bims-mesote 2025-04-20 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2025–04–20
eight papers selected by
Laura Mannarino, Humanitas Research

Haptoglobin phenotype: A germline risk factor for malignant pleural mesothelioma? A case-control study.
Discordant Response to Nivolumab Plus Ipilimumab and Identification of BRAF V600E Mutation in Biphasic Malignant Pleural Mesothelioma: Case Report.
Remarkable Antitumor Effects and Serious Multiple Immune-Related Adverse Events in Malignant Pleural Mesothelioma: Two Case Reports.
Radical hemithorax radiotherapy induces an increase in circulating PD-1+ T lymphocytes and in the soluble levels of PD-L1 in malignant pleural mesothelioma patients: a possible synergy with PD-1/PD-L1 targeting treatment?
Malignant Pleural Mesothelioma: From Pathophysiology to Innovative Actionable Targets.
Malignant mesothelioma-associated inflammatory microenvironment promotes tumor progression via GPNMB.
Pretreatment platelet level is associated with tumor proliferation and prognosis in malignant pleural mesothelioma.
Durvalumab Combined With Pemetrexed-Based Chemotherapy in Trial-Ineligible Patients With Mesothelioma: A Brief Report.

Clin Chim Acta. 2025 Apr 14. pii: S0009-8981(25)00188-3. [Epub ahead of print] 120309

Haptoglobin phenotype: A germline risk factor for malignant pleural mesothelioma? A case-control study.

Kevin Lamote, Sigurd Delanghe, Marijn M Speeckaert, Jan P van Meerbeeck, Joris R Delanghe.

   PURPOSE: The pathogenesis of malignant pleural mesothelioma (MPM) is linked to asbestos-induced chronic inflammation, oxidant formation, hemolysis and subsequent hemoglobin (Hb) release, potentiating oxidative injury. Haptoglobin (Hp) serves as a major antioxidant by binding free Hb in order to prevent its harmful effects. Dependent on the Hp-phenotype, this complexing can be divergent, leading to additional formation of reactive oxygen species (ROS) above those directly induced by asbestos or released by inflammatory cells. In order to determine the Hp-phenotype as a risk factor in MPM, this case-control study compared the Hp-phenotype distribution in MPM patients with asymptomatic persons with former occupational asbestos exposure (AEx) and controls from a European population.
MATERIALS AND METHODS: Hp-phenotyping was done on serum samples of 118 MPM patients and 96 AEx subjects by starch gel electrophoresis. The frequencies of Hp phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2) and alleles (Hp1, Hp2) were compared with those from 918 healthy control subjects.
RESULTS: The Hp 1-1 phenotype was overrepresented in MPM patients compared to AEx persons (P = 0.001) and healthy controls (P = 0.005). The relative risk for developing MPM when having the Hp 1-1 phenotype was 3.05 (1.47-6.34) for AEx subjects and 1.74 (1.19-2.54) for healthy controls compared to other phenotypes.
CONCLUSION: Our results indicate an important role of the Hp-phenotype in MPM pathogenesis suggesting that Hp 1-1 phenotypic persons are more prone for MPM development. Apart from the asbestos-induced radical formation, this finding confirms the role of oxidative stress in cancer development.

Keywords:  Epidemiology; Haptoglobin: mesothelioma; Hemoglobin; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.cca.2025.120309
JTO Clin Res Rep. 2025 May;6(5): 100820

Discordant Response to Nivolumab Plus Ipilimumab and Identification of BRAF V600E Mutation in Biphasic Malignant Pleural Mesothelioma: Case Report.

Olivia Wilkins, Adedamola Omogbehin, Peter J Bergquist, Chul Kim, Stephen V Liu, Joshua E Reuss.

  Therapeutic advancement for malignant pleural mesothelioma (MPM) has been limited. Combination immunotherapy with nivolumab plus ipilimumab is a frontline treatment option for advanced MPM that is typically deployed for patients with sarcomatoid or biphasic MPM. Here, we present a case of biphasic MPM that exhibited a unique response pattern to first-line treatment with nivolumab plus ipilimumab, with brisk response in pleural and mediastinal sites of disease, but rapid progression in osseous/soft tissue sites of disease complicated by pathologic spinal cord compression. Pathologic findings from bony metastasis at progression found pure epithelioid histology without any evidence of sarcomatoid differentiation. Next-generation sequencing of this specimen revealed a BRAF V600E mutation, and the patient was subsequently treated with dabrafenib plus trametinib, achieving ongoing clinical and imaging response in all sites of the disease, including bones. This case supports the use of next-generation sequencing profiling in MPM, particularly in circumstances in which novel discordant response patterns are observed.

