bims-mesote 2025-06-29 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2025–06–29
nine papers selected by
Laura Mannarino, Humanitas Research

Impact of Multimodal Surgical Resection and Personalized Targeted Therapy on Survival Outcomes in Early-Stage Malignant Pleural Mesothelioma: A Meta-Analysis.
Fibulin-3 in plasma and pleural effusion as a biomarker of mesothelioma.
Twice as Effective? Pressurized Intra-Thoracic Aerosol Chemotherapy: New Frontiers in Pleural Mesothelioma.
Retreatment With Nivolumab and Ipilimumab in Pleural Mesothelioma Following Disease Progression After a Durable Response: Case Series.
A Minimally Invasive Transthoracic Injection Technique for Reproducible Intrapleural Delivery in Mice.
Loss of MTAP expression is not an accurate surrogate for CDKN2A homozygous deletions in peritoneal mesothelioma.
Methodology for generating chorioallantoic membrane patient-derived xenograft (CAM-PDX) models of pleural mesothelioma and performing preclinical imaging for the translation of cancer studies and drug screening.
Immune Composition and Immunotherapy Outcomes of Mesothelioma with BAP1, CDKN2A, MTAP, and NF2 Alterations.
Different Diseases, Different Outcomes: A Comparative Study of Peritoneal and Pleural Subtypes.

Cureus. 2025 May;17(5): e84640

Impact of Multimodal Surgical Resection and Personalized Targeted Therapy on Survival Outcomes in Early-Stage Malignant Pleural Mesothelioma: A Meta-Analysis.

Alexis Quetzalcoatl Vega Morales, Jorge Luis Rivera Gastelum, Alfonso J Massé Ponce, Alexis Agustin A Dunay Silva, Emiliano Banda Dávila, Andrea Virginia Rivera Aguirre, Odalys Brigitte Villares Santillán, Michael David Naranjo Venegas.

  Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited evaluates the efficacy and safety of these treatments. A systematic review and meta-analysis were conducted, including 14 studies that compared multimodal therapies for early-stage MPM. Continuous variables were analyzed using random-effects modeling, with heterogeneity assessed using I² statistics. The primary outcomes included physical function, social function, and lethargy. The meta-analysis found no statistically significant differences between experimental and control groups in terms of physical function (standardized mean difference [SMD]: -0.34, 95% confidence interval [CI]: -1.14 to 0.45), social function (SMD: 0.01, 95% CI: -0.52 to 0.53), or lethargy (SMD: -0.34, 95% CI: -0.96 to 0.27). Heterogeneity across studies was moderate to high (I²: 47%-76%). These findings suggest limited improvements in quality-of-life domains with experimental approaches compared to controls. This systematic review and meta-analysis highlights the need for individualized, multimodal treatment strategies in MPM management. While extrapleural pneumonectomy and extended pleurectomy/decortication offer specific benefits, their impact on quality of life varies and may not consistently provide significant improvements. Future research should focus on large-scale, randomized trials with standardized protocols to optimize treatment outcomes.

Keywords:  extrapleural pneumonectomy; hemithoracic radiotherapy; malignant pleural mesothelioma; multimodal therapy; pleurectomy/decortication; systematic review and meta analysis

DOI:  https://doi.org/10.7759/cureus.84640
Radiol Oncol. 2025 Jun 01. 59(2): 225-232

Fibulin-3 in plasma and pleural effusion as a biomarker of mesothelioma.

Katja Adamic, Mateja Marc Malovrh, Urska Bidovec Stojkovic, Ales Rozman.

