bims-mesote 2023-12-17 papers

Issue of 2023–12–17
six papers selected by
Laura Mannarino, Humanitas Research

Target Oncol. 2023 Dec 08.

Malignant Pleural Mesothelioma: Staging and Radiological Response Criteria in Patients Treated with Immune Checkpoint Inhibitors.

Serafina Martella, Marco Maria Aiello, Valentina Bertaglia, Riccardo Cau, Nerina Denaro, Andrea Cadoni, Silvia Novello, Mario Scartozzi, Giuseppe Novello, Hector Josè Soto Parra, Luca Saba, Cinzia Solinas, Michele Porcu.

Malignant pleural mesothelioma (MPM) is a rare and challenging cancer associated with asbestos fiber exposure, which offers limited treatment options. Historically, platinum-based chemotherapy has been the primary approach, but recent developments have introduced immunotherapy as a promising alternative for the treatment of this disease. Nevertheless, the unique growth patterns and occasionally ambiguous progressive characteristics of MPM make the interpretation of radiological assessments complex. Immunotherapy further complicates matters by introducing unconventional treatment response patterns such as hyperprogression and pseudoprogression. Consequently, there is a growing imperative to integrate the standard RECIST criteria with the mesothelioma-specific mRECIST criteria (version 1.1), as outlined in iRECIST. This comprehensive review is driven by the intent to provide a valuable resource for radiologists and clinicians engaged in the diagnosis, treatment, and monitoring of MPM in the era of immunotherapy. Specifically, the current imaging methods employed for staging and follow-up will be exposed and discussed, with a focus on the technical specificities and the mRECIST 1.1 methodology. Furthermore, we will provide a discussion about major clinical trials related to the use of immunotherapy in MPM patients. Finally, the latest advancements in radiomics, the applications of artificial intelligence in MPM, and their potential impact on clinical practice for prognosis and therapy, are discussed.

DOI: https://doi.org/10.1007/s11523-023-01017-w

ArXiv. 2023 Nov 30. pii: arXiv:2312.00223v1. [Epub ahead of print]

Convolutional Neural Networks for Segmentation of Malignant Pleural Mesothelioma: Analysis of Probability Map Thresholds (CALGB 30901, Alliance).

Mena Shenouda, Eyjólfur Gudmundsson, Feng Li, Christopher M Straus, Hedy L Kindler, Arkadiusz Z Dudek, Thomas Stinchcombe, Xiaofei Wang, Adam Starkey, Samuel G Armato Iii.

Malignant pleural mesothelioma (MPM) is the most common form of mesothelioma. To assess response to treatment, tumor measurements are acquired and evaluated based on a patient's longitudinal computed tomography (CT) scans. Tumor volume, however, is the more accurate metric for assessing tumor burden and response. Automated segmentation methods using deep learning can be employed to acquire volume, which otherwise is a tedious task performed manually. The deep learning-based tumor volume and contours can then be compared with a standard reference to assess the robustness of the automated segmentations. The purpose of this study was to evaluate the impact of probability map threshold on MPM tumor delineations generated using a convolutional neural network (CNN). Eighty-eight CT scans from 21 MPM patients were segmented by a VGG16/U-Net CNN. A radiologist modified the contours generated at a 0.5 probability threshold. Percent difference of tumor volume and overlap using the Dice Similarity Coefficient (DSC) were compared between the standard reference provided by the radiologist and CNN outputs for thresholds ranging from 0.001 to 0.9. CNN annotations consistently yielded smaller tumor volumes than radiologist contours. Reducing the probability threshold from 0.5 to 0.1 decreased the absolute percent volume difference, on average, from 43.96% to 24.18%. Median and mean DSC ranged from 0.58 to 0.60, with a peak at a threshold of 0.5; no distinct threshold was found for percent volume difference. No single output threshold in the CNN probability maps was optimal for both tumor volume and DSC. This work underscores the need to assess tumor volume and spatial overlap when evaluating CNN performance. While automated segmentations may yield comparable tumor volumes to that of the reference standard, the spatial region delineated by the CNN at a specific threshold is equally important.

Cancers (Basel). 2023 Nov 22. pii: 5534. [Epub ahead of print]15(23):

Validation of a Gene Expression Approach for the Cytological Diagnosis of Epithelioid and Biphasic Pleural Mesothelioma on a Consecutive Series.

Rossella Bruno, Anello Marcello Poma, Greta Alì, Agnese Proietti, Alessandro Ribechini, Antonio Chella, Gabriella Fontanini.

Cytological diagnosis of pleural mesothelioma (PM) is controversial, even using ancillary markers (BAP1, MTAP and CDKN2A). Here, we aimed to prospectively validate a previously developed 117-gene expression panel for the differential cytological diagnosis of epithelioid, biphasic PM and mesothelial hyperplasia. Seventy-seven pleural effusions were classified using the 117-gene expression levels (NanoString system). Sixty-eight cases were also screened for ancillary markers. The performance of both gene panel and ancillary markers was evaluated using ROC metrics. A score using the top consistently deregulated genes between epithelioid and biphasic PM was built to subtype malignant effusions. The panel alone reached a diagnostic accuracy (0.89) comparable to the best marker combination (BAP1 plus MTAP: 0.88). Ancillary tests missed 8 PMs, 7 of which were correctly classified by the panel. The score built by averaging the expression levels of MSLN, CLDN15 and CFB showed an accuracy of 0.80 in subtyping epithelioid and biphasic effusions. The 117-gene panel is effective for PM cytological diagnosis of epithelioid and biphasic PM. This tool can be complementary to ancillary markers, reducing invasive procedures and allowing an earlier diagnosis. Finally, the possibility to subtype PM on effusions strengthens the panel's role in PM diagnosis and management.

