bims-mesote 2024-01-28 papers

Issue of 2024–01–28
five papers selected by
Laura Mannarino, Humanitas Research

Front Immunol. 2023 ;14 1333661

Immunotherapy of mesothelioma: the evolving change of a long-standing therapeutic dream.

Luana Calabrò, Giuseppe Bronte, Federica Grosso, Luigi Cerbone, Angelo Delmonte, Fabio Nicolini, Massimiliano Mazza, Anna Maria Di Giacomo, Alessia Covre, Maria Fortunata Lofiego, Lucio Crinò, Michele Maio.

Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PM patients. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced PM.

Keywords: adoptive cell therapy; epigenetic drugs; immune checkpoint inhibitors; immunotherapy; pleural mesothelioma

DOI: https://doi.org/10.3389/fimmu.2023.1333661

Int J Nanomedicine. 2024 ;19 633-650

Specific Targeting of Mesothelin-Expressing Malignant Cells Using Nanobody-Functionalized Magneto-Fluorescent Nanoassemblies.

Tina Briolay, Judith Fresquet, Damien Meyer, Brigitte Kerfelec, Patrick Chames, Eléna Ishow, Christophe Blanquart.

Introduction: Most current anti-cancer therapies are associated with major side effects due to a lack of tumor specificity. Appropriate vectorization of drugs using engineered nanovectors is known to increase local concentration of therapeutic molecules in tumors while minimizing their side effects. Mesothelin (MSLN) is a well-known tumor associated antigen overexpressed in many malignancies, in particular in malignant pleural mesothelioma (MPM), and various MSLN-targeting anticancer therapies are currently evaluated in preclinical and clinical assays. In this study, we described, for the first time, the functionalization of fluorescent organic nanoassemblies (NA) with a nanobody (Nb) targeting MSLN for the specific targeting of MSLN expressing MPM cancer cells.
Methods: Cell lines from different cancer origin expressing or not MSLN were used. An Nb directed against MSLN was coupled to fluorescent NA using click chemistry. A panel of endocytosis inhibitors was used to study targeted NA internalization by cells. Cancer cells were grown in 2D or 3D and under a flow to evaluate the specificity of the targeted NA. Binding and internalization of the targeted NA were studied using flow cytometry, confocal microscopy and transmission electron microscopy.
Results: We show that the targeted NA specifically bind to MSLN-expressing tumor cells. Moreover, such functionalized NA appear to be internalized more rapidly and in significantly larger proportions compared to naked ones in MSLN+ MPM cells, thereby demonstrating both the functionality and interest of the active targeting strategy. We demonstrated that targeted NA are mainly internalized through a clathrin-independent/dynamin-dependent endocytosis pathway and are directed to lysosomes for degradation. A 3D cell culture model based on MSLN-expressing multicellular tumor spheroids reveals NA penetration in the first superficial layers.
Conclusion: Altogether, these results open the path to novel anticancer strategies based on MSLN-activated internalization of NA incorporating drugs to promote specific accumulation of active treatments in tumors.

Keywords: cancer; mesothelin; nanoassemblies; nanobody; targeting

DOI: https://doi.org/10.2147/IJN.S435787

J Thorac Dis. 2023 Dec 30. 15(12): 6661-6673

Impact of guideline therapy on survival of patients with stage I-III epithelioid mesothelioma.

Douglas Z Liou, Yoyo Wang, Prasha Bhandari, Joseph B Shrager, Natalie S Lui, Leah M Backhus, Mark F Berry.

Background: Modern treatment guidelines recommend multimodal therapy with at least chemotherapy and surgery for patients with potentially resectable epithelioid mesothelioma. This study evaluated guideline compliance for patients with stage I-III epithelioid mesothelioma and tested the hypothesis that guideline-concordant therapy improved survival.
Methods: The National Cancer Database was queried for patients with stage I-III epithelioid malignant pleural mesothelioma between 2004 and 2016. The impact of therapy was evaluated using logistic regression, Kaplan-Meier analysis, Cox-proportional hazards analysis, and propensity-scoring methods.
Results: During the study period, guideline-concordant therapy was used in 677 patients (19.1%), and 2,857 patients (80.8%) did not have guideline-concordant therapy. Younger age, being insured, living in a census tract with a higher income, clinical stage, and being treated at an academic or research program were all predictors of receiving guideline-concordant therapy in multivariable analysis. Guideline-concordant therapy yielded improved median survival [24.7 (22.4-26.1) vs. 13.7 (13.2-14.4) months] and 5-year survival [17.7% (14.7-21.3%) vs. 8.0% (7.0-9.3%)] (P<0.001), and continued to be associated with better survival in both multivariable analysis and propensity-matched analysis. In the patients who received guideline therapy, median survival [24.9 (21.9-27.2) vs. 24.5 (21.7-28.1) months] and 5-year survival [14.9% (10.9-20.2%) vs. 20.1% (16.0-25.4%)] was not significantly different between patients who underwent induction (n=304) versus adjuvant (n=373) chemotherapy (P=0.444).
Conclusions: Guideline-concordant therapy for potentially resectable epithelioid mesothelioma is associated with significantly improved survival but used in a minority of patients. The timing of chemotherapy with surgery in this study did not have a significant impact on overall survival.

