73 patients were included in this study. A cutoff value of 15 was set for a high or low PD-L1 TPS. In total, 71.2% (n=52) and 28.8% (n=21) of individuals harbored low or high PD-L1 expression, respectively. PD-L1High was associated with worse median progression-free Survival (mPFS) [4.9 vs. 10.8 months; HR 2.724, 95% CI (1.44-5.14); p = 0.002] and Overall Survival (OS) [6.0 vs. 20.9 months; HR 6.87, 95% CI (3.4-8.7); p<0.001] compared to patients with PD-L1Low. Multivariate analysis confirmed that PD-L1 expression was an independent factor for PFS and OS in patients with MPM and CALGB score of 5-6.
    Conclusion: PD-L1 addition to CALGB scale improves its prognostic estimation of MPM survival and should be considered in future research.
    Keywords:  CALGB; PD-L1; immunohistochemistry; mesothelioma; prognostic factor
    DOI:  https://doi.org/10.3389/fonc.2023.1269029
  7. PLoS One. 2023 ;18(12): e0295745
    Efficacy and safety profile of combining antiangiogenic agents with chemotherapy in patients with advanced malignant pleural mesothelioma: A systematic review and meta-analysis of randomized controlled trials.
    Wei Tian, Qian Guo, Daidi Fu, Xiao Ma, Rui Wang.
       OBJECTIVES: Several prospective trials had been reported on chemotherapy with or without antiangiogenic agents in patients with advanced malignant pleural mesothelioma (MPM), with diverse results. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of the combination regimen.
    METHODS: We systematically identified trials in several databases, including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts. All the randomized controlled trials (RCTs) about chemotherapy combined with antiangiogenic agents in advanced MPM were identified. Overall survival (OS) was the primary outcome, while progression-free survival (PFS), overall response rate (ORR) and serious toxicities were the secondary outcomes. Review Manager 5.3 was used to perform the statistical analyses. Stata 12.0 was used to assess the publication bias of egger's test.
    RESULTS: 5 randomized controlled trials containing 1250 patients were finally included in this analysis. Statistical analyses showed that the addition of antiangiogenic agents to chemotherapy could prolong OS [HR 0.79 (0.71-0.89), p<0.0001] and PFS [HR 0.75 (0.68-0.84), p<0.00001] in advanced MPM, especially in the epithelioid subgroup, with a tolerable toxicity profile. No significant difference was found in the analysis of ORR [HR 1.13 (0.95-1.35), p = 0.18]. Heterogeneity was found in the analyses of PFS and ORR, which might be caused by the limitation in uniform evaluation of tumor response.
    CONCLUSIONS: The combination of antiangiogenic agents with chemotherapy showed superior over chemotherapy alone in patients with advanced MPM. More prospective trials should be warranted to identify patients who would most likely benefit from the combination regimen.
    DOI:  https://doi.org/10.1371/journal.pone.0295745
  8. Clin Cancer Res. 2023 Dec 18.
    Niraparib plus Dostarlimab in Pleural Mesothelioma or Non-Small Cell Lung Cancer harboring HRR mutations: interim results of the UNITO-001 phase 2 prospective trial.
    Francesco Passiglia, Luisella Righi, Paolo Bironzo, Angela Listì, Giovanni Farinea, Enrica Capelletto, Silvia Novello, Alessandra Merlini, Giorgio V Scagliotti.
       INTRODUCTION: Treatment of homologous recombination repair deficient (HRD)-tumours with PARP inhibitors has the potential to further increase tumour immunogenicity, suggesting a synergistic effect with immunotherapy. Here we present the preliminary results of niraparib in combination with dostarlimab for pleural mesothelioma (PM) or non-small cell lung cancer (NSCLC) harboring HRR mutations.
    METHODS: UNITO-001 is a phase 2, prospective, study aiming to investigate the combination of niraparib plus dostarlimab in pre-treated patients with HRD and programmed death ligand-1 (PD-L1) ≥ 1% NSCLC and/or PM. The primary endpoint is progression free survival (PFS).
    RESULTS: A total of 17 out of 183 (10%) screened patients (12 MPM and 5 NSCLC) were included. The objective response rate (ORR) was 6% (95%CIs: 0.1-28.7) and the disease control rate (DCR) was 53% (95%CIs: 27.8-77). Median PFS was 3.1 (95%CIs: 2.7-N.A) and median overall survival (OS) was 4.2 (95%CIs 1.58-N.A) months. The PFS was 14.1 months in one PM patient harboring a germline BAP1 mutation. The treatment duration was 9.8 months in one PM patient harboring a somatic BRCA2 mutation. The most common adverse events (AEs) were grade 1-2 lymphopenia (59%), anemia (35%), hyponatremia (29%) and hypokalemia (29%). Grade ≥ 3 AEs were reported in 23% of the patients.