Keywords: gene expression; mesothelial hyperplasia; pleural effusions; pleural mesothelioma; subtyping

DOI: https://doi.org/10.3390/cancers15235534

Carcinogenesis. 2023 Dec 09. pii: bgad090. [Epub ahead of print]

ASBESTOS BURDEN IN LUNGS OF MESOTHELIOMA PATIENTS WITH PLEURAL PLAQUES, LUNG FIBROSIS AND/OR FERRUGINOUS BODIES AT HISTOLOGY: a postmortem sem-eds study.

S D Visonà, B Bertoglio, S Capella, E Belluso, B Austoni, C Colosio, Z Kurzhunbaeva, T Ivic-Pavlicic, E Taioli.

The causal attribution of asbestos related diseases to past asbestos exposures is of crucial importance in clinical and legal contexts. Often this evaluation is made based on the history of exposure, but this method presents important limitations. To assess past asbestos exposure, pleural plaques (PP), lung fibrosis and histological evidence of ferruginous bodies (FB) can be used in combination with anamnestic data. However, such markers have never been associated with a threshold value of inhaled asbestos. With this study we attempted to shed light on the dose-response relationship of PP, lung fibrosis and FBs, investigating if their prevalence in exposed individuals who died from malignant mesothelioma (MM) is related to the concentration of asbestos in lungs assessed using scanning electron microscopy equipped with energy dispersive spectroscopy. Moreover, we estimated the values of asbestos concentration in lungs associated with PP, lung fibrosis and FB. Lung fibrosis showed a significant positive relationship with asbestos lung content, whereas PP and FB did not. We identified, for the first time, critical lung concentrations of asbestos related to the presence of PP, lung fibrosis and FB at histology (respectively, 19 800, 26 400 and 27 400 fibers per gram of dry weight), that were all well-below the background levels of asbestos identified in our laboratory. Such data suggest that PP, lung fibrosis and FB at histology should be used with caution in the causal attribution of MM to past asbestos exposures, while evaluation of amphibole lung content using analytical electron microscopy should be preferred.

Keywords: asbestos; ferruginous bodies; lung fibrosis; mesothelioma; pleural plaques

DOI: https://doi.org/10.1093/carcin/bgad090

BMC Cancer. 2023 Dec 07. 23(1): 1206

LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study.

Ken Arimura, Kenzo Hiroshima, Yoji Nagashima, Tadao Nakazawa, Akira Ogihara, Mami Orimo, Yasuto Sato, Hideki Katsura, Masato Kanzaki, Mitsuko Kondo, Etsuko Tagaya.

BACKGROUND: Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM.
METHODS: We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan-Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed.
RESULTS: LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM.
CONCLUSIONS: LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM.
TRIAL REGISTRATION: This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022-0048) at Tokyo Women's Medical University.

Keywords: IHC; Immune checkpoint inhibitors; LAG3; Malignant pleural mesothelioma; Novel prognostic biomarker; TCGA; mRNA

DOI: https://doi.org/10.1186/s12885-023-11636-1

J Thorac Dis. 2023 Nov 30. 15(11): 6140-6150

Impact of hyperthermic intrathoracic chemotherapy (HITHOC) during resection of pleural mesothelioma on patient survival.

Irmina A Elliott, Hao He, Natalie S Lui, Douglas Z Liou, Brandon A Guenthart, Joseph B Shrager, Mark F Berry, Leah M Backhus.

Background: Pleural mesothelioma (PM) is rare but portends a poor prognosis. Multimodal treatment, including aggressive surgical resection, may offer the best chance of treatment response and improved survival. Single-center studies suggest that hyperthermic intrathoracic chemotherapy (HITHOC) during surgical resection improves outcomes, but the impact of HITHOC on postoperative morbidity and survival has not been examined on a larger scale.
Methods: The National Cancer Database was queried for patients undergoing resection for PM from 2006-2017. Patients were excluded if staging or survival data was incomplete. After propensity-score matching, patients who underwent HITHOC were compared to patients who did not (case-control study). Perioperative outcomes and survival were analyzed.
Results: The final cohort consisted of 3,232 patients; of these, 365 patients underwent HITHOC. After propensity-score matching, receipt of HITHOC was associated with increased length of stay (12 vs. 7 days, P<0.001) and increased 30-day readmissions (9.9% vs. 4.9%, P=0.007), but decreased 30-day mortality (3.2% vs. 6.0%, P=0.017) and 90-day mortality (7.5% vs. 10.9%). Kaplan-Meier modeling demonstrated that HITHOC was associated with improved survival in the overall cohort (median 20.5 vs. 16.8 months, P=0.001). In multivariable analysis, HITHOC remained associated with improved overall survival [hazard ratio (HR) =0.80; 95% confidence interval (CI): 0.69-0.92; P=0.002], and this persisted in the propensity-matched analysis (HR =0.73; 95% CI: 0.61-0.88; P=0.001).
Conclusions: Using a large national database, we describe the impact of HITHOC on survival in patients with PM. Despite observed increased short-term morbidity, in multivariable analysis HITHOC was associated with an overall survival advantage for patients undergoing surgical resection of PM.

Keywords: Mesothelioma; chemotherapy; pleural neoplasm; surgical margins

DOI: https://doi.org/10.21037/jtd-23-466