Keywords: Mesothelioma; guidelines; mortality; outcomes; surgery

DOI: https://doi.org/10.21037/jtd-23-1334

Diagn Cytopathol. 2024 Jan 20.

Investigation of MTAP and BAP1 staining loss and P16/CDKN2A deletion in pleural cytology specimens and its role in the diagnosis of mesothelioma.

Nazli Sena Şeker, Emel Tekin, Güntülü Ak, Muzaffer Metintaş, Selma Metintaş, Emine Dündar.

BACKGROUND: Mesothelioma is a malignant neoplasm with a poor survival rate. We aimed to investigate the importance of BAP1, MTAP (IHC), and p16/CDKN2A homozygous deletion (FISH) in cytologic material obtained from pleural effusion sampling, which is a less invasive procedure in the diagnosis of mesothelioma.
METHODS: Our study discussed pleural cytology samples of cases with histopathologically proven mesothelioma diagnoses between 2017 and 2022. As the control group, materials that had pleural effusion sampling for other reasons and reactive mesothelial hyperplasia were included in the study. Cell blocks prepared from these materials were subjected to fluorescent in situ hybridization for p16/CDKN2A homozygous deletion and immunohistochemistry for BAP1 and MTAP.
RESULTS: The specificity of the P16/CDKN2A homozygous deletion in diagnosing mesothelioma is 100%. Its sensitivity is 68.75%. The specificity of BAP1 immunohistochemical nuclear expression loss is 95%, while the sensitivity is 60%. Loss of nuclear expression of MTAP alone has the lowest specificity and sensitivity, with a specificity of 86% and a sensitivity of 43%. The highest sensitivity is reached when BAP1 loss and p16/CDKN2A homozygous deletion are evaluated together, increasing to 81%. The specificity is 95%.
CONCLUSION: It has been determined that any marker alone cannot be used for a definitive mesothelioma diagnosis in pleural effusion cytological specimens; however, sensitivity increases in some combinations. The combination of BAP1 immunohistochemistry and p16/CDKN2A homozygous deletion detected by FISH, which has a higher specificity and sensitivity, can be routinely used in the diagnosis of mesothelioma under the guidance of clinical and radiologic information.

Keywords: cytology; mesothelioma; pleural effusion

DOI: https://doi.org/10.1002/dc.25272

J Thorac Dis. 2023 Dec 30. 15(12): 6555-6569

Asbestos burden in lungs of non-occupationally exposed women from Broni (Pavia, Italy): a postmortem SEM-EDS study.

Silvia Damiana Visonà, Silvana Capella, Paola Borrelli, Simona Villani, Cristina Favaron, Zhyldyz Kurzhunbaeva, Claudio Colosio, Elena Belluso.

Background: In Italy the incidence of malignant mesothelioma (MM) among women is remarkably high, due to the several contexts in which women had been exposed to asbestos. However, very few studies in literature focus on the inorganic lung content in women. The aim of this retrospective, observational study is to investigate the asbestos lung burden, in terms of concentration, dimensions and type of asbestos, in 42 women who died from MM and had been non-occupationally exposed to asbestos during the activity of the asbestos-cement plant located in Broni (Pavia, Northern Italy) where mainly chrysotile, crocidolite and amosite were used.
Methods: Lung samples taken during forensic autopsies have been digested using sodium hypochlorite and filtered through a cellulose-ester membrane. The filter was examined using a scanning electron microscope and the chemical composition of the fibers was analyzed using an electron dispersive spectroscopy. The number of detected inorganic fibers, asbestos fibers and asbestos bodies (ABs) were normalized to 1 gram of dry tissue.
Results: In six samples no asbestos has been detected. Overall, the most represented kind of asbestos was amosite, followed by crocidolite, tremolite/actinolite asbestos and chrysotile. The concentration of all inorganic fibers was significantly higher in women with environmental and household exposures compared with those with only environmental exposure (P=0.025), as well as the concentration of asbestos fibers (P=0.019) and ABs (P=0.049). We found a significant correlation between the concentration of asbestos fibers and the duration of exposure (rho =0.413, P=0.008), as well as with the latency of MM (rho =0.427, P=0.005). The distance of the residential address from the factory and the time spent daily in contact with asbestos did not influence the lung asbestos burden.
Conclusions: These results suggest the relevance of the lung clearance of asbestos, regarding mainly chrysotile. As a consequence, although scanning electron microscopy -energy dispersive X-ray spectroscopy (SEM-EDS) is considered the most reliable tool for assessing previous exposure to asbestos, its results should be interpreted with caution, especially in a legal context. In addition, our data confirm the relevance of environmental and household exposure in determining asbestos concentration in lungs and highlight the importance of household exposure.

Keywords: Asbestos; mesothelioma; non-occupational exposure; scanning electron microscopy -energy dispersive X-ray spectroscopy (SEM-EDS)

DOI: https://doi.org/10.21037/jtd-23-1061