Keywords:  BRAF V600E; Case report; Dabrafenib; Malignant pleural mesothelioma; Trametinib

DOI:  https://doi.org/10.1016/j.jtocrr.2025.100820
Case Rep Oncol Med. 2025 ;2025 8768823

Remarkable Antitumor Effects and Serious Multiple Immune-Related Adverse Events in Malignant Pleural Mesothelioma: Two Case Reports.

Koharu Harada, Hidehiro Irie, Akifumi Mitsuishi, Takahiro Fukui, Nao Takada, Ryosuke Nagaoka, Yohei Funatsu, Hidefumi Koh.

  We describe two patients who experienced serious multiple immune-related adverse events (irAEs), treatment interruption, and steroid administration. Despite these challenges, they achieved a remarkable antitumor effect beyond the expected. Various carcinomas demonstrated a possible correlation between the antitumor effect of immune checkpoint inhibitors and the intensity of irAEs, but few studies report on malignant pleural mesothelioma (MPM). Our two cases exhibited much stronger irAEs than usual. These two cases still demonstrated a complete response (CR) or near CR partial response, indicating a correlation between irAEs and the antitumor effect in MPM.

Keywords:  antitumor effect; immune-related adverse events; ipilimumab; malignant pleural mesothelioma; nivolumab

DOI:  https://doi.org/10.1155/crom/8768823
Front Immunol. 2025 ;16 1534766

Radical hemithorax radiotherapy induces an increase in circulating PD-1+ T lymphocytes and in the soluble levels of PD-L1 in malignant pleural mesothelioma patients: a possible synergy with PD-1/PD-L1 targeting treatment?

Alberto Revelant, Francesca Gessoni, Marcella Montico, Raja Dhibi, Giulia Brisotto, Mariateresa Casarotto, Martina Zanchetta, Veronica Paduano, Filippo Sperti, Chiara Evangelista, Fabiana Giordari, Valli De Re, Marco Trovò, Emilio Minatel, Maurizio Mascarin, Agostino Steffan, Elena Muraro.

  Malignant Pleural Mesothelioma (MPM) is an aggressive tumor associated with asbestos exposure, characterized by a poor prognosis, managed with surgery, chemotherapy and radiotherapy. Recently, immunotherapy gives a survival advantage compared to chemotherapy, but limited to the non-epithelioid histotype, the rarest type. Radical hemithorax radiotherapy (RHRT) improves the Overall Survival (OS) of MPM patients, irrespective of histotype, and is able to induce immunomodulatory effects. In this study we aim to investigate changes in circulating T lymphocytes phenotype and activity, in MPM patients undergoing RHRT, to evaluate a possible therapeutic space for immunotherapy in this setting. To assess immunomodulatory effects of RHRT we evaluate peripheral blood samples of 35 MPM patients collected before treatment, at the end of RT, and 1 month later. We first notice that higher Lymphocyte-to-Monocyte Ratio (LMR) levels, before RT, are associated with an improved OS. The immune monitoring performed by ELISA assays reveals a significant increase in the serum levels of soluble PD-L1 (sPD-L1) and IFN-γ at the end of RHRT. Furthermore, the percentage of PD-1+ cells, evaluated by flow cytometry, significantly raise after RHRT in T cells, both CD4+ and CD8+. Also the proportion of proliferative cells is significantly expanded after RHRT in all T cell subtypes. After treatment we observe a significant increase in the number of patients showing WT-1 specific CD4+ T cells, measured by intracellular staining. The TCR repertoire analysis, investigated by Next Generation Sequencing, reveals an increased number of expanded T-cell clones after RHRT, and an association between TCR clonality and the percentage of proliferating cytotoxic T lymphocytes. The comparison of TCR sequences obtained in our cohort with those described in a literature cohort of MPM patients, reveals common entries, specific for MPM-associated antigens including WT-1. In this setting, pre-treatment levels of LMR seem to have a positive prognostic role, and RHRT would appear to induce immunomodulating effects, potential biomarkers for immunotherapy eligibility: i.e. increased PD-1+ T lymphocytes, proliferating T cells, expanded T cell clones and augmented levels of sPD-L1. These data suggest the design of a prospective study evaluating a maintenance immunotherapy after RHRT in MPM, even in the epithelioid histotype.

