bims-mesote 2023-11-12 papers

Issue of 2023–11–12
eight papers selected by
Laura Mannarino, Humanitas Research

Lancet. 2023 Nov 03. pii: S0140-6736(23)01883-4. [Epub ahead of print]

Pembrolizumab plus chemotherapy for pleural mesothelioma.

DOI: https://doi.org/10.1016/S0140-6736(23)01883-4

Lancet. 2023 Nov 03. pii: S0140-6736(23)01613-6. [Epub ahead of print]

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.

BACKGROUND: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma.
METHODS: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual.
FINDINGS: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group.
INTERPRETATION: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma.
FUNDING: The Canadian Cancer Society and Merck & Co.

DOI: https://doi.org/10.1016/S0140-6736(23)01613-6

Nat Commun. 2023 Nov 03. 14(1): 7056

Development of mesothelioma-specific oncolytic immunotherapy enabled by immunopeptidomics of murine and human mesothelioma tumors.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. As the available therapeutic options show a lack of efficacy, novel therapeutic strategies are urgently needed. Given its T-cell infiltration, we hypothesized that MPM is a suitable target for therapeutic cancer vaccination. To date, research on mesothelioma has focused on the identification of molecular signatures to better classify and characterize the disease, and little is known about therapeutic targets that engage cytotoxic (CD8+) T cells. In this study we investigate the immunopeptidomic antigen-presented landscape of MPM in both murine (AB12 cell line) and human cell lines (H28, MSTO-211H, H2452, and JL1), as well as in patients' primary tumors. Applying state-of-the-art immuno-affinity purification methodologies, we identify MHC I-restricted peptides presented on the surface of malignant cells. We characterize in vitro the immunogenicity profile of the eluted peptides using T cells from human healthy donors and cancer patients. Furthermore, we use the most promising peptides to formulate an oncolytic virus-based precision immunotherapy (PeptiCRAd) and test its efficacy in a mouse model of mesothelioma in female mice. Overall, we demonstrate that the use of immunopeptidomic analysis in combination with oncolytic immunotherapy represents a feasible and effective strategy to tackle untreatable tumors.

DOI: https://doi.org/10.1038/s41467-023-42668-7

Front Public Health. 2023 ;11 1236558

The role of single nucleotide polymorphisms related to iron homeostasis in mesothelioma susceptibility after asbestos exposure: a genetic study on autoptic samples.

Pierangela Grignani, Silvia Damiana Visonà, Maria Vittoria Fronda, Paola Borrelli, Maria Cristina Monti, Barbara Bertoglio, Adelaide Conti, Paolo Fattorini, Carlo Previderè.

Asbestos-related diseases still represent a major public health problem all over the world. Among them, malignant mesothelioma (MM) is a poor-prognosis cancer, arising from the serosal lining of the pleura, pericardium and peritoneum, triggered by asbestos exposure. Literature data suggest the key role of iron metabolism in the coating process leading to the formation of asbestos bodies, considered to be both protective and harmful. Two sample sets of individuals were taken into consideration, both residing in Broni or neighboring cities (Northwestern Italy) where an asbestos cement factory was active between 1932 and 1993. The present study aims to compare the frequency of six SNPs involved in iron trafficking, previously found to be related to protection/predisposition to MM after asbestos exposure, between 48 male subjects with documented asbestos exposure who died of MM and 48 male subjects who were exposed to asbestos but did not develop MM or other neoplastic respiratory diseases (Non-Mesothelioma Asbestos Exposed - NMAE). The same analysis was performed on 76 healthy male controls. The allelic and genotypic frequencies of a sub-group of 107 healthy Italian individuals contained in the 1000 genomes database were considered for comparison. PCR-multiplex amplification followed by SNaPshot mini-sequencing reaction was used. The findings presented in this study show that the allelic and genotypic frequencies for six SNP markers involved in iron metabolism/homeostasis and the modulation of tumor microenvironment are not significantly different between the two sample sets of MM and NMAE. Therefore, the SNPs here considered do not seem to be useful markers for individual susceptibility to mesothelioma. This finding is not in agreement with previous literature.

Keywords: SNP; asbestos; iron metabolism; malignant mesothelioma; single base extension (SBE)

DOI: https://doi.org/10.3389/fpubh.2023.1236558

AME Case Rep. 2023 ;7 32

Co-existing pericardial and pleural malignant mesothelioma responding well to nedaplatin and pemetrexed: a case report.

Mindan Wu, Zhixuan Li, Junfu Cai, Xianyang Zhong, Wenchuan Zheng, Shuhan Wu, Maohuang Lin, Qichuan Zhang.

Background: Malignant mesothelioma (MM) is a rare cancer with poor prognosis. It is less common that two serosal cavities are involved when the patient seeks medical attention firstly. The current first-line chemotherapy for advanced MM is a combination with cisplatin and pemetrexed. However, nedaplatin, a second-generation platinum-based antitumor agent, has the similar therapeutic effects as cisplatin but lower toxicity and higher water solubility. To our knowledge, this is the first case of co-existing pericardial and pleural MM treated with nedaplatin and pemetrexed and responding well.
Case Description: A 33-year-old woman, who had worked in a kiln for more than 10 years, suffered from dyspnea and chest tightness for 6 days. Chest computed tomography (CT) showed a massive pericardial effusion. She was diagnosed tuberculous pericarditis and received 6 months antituberculosis treatment (rifampicin, isoniazide, pyrazinamide, ethambutol). But it was ineffective and she was re hospitalized again due to massive pleural effusion and pericardial effusion. She was diagnosed with co-existing pericardial and pleural MM finally based on pleural biopsy and cytology of pericardial effusion. She was responding well excitedly to chemotherapy with nedaplatin and pemetrexed with high tolerance. Bone marrow toxicity or recurrent massive pericardial or pleural effusion were not observed during chemotherapy. However, she gave up chemotherapy and has survived for 22 months, from the onset symptoms.
Conclusions: In terms of clinical tolerance and less adverse reactions, we suggest that chemotherapy of nedaplatin with pemetrexed may be a more appropriate treatment in advanced MM. Further clinical trials are warrant.