   BACKGROUND: Malignant pleural mesothelioma (MPM) is a global health concern linked to asbestos exposure. In Slovenia, regions with high asbestos exposure rates make MPM a significant public health issue. Although thoracoscopic biopsy is the gold standard for MPM diagnosis, its invasiveness highlights the need for reliable, non-invasive diagnostic biomarkers.
PATIENTS AND METHODS: This prospective study evaluated the diagnostic potential of fibulin-3 as a biomarker for MPM, focusing on its ability to distinguish MPM from other pleural conditions, its association with disease stage and histological subtype, and its prognostic value for survival. Ninety patients, who underwent diagnostic thoracoscopic biopsy from January 2013 to October 2014, were included. Fibulin-3 levels in plasma and pleural effusion were measured using enzyme-linked immunosorbent assay (ELISA), and clinical data were analysed with statistical tests, including receiver operating characteristic (ROC) analysis.
RESULTS: The study cohort comprised 32 patients with MPM, 24 with metastatic pleural carcinoma, and 34 with benign pleural diseases. Plasma fibulin-3 levels were significantly elevated (p = 0.0132) in MPM patients compared to those with benign pleural effusions due to asbestos exposure, with a cut-off of 12.31 ng/mL showing 100% specificity but low sensitivity (39.39%). Elevated fibulin-3 levels in pleural effusion correlated with advanced disease (p = 0.0463) and aggressive histological subtypes (p = 0.0324). No significant survival correlation was observed.
CONCLUSIONS: While plasma fibulin-3 is a highly specific biomarker for MPM, its low sensitivity limits its standalone diagnostic utility. Its potential role in risk stratification and early detection of MPM at-risk populations using combination of different and new biomarkers warrants further study.

Keywords:  asbestos; biomarker; fibulin-3; mesothelioma; pleural effusion

DOI:  https://doi.org/10.2478/raon-2025-0024
Med Sci (Basel). 2025 Jun 02. pii: 72. [Epub ahead of print]13(2):

Twice as Effective? Pressurized Intra-Thoracic Aerosol Chemotherapy: New Frontiers in Pleural Mesothelioma.

Maria Giovanna Mastromarino, Elena Guerrini, Raffaele Guerrieri, Gianmarco Elia, Alessandra Lenzini, Vittorio Aprile, Greta Alì, Stylianos Korasidis, Marcello Carlo Ambrogi, Marco Lucchi.

  Pressurized intra-thoracic aerosol chemotherapy (PITAC) is a novel and promising strategy for the treatment of malignant pleural effusion (MPE). PITAC enables effective pleurodesis while potentially exerting an antineoplastic effect by delivering chemotherapeutic agents as a therapeutic aerosol into the thoracic cavity via a nebulizer. Our preliminary study involved nine patients with unresectable pleural mesothelioma (PM) treated with PITAC. Among them, one case was particularly emblematic for demonstrating notable oncological improvements in addition to well-known palliative benefits. This patient underwent two PITAC procedures, one year apart, without perioperative complications. Redo pleural biopsies from both previous and new sites revealed only fibrous tissue and inflammatory cells, with no evidence of malignancy. Beyond achieving pleurodesis, PITAC-by combining cytotoxic and sclerosing effects-may offer effective local antineoplastic control and represent a promising avenue for enhancing loco-regional therapy in PM.

Keywords:  local antineoplastic control; malignant pleural effusion; mesothelioma; palliative care; pleural mesothelioma; pressurized intra-thoracic aerosol chemotherapy (PITAC)

DOI:  https://doi.org/10.3390/medsci13020072
JTO Clin Res Rep. 2025 Jul;6(7): 100835

Retreatment With Nivolumab and Ipilimumab in Pleural Mesothelioma Following Disease Progression After a Durable Response: Case Series.

Illaa Smesseim, Paul Baas, Jacobus A Burgers.

  The CheckMate 743 trial established nivolumab and ipilimumab as the standard first-line treatment for unresectable pleural mesothelioma. However, optimal management following disease progression after a durable response to dual immunotherapy remains unclear. We report two cases of patients with pleural mesothelioma (epithelioid subtype) initially treated with nivolumab-ipilimumab, achieving prolonged disease control. Both patients experienced disease progression several years after treatment discontinuation and were subsequently retreated with nivolumab-ipilimumab on regulatory approval. In both cases, retreatment resulted in stable disease for at least 12 months. However, immune-related toxicities occurred, with one patient developing recurrent colitis and the other experiencing nephrotic syndrome, ultimately leading to treatment discontinuation. These cases suggest that retreatment with dual immunotherapy may be a viable strategy for selected patients with previous durable responses, although the risk of immune-related toxicity remains significant. Given the lack of prospective data, further research is needed to determine whether rechallenge with nivolumab-ipilimumab offers superior outcomes compared with chemotherapy or best supportive care in this setting. Rechallenging patients with pleural mesothelioma with nivolumab-ipilimumab after a durable response is feasible but associated with immune-related toxicity.

Keywords:  CheckMate 743; Immunotherapy; Ipilimumab; Mesothelioma; Nivolumab; Retreatment

DOI:  https://doi.org/10.1016/j.jtocrr.2025.100835
Methods Protoc. 2025 May 28. pii: 55. [Epub ahead of print]8(3):

A Minimally Invasive Transthoracic Injection Technique for Reproducible Intrapleural Delivery in Mice.

