bims-mesote 2024-03-31 papers

Issue of 2024–03–31
four papers selected by
Laura Mannarino, Humanitas Research

J Thorac Oncol. 2024 Mar 21. pii: S1556-0864(24)00086-8. [Epub ahead of print]

The IASLC Mesothelioma Staging Project: Proposals for Revisions of the 'T' Descriptors in the Forthcoming 9th Edition of the TNM Classification for Pleural Mesothelioma.

IASLC Staging and Prognostic Factors Committee

BACKGROUND: The primary tumor (T) component in the 8th edition of pleural mesothelioma (PM) staging system is based on pleural involvement and extent of invasion. Quantitative assessment of pleural tumor has been shown to be prognostic. We explored quantitative and qualitative metrics to develop recommendations for T descriptors in the upcoming 9th edition of the PM staging system.
METHODS: The International Association for the Study of Lung Cancer (IASLC) prospectively collected data on PM patients. Sum of maximum pleural thickness (Psum) was recorded. Optimal combinations of Psum and 8th edition cT descriptors were assessed using recursive binary splitting algorithm, with bootstrap resampling to correct for the adaptive nature of the splitting algorithm and validated in the 8th edition data. Overall survival (OS) was calculated by the Kaplan-Meier method and differences in OS assessed by the log-rank test.
RESULTS: Of 7,338 patients submitted, 3,598 were eligible for cT analysis and 1,790 had Psum measurements. Recursive partitioning identified optimal cutpoints of Psum at 12 and 30 mm which, in combination with extent of invasion, yielded four prognostic groups for OS. Fmax >5mm indicated poor prognosis. cT4 category (based on invasion) showed similar performance to 8th edition. Three 8th edition descriptors were eliminated based on low predictive accuracy. Eighth edition pT descriptors remained valid in 9th edition analyses.
CONCLUSION: Given reproducible prognostication by Psum, size criteria will be incorporated into cT1-T3 categories in the 9th edition. Current cT4 category and all pT descriptors will be maintained, with reclassification of fissural invasion as pT2.

Keywords: Pleural Mesothelioma; Staging; T component

DOI: https://doi.org/10.1016/j.jtho.2024.03.007

Eur J Cancer Prev. 2024 Mar 11.

Pleural mesothelioma in situ: a comprehensive review.

Federica Danuzzo, Federico Raveglia, Francesca Spinelli, Chiara Maria Sibilia, Enrico Cassina, Lidia Libretti, Emanuele Pirondini, Antonio Tuoro, Francesca Bono, Maria Emilia Paladino, Diego Cortinovis, Francesco Petrella.

Pleural mesothelioma is a rare and aggressive cancer that affects the pleura. In recent years, there has been increasing interest and attention in detecting and diagnosing early-stage or precancerous forms of mesothelioma because of its severe prognosis and short life expectancy at the time of diagnosis. Mesothelioma in situ represents a clear opportunity to improve and innovate the diagnostic approach and the multimodality treatment of mesothelioma: the diagnosis of pleural mesothelioma at the 'in-situ phase' means early disease detection and thus paves the way to new possible curable strategies. Since 2021, when mesothelioma in situ was finally identified and described as a new histological entity, its diagnosis and management became a challenge and the subject of ongoing research; several aspects remain open and still outstanding as regards diagnostic techniques, time and probability of progression, need for and methods of follow up, aggressive and early surgery. This narrative review aims to provide a comprehensive overview of mesothelioma in situ covering its definition, risk factors, diagnostic criteria, and tricky aspects of early detection. It also highlights its clinical significance, new perspectives, and potential future indications in the context of pleural mesothelioma multidisciplinary management.

DOI: https://doi.org/10.1097/CEJ.0000000000000883

Br J Cancer. 2024 Mar 22.

Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma.

Nick Landman, Danielle Hulsman, Jitendra Badhai, Jawahar Kopparam, Julian Puppe, Gaurav Kumar Pandey, Maarten van Lohuizen.

BACKGROUND: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time.
METHODS: A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed.
RESULTS: Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1.
CONCLUSIONS: We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.

DOI: https://doi.org/10.1038/s41416-024-02661-3

Ann Work Expo Health. 2024 Mar 26. pii: wxae018. [Epub ahead of print]

Lung fibre burden and risk of malignant mesothelioma in shipyard workers: a necropsy-based case-control study.

Dario Mirabelli, Anna Benedetta Somigliana, Danila Azzolina, Dario Consonni, Pietro Gino Barbieri.

OBJECTIVES: In Italy, the highest pleural cancer mortality and incidence have been observed among Italian regions where the 2 largest Italian shipyards were (and are) located. The objective of this study was to assess the exposure-response relationship for mesothelioma among male workers employed in the Monfalcone, Italy, shipyard.
METHODS: We conducted a necropsy-based case-control study. Cases (N = 102) were mesothelioma decedents and controls were those with lung cancer (N = 84). Complete job histories were available; the lung fibre content was measured using a scanning electron microscope with X-ray fluorescence, after sample preparation according to the European Respiratory Society guidelines. Odds ratios and 95% confidence intervals of mesothelioma by fibre type and lung fibre burden, as a categorical or continuous variable, were assessed by unconditional logistic regression, adjusted for age and time since exposure cessation. Analyses for the amphibole and chrysotile lung fibre burden were mutually adjusted. We calculated a cumulative exposure index by applying a job-exposure matrix to the job histories of study cases and assessed its correlation with the lung fibre burden.
RESULTS: We found an odds ratio of 22.0 (confidence intervals 5.66-85.7) for the highest lung fibre burden category (mean 43.8 million total asbestos fibres per gram of dry tissue) compared with the reference (mean 0.48). Using log10-transformed lung fibre burden, we found that the odds ratio was 3.71 (confidence intervals 2.03-6.79) for a 10-fold lung fibre burden increase. Results for the amphibole lung fibre burden were similar. Odds ratios increased over chrysotile lung fibre burden categories (P-trend = 0.025), and the odds ratio for a 10-fold increase was 4.73 (confidence intervals 0.32-70.4).
CONCLUSIONS: The cumulative exposure index was correlated with total and amphibole lung fibre burden, but not with chrysotile lung fibre burden. Mesothelioma risk was proportional to total, amphibole, and chrysotile lung fibre burden in shipyard workers.

Keywords: asbestos; exposure–response assessment; lung cancer; lung fibre burden; pleural mesothelioma

DOI: https://doi.org/10.1093/annweh/wxae018