bims-mesote 2025-09-28 papers

Issue of 2025–09–28
four papers selected by
Laura Mannarino, Humanitas Research

Cancer Res. 2025 Sep 24.

Pharmacogenomic Characterization of a Large Cohort of Patient-Derived Cell Lines Identifies Therapeutic Strategies for Pleural Mesothelioma.

Jean-Baptiste Assié, Clément Meiller, Esther Stern, Julie Lasvergnas, Maya Arnould, Long Pan, François Montagne, Ruth Sequeiros, Charles Al Zreibi, Elaine Del Nery, Auguste Genovesio, Sylvie Lantuejoul, Françoise Le Pimpec-Barthes, Jessica Zucman-Rossi, Marie-Claude Jaurand, Christophe Blanquart, Ori Wald, Didier Jean.

Pleural mesothelioma (PM) urgently requires effective treatments. This study aimed to identify potential therapies using a drug repurposing strategy in the context of the molecular heterogeneity of PM. We performed a multiomics study of a large cohort of patient-derived primary PM cell lines (n=58) and conducted a multi-step pharmacological study starting with a large-scale drug screen with 1327 compounds using 11 cell lines to select drugs of interest. Integrated multiomics analysis demonstrated that the molecular landscape of the cell line cohort recapitulates the main findings in tumors and revealed important features of PM. Large-scale drug screening identified 233 active compounds belonging to recurrent therapeutic classes. Subsequent validation of 35 compounds highlighted a subset of 12 compounds performing better than standard chemotherapy, including entinostat and fluvastatin, with therapeutic activity related to molecular sarcomatoid phenotype, BAP1 mutation, and YAP/TAZ activity. Importantly, both compounds displayed the same efficacy in 2D and 3D culture models, and a single treatment with entinostat improved survival in an immunocompetent mouse model compared with fluvastatin and standard cisplatin-pemetrexed chemotherapy, which showed similar anti-tumor effects. Strikingly, entinostat improved the efficacy of immunotherapy based on anti-PD1 antibody. Combination of entinostat with anti-PD1 even eradicated tumors in several mice and immunized them against re-transplantation of tumor cells. Overall, the drug sensitivity data provided by this study represents a resource to facilitate future clinical investigations to improve treatment of PM.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3822

Front Oncol. 2025 ;15 1557097

External validation of pathological T adjustments in the ninth edition of the pleural mesothelioma tumor-node-metastasis classification.

Zheng Liu, Jingsheng Cai, Yun Li, Wenhan Weng.

Introduction: In the ninth edition pleural mesothelioma (PM) pathological (p) T staging, patients with fissural invasion are upgraded from T1 to T2. This study aimed to externally validate this staging modification.
Methods: Resected pT1/2 PM patients were selected. The Kaplan-Meier method was applied to assess survival differences, and propensity score matching was utilized to balance baseline characteristics. Univariable and multivariable Cox analyses were conducted to determine prognostic factors. Multiple model parameters were used to evaluate the performance of the ninth and eighth edition pT staging in distinguishing between T1 and T2 patients.
Results: A total of 818 eligible patients were included, among whom 325 initially classified as T1 were reclassified as T2 due to fissural invasion, resulting in 57 patients remaining with pT1 disease. Survival analyses demonstrated that both before and after matching, the ninth edition T staging effectively differentiated between T1 and T2 patients, whereas the eighth edition did not perform as satisfactorily in distinguishing between the groups. Cox regression analyses further confirmed that the ninth edition T staging was a strong prognostic factor, whereas the eighth edition T staging was not prognostic. Lastly, model parameter results indicated that the ninth edition T staging performed better in distinguishing between T1 and T2 patients compared to the eighth edition.
Discussion: Our study provided validation and endorsement for the revisions implemented in the ninth edition pT staging, specifically the reclassification of patients with fissural invasion from pT1 to pT2. This research contributed to the precise staging of PM patients.

Keywords: IASLC; T category; TNM classification; fissural invasion; pleural mesothelioma

DOI: https://doi.org/10.3389/fonc.2025.1557097

Respirol Case Rep. 2025 Sep;13(9): e70342

Radiotherapy-Induced Pleural Mesothelioma in a Childhood Leukaemia Survivor: A Case Report.

