bims-mesote 2024-07-28 papers

Issue of 2024–07–28
four papers selected by
Laura Mannarino, Humanitas Research

Exp Lung Res. 2024 ;50(1): 136-145

Leucine rich α2 glycoprotein 1 derived from malignant pleural mesothelioma cells facilitates macrophage M2 phenotypes.

Dandan Wang, Wenjing Pei, Yanfei Liu, Rongliang Mo, Xinru Li, Wenhui Gu, Yi Su, Jing Ye, Jiegou Xu, Dahai Zhao.

Background: Macrophages constitute the main part of infiltrating immune cells in Malignant pleural mesothelioma (MPM) and abnormally high ratios of M2 macrophages are present in both pleural effusion and tissue samples of MPM patients. Whether MPM cells affect formation of M2 macrophages is poorly understood. In this study, we focused on identification of MPM-cells-derived soluble factors with M2-promoting effects. Methods: Media of malignant pleural mesothelioma cells were collected and soluble factors affecting macrophages were analyzed by mass spectrometry. TGF-β receptor inhibitor SB431542 was used as the entry point to explore the downstream mechanism of action by qRT-PCR, WB and immunofluorescence. Results: The serum-free culture media collected from the human MPM cells Meso1 and Meso2 significantly enhanced expression of the M2 signature molecules including IL-10, TGF-β and CD206 in the human macrophages THP-1, while the culture medium of the human MPM cells H2452 did not show such M2-promoting effects. Analysis of proteins by mass spectrometry and ELISA suggested that Leucine rich α2 glycoprotein 1(LRG1) was a potential candidate. LRG1 time- and dose-dependently increased expression of the M2 signature molecules, confirming its M2-promoting effects. Furthermore, LRG1's M2-promoting effects were reduced by the TGF-β receptor inhibitor SB431542, and LRG1 increased phosphorylation of Smad2, indicating that M2-promoting effects of LRG1 were via the TGF-β receptor/Smad2 signaling pathway. Conclusions: Our results provide a potential M2-promoting new member, LRG1, which contributes to the immune escape of MPM via the TGF-β receptor/Smad2 signaling pathway.

Keywords: LRG1; M2 macrophages; Malignant pleural mesothelioma; Smad2; TGF-β receptor

DOI: https://doi.org/10.1080/01902148.2024.2380988

Cancers (Basel). 2024 Jul 11. pii: 2513. [Epub ahead of print]16(14):

The Role of Hyperthermic Intrathoracic Chemotherapy (HITHOC) in Thoracic Tumors.

Federica Danuzzo, Maria Chiara Sibilia, Sara Vaquer, Andrea Cara, Enrico Mario Cassina, Lidia Libretti, Emanuele Pirondini, Federico Raveglia, Antonio Tuoro, Francesco Petrella.

Pleural mesothelioma (PM) is a rare but aggressive thoracic tumor with a poor prognosis. Multimodal treatment-including induction chemotherapy, aggressive surgical resection, radiotherapy and immunotherapy in selected cases-currently represents the best therapeutic option. Single-center studies advocate hyperthermic intrathoracic chemotherapy (HITHOC) during surgical resection as an additional therapeutic option, although its impact on post-operative morbidity and survival has not yet been evaluated on a larger scale. HITHOC can be applied not only in the case of mesothelioma, but also in the case of thymoma with pleural involvement or-in very selected cases-in patients with secondary pleural metastases. Despite favorable outcomes and reduced clinical risks, there is no uniform approach to HITHOC, and a wide variety of indications and technical applications are still reported. Based on available data, HITHOC seems to offer a clear benefit in regard to overall survival of all mesothelioma patients; however, multicenter randomized controlled trials are required to validate and standardize this approach. The aim of this review is to focus on the present role of HITHOC in thoracic tumors with pleural involvement as well as on future challenges, particularly in the light of possible combined therapy of thoracic tumors still presenting poor prognoses.

Keywords: hyperthermic intrathoracic chemotherapy (HITHOC); mesothelioma; pleural malignancies

DOI: https://doi.org/10.3390/cancers16142513

J Clin Pathol. 2024 Jul 26. pii: jcp-2024-209592. [Epub ahead of print]

Combined detection of SHOX2 and PTGER4 methylation with serum marker CYFRA21-1 for improved diagnosis of malignant pleural mesothelioma.

Nana Zhang, Yongmeng Li, Zuyu Sun, Yujie Dong, Lijuan Zhou, Chen Zhang, Zichen Liu, Qiuyi Zhang, Kun Li, Fudong Xu, Li Zhang, Bin She, Xiaosha Ren, Nanying Che.

AIMS: To investigate the performance of a combined biomarker approach using the methylation status of the short stature homeobox 2 (SHOX2) and prostaglandin E2 receptor EP4 (PTGER4) genes, along with the serum levels of CYFRA21-1, for differential diganosis of malignant pleural mesothelioma (MPM) from benign reactive mesothelial hyperplasia (RMH).
METHODS: We analysed 48 MPM tissue or pleural effusion cell block specimens and 42 cases with RMH. Real-time quantitative methylation-specific PCR was used to examine the methylation status of SHOX2, PTGER4, ras association domain family 1 isoform A, septin 9 gene and homeobox gene A9 genes. Additionally, we employed electrochemiluminescence immunoassay to measure nine serum tumour markers commonly used in pan-cancer screening tests.
RESULTS: The receiver operating curve indicated that SHOX2, PTGER4 gene methylation and serum biomarker CYFRA21-1 exhibited good diagnostic performance in identifying MPM, with area under curves (AUCs) of 0.761, 0.904 and 0.847, respectively. The combination of SHOX2, PTGER4 methylation and CYFRA21-1 yielded an AUC value of 0.972. The diagnostic sensitivity and specificity of this panel in differentiating MPM from RMH were 91.3% (42/46) and 97.6% (41/42), respectively. Both tissue and cell block specimens can be used in the diagnostic process. Furthermore, elevated CYFRA21-1 levels were associated with poor prognosis (p<0.05). Hypermethylation level of PTGER4 may indicate an unfavourable prognosis of MPM, but the difference was not statistically significant.
CONCLUSIONS: The combined detection of SHOX2 and PTGER4 methylation alongside serum CYFRA21-1 level significantly enhances the diagnosis of MPM. Additionally, CYFRA21-1 can serve as a prognostic indicator for MPM.

Keywords: Biomarkers, Tumor; Diagnostic Techniques and Procedures; Pathology, Molecular

DOI: https://doi.org/10.1136/jcp-2024-209592

ESMO Open. 2024 Jul 25. pii: S2059-7029(24)01413-3. [Epub ahead of print]9(8): 103644

Update on gene fusions and the emerging clinicopathological landscape of peritoneal and pleural mesotheliomas and other neoplasms.

RENAPE and the NETMESO/MESOPATH Networks

BACKGROUND: Mesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically.
METHODS: Clinical, pathological, and comprehensive transcriptome and mutation data were collected for each case.
RESULTS: A total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions.
CONCLUSIONS: This study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients.

Keywords: ALK; EWSR1; MAP3K8; SUFU; gene fusion; mesothelioma

DOI: https://doi.org/10.1016/j.esmoop.2024.103644