    CONCLUSION: This preliminary analysis highlighted the lack of antitumor activity for the combination of niraparib and dostarlimab in patients with PM and/or advanced NSCLC harboring BAP1 somatic mutations. A potential antitumor activity emerged for PM with germline BAP1 and/or BRCA2 somatic mutations along with a good tolerability profile.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2431
  9. Cancers (Basel). 2023 Dec 06. pii: 5716. [Epub ahead of print]15(24):
    Clinical Next Generation Sequencing Application in Mesothelioma: Finding a Golden Needle in the Haystack.
    Luigi Cerbone, Sara Orecchia, Pietro Bertino, Sara Delfanti, Antonina Maria de Angelis, Federica Grosso.
      Mesothelioma comprises a group of rare cancers arising from the mesothelium of the pleura, peritoneum, tunica vaginalis testis and pericardium. Mesothelioma is generally associated with asbestos exposure and has a dismal prognosis, with few therapeutic options. Several next generation sequencing (NGS) experiments have been performed on mesothelioma arising at different sites. These studies highlight a genomic landscape mainly characterized by a high prevalence (>20%) of genomic aberrations leading to functional losses in oncosuppressor genes such as BAP1, CDKN2A, NF2, SETD2 and TP53. Nevertheless, to date, evidence of the effect of targeting these alterations with specific drugs is lacking. Conversely, 1-2% of mesothelioma might harbor activating mutations in oncogenes with specifically approved drugs. The goal of this review is to summarize NGS applications in mesothelioma and to provide insights into target therapy of mesothelioma guided by NGS.
    Keywords:  mesothelioma; next generation sequencing; target therapy
    DOI:  https://doi.org/10.3390/cancers15245716
  10. Lung Cancer. 2023 Dec 14. pii: S0169-5002(23)00978-9. [Epub ahead of print]187 107440
    Nivolumab and ipilimumab in the real-world setting in patients with mesothelioma.
    D W Dumoulin, L H Douma, M M Hofman, V van der Noort, R Cornelissen, C J de Gooijer, J A Burgers, J G J V Aerts.
       OBJECTIVES: Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3-4 treatment related adverse events (TRAE's) and TRAE's led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers.
    METHODS: Clinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2-5 TRAE's and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported.
    RESULTS: Between January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 - 13.1). Grade 3-4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE's. ORR was 21.7 % (95 % CI 15.7-27.7), median DOR was 5.7 months (IQR 3.2-8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8-63.2). The mPFS was 5.5 months (95 %CI 4.1-6.9), mOS was 14.1 months (95 % CI 11.1-18.2).
    CONCLUSIONS: Nivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE's, leading to discontinuation of treatment in 25% of the patients.
    Keywords:  Checkpoint inhibition; Immune monitoring; Immunotherapy; Ipilimumab; Malignant pleural mesothelioma/MPM; Nivolumab
    DOI:  https://doi.org/10.1016/j.lungcan.2023.107440
  11. Pharmaceuticals (Basel). 2023 Nov 21. pii: 1635. [Epub ahead of print]16(12):
    Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma.
    Lale Evsen, Patrick J Morris, Craig J Thomas, Michele Ceribelli.
      The hippo signaling pathway is a central tumor suppressor cascade frequently inactivated in selected human cancers, leading to the aberrant activation of TEAD transcription factors. Whereas several TEAD auto-palmitoylation inhibitors are currently in development, a comprehensive assessment of this novel drug-modality is missing. Here, we report a comparative analysis among six TEADi(s) using cell-based and biochemical assays in Hippo pathway deficient mesothelioma. Our analysis revealed varying potency and selectivity across TEADi, also highlighting their limited efficacy. To overcome this limitation, we performed an unbiased, quantitative high-throughput drug screening by combining the TEADi VT-103 with a library of approximately 3000 oncology-focused drugs. By exploiting this library's mechanistic redundancy, we identified several drug-classes robustly synergized with TEADi. These included glucocorticoid-receptor (GR) agonists, Mek1/2 inhibitors, mTOR inhibitors, and PI3K inhibitors, among others. Altogether, we report a coherent single-agent dataset informing on potency and selectivity of TEAD-palmitoylation inhibitors as single-agents. We also describe a rational pipeline enabling the systematic identification of TEAD druggable co-dependencies. This data should support the pre-clinical development of drug combination strategies for the treatment of Hippo-deficient mesothelioma, and more broadly, for other cancers dependent on the oncogenic activity of YAP/TEAD.
    Keywords:  Hippo signaling; TEAD; TEAD inhibitors; TEAD-palmitoylation; YAP; drug combination; high-throughput drug screening; malignant pleural mesothelioma
    DOI:  https://doi.org/10.3390/ph16121635
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