Keywords:  anti-tumor immunity; biomarkers; malignant pleural mesothelioma; radiotherapy; tcr

DOI:  https://doi.org/10.3389/fimmu.2025.1534766
Cancers (Basel). 2025 Mar 30. pii: 1160. [Epub ahead of print]17(7):

Malignant Pleural Mesothelioma: From Pathophysiology to Innovative Actionable Targets.

Francesco Rocco Bertuccio, Simone Montini, Maria Antonietta Fusco, Antonella Di Gennaro, Gaetano Sciandrone, Francesco Agustoni, Giulia Galli, Chandra Bortolotto, Jessica Saddi, Guido Baietto, Giulio Melloni, Gioacchino D'Ambrosio, Angelo Guido Corsico, Giulia Maria Stella.

   BACKGROUND: Pleural mesothelioma (PM) is a rare and highly aggressive cancer which arises from mesothelial layer and primarily linked to asbestos exposure, genetic predispositions, and specific mutations. Despite current treatment modalities, including chemotherapy, antiangiogenic therapy and more recently immunotherapy, the prognosis remains dismal, with a median survival time of 6-18 months.
OBJECTIVES: The urgent need for novel therapeutic strategies has prompted research into molecular targets and precision medicine approaches. At present, many potential targets for therapeutic strategies have been identified, and emerging clinical trials are demonstrating certain clinical efficacy.
METHODS: This review examines advancements in understanding PM's genetic and epigenetic landscape, signaling pathways, and promising therapeutic targets.
RESULTS: We also discuss the results of recent clinical trials and their potential implications for future treatment paradigms.

Keywords:  actionable targets; genetics; personalized medicine; pleural mesothelioma

DOI:  https://doi.org/10.3390/cancers17071160
J Transl Med. 2025 Apr 18. 23(1): 454

Malignant mesothelioma-associated inflammatory microenvironment promotes tumor progression via GPNMB.

Cristina Belgiovine, Elisabeth Digifico, Marco Erreni, Anna Rita Putignano, Laura Mannarino, Sonia Valentino, Fabio Grizzi, Fabio Pasqualini, Camilla Recordati, Luca Bertola, Paolo Zucali, Daniela Pistillo, Valentina Paleari, Alberto Mantovani, Maurizio D'Incalci, Federica Marchesi, Paola Allavena.

   BACKGROUND: Tumor-Associated Macrophages (TAMs) are the main immune component of the tumor stroma with heterogeneous functional activities, predominantly suppressing the immune response and promoting tumor progression, also via secretion of different factors. Among these, GPNMB (Glycoprotein non-metastatic B) is usually associated with disease progression in several tumor types. Malignant pleural mesothelioma (MPM) a severe neoplasia with poor prognosis, is characterized by an abundancy of TAMs, testifying the presence of a long-lasting inflammation which is pathogenetic of the disease. However, the role of GPNMB in MPM is unclear.
METHODS: Clinical samples from patients with MPM were used to measure RNA and protein levels of GPNMB. The functional role of GPNMB in vivo was studied in an orthotopic mouse model of mesothelioma using the murine cell lines AB1 and AB22. Experiments included in vivo tumor growth in wild type and in GPNMB-deficient mice and blocking of GPNMB-induced signaling with anti-CD44 antibodies.
RESULTS: We show that in human and murine MPM tissues the protein GPNMB is mainly produced by infiltrating TAMs. Gpnmb RNA levels in MPM patients from TCGA are significantly associated with lower survival. Using an orthotopic mouse model of mesothelioma we observed that in GPNMB-defective mice (DBA2/J mice) unable to produce the protein, tumors formed by AB1 and AB22 mesothelioma cells grow significantly less than in GPNMB-proficient mice (DBA2/J-Gpnmb+ mice), indicating that host GPNMB is involved in tumor progression. Likewise, the ectopic expression of GPNMB in AB1 and AB22 cells causes an acceleration of tumor growth in vivo, significantly different compared to mock-transduced cells. Treatment of tumor-bearing mice with blocking anti-CD44 (a major receptor for GPNMB) results in a significant reduction of tumor growth.
CONCLUSIONS: Overall, these results indicate that the protein GPNMB, a product and marker gene of TAMs, is a driver of mesothelioma progression and may constitute a promising therapeutic target.