Keywords: Malignant pericardial mesothelioma; case report; chemotherapy; malignant pleural mesothelioma; nedaplatin

DOI: https://doi.org/10.21037/acr-22-102

Cell Death Dis. 2023 Nov 08. 14(11): 725

Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.

Yakinthi Chrisochoidou, Rajat Roy, Pooyeh Farahmand, Guadalupe Gonzalez, Jennifer Doig, Lukas Krasny, Ella F Rimmer, Anne E Willis, Marion MacFarlane, Paul H Huang, Neil O Carragher, Alison F Munro, Daniel J Murphy, Kirill Veselkov, Michael J Seckl, Miriam F Moffatt, William O C Cookson, Olivier E Pardo.

Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients.

DOI: https://doi.org/10.1038/s41419-023-06240-x

J Occup Med Toxicol. 2023 Nov 09. 18(1): 24

Quantitative assessment of asbestos fibers in some normal and pathological extra-abdominal tissues-a scoping review.

Francesca Graziosi, Paola Caffaro, Mattia Bonetti, Francesco Roccuzzo, Samantha Rota, Paolo Boffetta, Yohama Auxiliadora Caraballo-Arias, Carlotta Zunarelli, Nataliia Danilevskaia, Francesco Saverio Violante.

BACKGROUND: Asbestos is a mineral present in nature and it has been used for years in numerous settings. Asbestos enters the bloodstream and lymphatic system mainly through breathing.
OBJECTIVES: Studies with asbestos fiber's quantification in human tissues are scarce except for the lung. This article summarizes asbestos studies in some extra-abdominal tissues.
METHODS: A scoping review of articles that quantified asbestos fibers in extra-abdominal tissues (lymph nodes, pharynx, larynx, trachea, heart) by electron microscopy (Scanning-SEM or Transmission-TEM) was performed.
RESULTS: The 10 studies selected comprised 52 cases, out of whom 108 samples were analyzed. Mostly samples were lymph node tissues (102), followed by larynx (3) and myocardium (3). No studies were found that determined the presence of asbestos in the pharynx or trachea. The concentration of asbestos fibers detected in the lymph nodes was from 0.003 million fibers per gram of dry tissue (mfgdt) up to 7400 mfgdt, in the larynx the range was from 0.5 mfgdt up to 3.6 mfgdt, in myocardium no asbestos fibers were detected.
DISCUSSION: The studies included were heterogeneous in terms of case and sample characteristics and analytical techniques. As subjects exposed to asbestos are often positive for fibers in thoracic lymph nodes, we suggest that whenever a human tissue sample is analyzed for asbestos presence, the relevant draining lymph node should be concomitantly studied.

Keywords: Amphiboles; Asbestos fibers; Chrysotile; Electron microscopy; Lymph node; Scoping review

DOI: https://doi.org/10.1186/s12995-023-00392-4

Diagn Cytopathol. 2023 Nov 09.

Morphological markers of chromosomal instability as predictors of malignancy in pleural effusion.

Phiza Aggarwal, Uma Handa, Ranjeev Bhagat, Deepak Aggarwal.

BACKGROUND: Malignancy in pleural effusion is an indication of poor prognosis. The distinction between malignant cells and reactive mesothelial cells in effusion cytology is sometimes difficult and requires ancillary techniques. Evaluation of morphological indicators of chromosomal instability (CI) like micronuclei (MN), chromatin bridging (CB), nuclear budding (NB), and multipolar mitosis (MM) on routine cytology smears is a promising tool to distinguish malignant from benign ascitic fluids. However, it has been scarcely evaluated in pleural effusions. The present study was conducted to evaluate the diagnostic value of these markers in differentiating between malignant and benign pleural fluids.
METHODS: It is a cross sectional study in which a total of 72 pleural fluid samples over a period of 2 years received in the cytology department of the hospital were evaluated. The cytological analysis was done by two independent cytopathologists and interpreted as either malignant or benign. Four morphological markers of CI were counted in the May-Grünwald Giemsa (MGG) stained smears of all the cases and the score was compared with the conventional cyto-morphological diagnosis.
RESULTS: Out of 72 cases, there were 42 malignant and 30 benign effusions on cytological examination. The mean score of micronuclei count, nuclear budding, chromatin bridging and multipolar mitosis in malignant effusions were 7.26 ± 2.74, 9.55 ± 5.53, 1.83 ± 1.17, and 2.21 ± 1.62 respectively that was significantly higher than the benign effusions (1 ± 0.71, 1.1 ± 0.86, 0.38 ± 0.50, and 0.15 ± 0.37 respectively) (p < .05). On Receiver operating characteristic (ROC) curve analysis, a cut-off of 5 for the MN count had a sensitivity of 88% and specificity of 100% in detecting malignant pleural effusion [Area under curve (AUC) 95.8%, p < .001].
CONCLUSION: Evaluation of morphological indicators of CI on routine MGG stained smears is a simple and cost-effective method to differentiate between benign and malignant pleural fluids.

Keywords: chromatin bridging; chromosomal instability; micronuclei; multipolar mitosis; nuclear budding; pleural effusion

DOI: https://doi.org/10.1002/dc.25249