Sho Saeki, Rin Kurosawa, Akihiro Yamada, Minori Shimamura, Megumi Inaba, Takahiro Tashiro, Akiko Sakagami, Naomi Hirata, Yasumiko Jodai, Shinji Iyama, Yusuke Tomita, Takuro Sakagami.

We report the case of a 41-year-old woman who developed an epithelioid-type pleural mesothelioma (PM) decades after treatment for childhood acute myeloid leukaemia (AML), who was treated with chemotherapy and total body irradiation (TBI). The diagnosis was confirmed by thoracoscopic pleural biopsy and immunohistochemical staining. Although PM is classically associated with asbestos exposure, the patient had no known history of exposure. This case report highlights the fact that PM can occur as a late-onset secondary malignancy following radiation therapy in childhood cancer survivors. Although radiation-induced PM has been reported primarily in survivors of Hodgkin lymphoma or breast cancer, incidences following treatment for leukaemia are exceptionally rare. This case report highlights the importance of considering prior therapeutic irradiation, including total-body irradiation, as a potential etiological factor for non-asbestos-related PM. It also emphasises the need for the long-term surveillance and monitoring of childhood cancer survivors, particularly those who have received radiation therapy.

Keywords: case report; leukaemia survivor; pleural mesothelioma; secondary malignancy

DOI: https://doi.org/10.1002/rcr2.70342

Crit Rev Clin Lab Sci. 2025 Sep 22. 1-24

Pleural fluid biomarkers for the diagnosis and management of malignant pleural effusions: a clinical review.

Jose Diego Santotoribio.

Initial pleural fluid analysis is a fundamental step in the evaluation of suspected malignant pleural effusion (MPE). Most MPEs present as exudates, often hemorrhagic, with mononuclear cell predominance. Basic biochemical parameters-glucose, total protein, LDH, ADA, and pH-help distinguish MPE from other causes and offer prognostic information. Low glucose and pH, and elevated LDH, are associated with higher tumor burden and poorer outcomes. Flow cytometry can detect high-fluorescence cells suggestive of malignancy, while additional markers like CRP, cholesterol, amylase, and lipids provide complementary diagnostic value, especially when interpreted alongside tumor markers (TMs). Among TMs in pleural fluid, CEA is the most validated and widely used, showing high specificity for MPE. Others-such as CA 15.3, CYFRA 21-1, CA 125, CA 19.9, NSE, and HE4-offer variable sensitivity and specificity depending on tumor type and clinical context. False positives can occur in benign or inflammatory conditions, emphasizing the need for cautious interpretation. Other cancer biomarkers in pleural fluid-such as VEGF, Apolipoprotein E, calprotectin, endostatin, and homocysteine-may enhance diagnostic and prognostic capabilities. VEGF and endostatin reflect tumor angiogenesis and may also serve as therapeutic targets, while homocysteine shows promise in detecting MPEs not identified by conventional TMs. Multimarker strategies significantly improve diagnostic accuracy. Combinations of two pleural fluid TMs, such as CEA with CA 15.3, or diagnostic models like the MPER score (CEA + homocysteine), have shown excellent performance. Panels with three or more markers, including inflammatory or metabolic biomarkers (ADA, CRP, and %polymorphonuclear leukocytes) further enhance sensitivity and specificity. Molecular analysis in pleural fluid has emerged as a promising approach for the diagnosis of MPE, enabling the detection of mRNA, DNA methylation patterns, lncRNAs, miRNAs, or circulating tumor DNA. Although these biomarkers have demonstrated good diagnostic accuracy, they are not yet implemented in routine clinical practice, and most studies have primarily focused on MPE due to lung cancer. In malignant pleural mesothelioma, where cytology has limited sensitivity, the most extensively investigated markers in pleural fluid are mesothelin and fibulin-3. Among conventional tumor markers, the pleural fluid CYFRA 21-1/CEA ratio has shown high diagnostic accuracy, further enhanced when combined with mesothelin. Pleural fluid fibulin-3 has also been identified as an independent prognostic factor for survival.

Keywords: cancer; malignant pleural effusion; pleural effusion; pleural fluid; tumor markers

DOI: https://doi.org/10.1080/10408363.2025.2559697