Keywords:  Anti-CD44; GPNMB; Malignant mesothelioma; Orthotopic model; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12967-025-06407-4
Gen Thorac Cardiovasc Surg. 2025 Apr 15.

Pretreatment platelet level is associated with tumor proliferation and prognosis in malignant pleural mesothelioma.

Ryota Sumitomo, Kentaro Tsuji, Hiroyuki Katsuragawa, Tetsuya Fukui, Toshi Menju, Masashi Kobayashi, Hiroaki Sakai, Hiroshi Date.

   OBJECTIVE: The present study aimed to investigate the relationship between serum-based inflammatory biomarkers and MPM tumor biology and prognosis.
METHODS: A total of 83 patients with MPM who were diagnosed and started treatment between January 1998 and December 2010 were studied. Clinicopathological variables were evaluated, including age, sex, clinical stage, histology, surgical resection, and chemotherapy. The cut-off values for pretreatment levels of white blood cell count, neutrophil count, lymphocyte count, platelet count, C-reactive protein, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index were determined using receiver operating characteristic curve analysis for predicting 5-year survival. Univariate and multivariate Cox regression analyses were performed to estimate the prognostic impact on 5-year overall survival.
RESULTS: The mean Ki-67 proliferation index in MPM cells was 35.1 ± 29.5% and the median overall survival of patients was 15.0 months. The Ki-67 proliferation index in MPM cells was significantly higher in the platelet-high group compared with that in the platelet-low group (42.1 ± 31.9 vs. 27.7 ± 25.1%; P = 0.027). Multivariate Cox regression analyses identified platelet count (hazard ratio = 1.929; P = 0.022) and PLR (hazard ratio = 1.776; P = 0.040) as significant prognostic factors.
CONCLUSION: Pretreatment platelet level may be a useful prognostic marker for 5-year overall survival related to tumor proliferation in patients with MPM.

Keywords:  Ki-67; Malignant pleural mesothelioma; Platelet; Prognosis; Tumor proliferation

DOI:  https://doi.org/10.1007/s11748-025-02148-9
JTO Clin Res Rep. 2025 May;6(5): 100775

Durvalumab Combined With Pemetrexed-Based Chemotherapy in Trial-Ineligible Patients With Mesothelioma: A Brief Report.

Ibiayi Dagogo-Jack, Aubrey Lasko, Elizabeth A Krueger, Kitman Tsang, Revati Rao, Grace Hambelton, Subba R Digumarthy.

   Introduction: Chemoimmunotherapy is associated with promising activity in mesothelioma in phase II to III trials. Studies exploring this approach in patients ineligible for clinical trials are lacking. We assembled a cohort of patients receiving pemetrexed-based chemotherapy with durvalumab outside of clinical trials.
Methods: Patients with pleural mesothelioma received pemetrexed plus durvalumab or carboplatin plus pemetrexed plus durvalumab via off-label authorization at Massachusetts General Hospital. Response to chemoimmunotherapy was assessed per modified Response Evaluation Criteria in Solid Tumors version 1.1. A retrospective chart review was conducted to assess safety per Common Terminology Criteria for Adverse Events version 5.0.
Results: Twelve patients were included in the series. Nine patients were treated with triplet chemoimmunotherapy. Three patients received doublet chemoimmunotherapy because of platinum ineligibility. Concurrent active malignancies and symptomatic cardiac disease were present in three patients (25%) and two patients (17%), respectively. Ten patients had measurable disease at baseline. With the triplet regimen, partial responses were observed in four of the seven (57%) patients with measurable disease. All three patients receiving pemetrexed plus durvalumab had measurable disease and experienced a partial response. Primary progression was not observed with either regimen. Overall, eight patients (75%) remained on treatment for more than 6 months without progression. Five patients developed immune-related adverse events (n = 1 each pyrexia, arthritis, neutropenia, Raynaud's disease, stomatitis). Three patients discontinued treatment because of toxicity or symptomatic comorbid conditions (n = 1 grade 3 heart failure, n = 1 grade 2 fever + progressive kidney cancer, n = 1 grade 2 fatigue).
Conclusions: Antitumor activity of chemoimmunotherapy reported in phase II to III clinical trials is generalizable to the broader patient population with mesothelioma. However, the tolerability of chemoimmunotherapy is impacted by comorbid conditions in real-world patients.

Keywords:  Chemoimmunotherapy; Durvalumab; Immunotherapy; Mesothelioma

DOI:  https://doi.org/10.1016/j.jtocrr.2024.100775