Sophie Rovers, Pooyeh Farahmand, Dana Liu, Louize Brants, Christophe Hermans, Dieter Peeters, Danielle McKinven, Jennifer Doig, Filip Lardon, Jan van Meerbeeck, Elly Marcq, Daniel J Murphy, Evelien Smits.

  The development of standardised, reproducible preclinical models is essential for advancing pleural mesothelioma (PM) research. Here, we present a simple and reliable minimally invasive transthoracic intrapleural injection technique that could improve the efficiency of orthotopic PM model generation. By incorporating a simple needle sleeve to control the injection depth, this method eliminates the need for surgery or general anaesthesia, reducing technical complexity and animal stress while ensuring precise delivery into the pleural cavity. We demonstrate the effectiveness of this approach by achieving a 100% tumour engraftment rate following the injection of AE17 tumour cells. Additionally, this technique has been successfully used for asbestos fibre injection in mesothelioma models, highlighting its versatility. By providing a more accessible, standardised alternative to existing methods, this protocol improves the reliability of PM models and facilitates broader adoption by researchers, including those with limited experience in invasive procedures.

Keywords:  intrapleural injection; minimally invasive methods; orthotopic models; pleural mesothelioma; preclinical models; transthoracic injection

DOI:  https://doi.org/10.3390/mps8030055
Histopathology. 2025 Jun 25.

Loss of MTAP expression is not an accurate surrogate for CDKN2A homozygous deletions in peritoneal mesothelioma.

Andrea Quaranta, Andrea Marzullo, Francesco Fortarezza, Sonia Maniglio, Concetta Caporusso, Floriana Pentimone, Federica Pezzuto, Domenica Cavone, Teresa Lettini, Mario Magistro, Cecilia Salzillo, Luigi Vimercati, Paolo Graziano, Gabriella Serio, Antonio d'Amati.

   AIMS: Mesothelioma is a malignant neoplasm of the serosal membranes originating from mesothelial cells. Peritoneal mesothelioma is the second most common mesothelial neoplasm after pleural mesothelioma, accounting for approximately 6%-15% of cases. Due to its high morphological variability, often mimicking other lesions, mesothelioma remains a diagnostic challenge. CDKN2A homozygous deletion has been established as a highly accurate biomarker for differentiating mesothelioma from benign mesothelial proliferations. MTAP immunohistochemistry (IHC) has been proposed as a cheaper and more reproducible surrogate for CDKN2A homozygous deletion (HD) detected by FISH in pleural mesothelioma. The aim of our study was to evaluate the reliability of MTAP IHC as a surrogate marker for CDKN2A HD in peritoneal mesothelioma.
METHODS AND RESULTS: Thirty-nine FFPE tissue samples of PeM were analysed for CDKN2A copy number status by FISH. MTAP IHC was performed using antibody clone 2G4, and cytoplasmic positivity was evaluated using two different cut-offs (1% and 30%). Agreement between IHC and FISH was assessed using Cohen's Kappa. A ROC curve analysis was performed to evaluate the overall diagnostic performance of MTAP IHC. McNemar's test was used to identify statistically significant discordance between the techniques, and a power analysis was conducted to confirm the adequacy of the sample size. Additionally, 14 benign peritoneal lesions were included as external controls and underwent both FISH and IHC. All control samples showed preserved MTAP expression and no CDKN2A deletion. CDKN2A HD was detected in 27/39 cases. MTAP loss was observed in 13 cases, while the remaining 26 cases showed variable levels of MTAP positivity (15%-100%; mean: 36.4%; median: 25%). Cohen's Kappa revealed a low, non-significant concordance between MTAP IHC and CDKN2A HD (cut-off 1%: Kappa = 0.091, P = 0.462; cut-off 30%: Kappa = 0.083, P = 0.326). ROC curve analysis (AUC = 0.569) confirmed the poor discriminatory performance of MTAP IHC. McNemar's test showed a statistically significant discordance between MTAP IHC and CDKN2A FISH results. Power analysis confirmed that the sample size (n = 39) was adequate.
CONCLUSIONS: These findings may reflect biological and pathogenetic differences between pleural and peritoneal mesotheliomas. Larger, multicentric studies are needed to validate the diagnostic role of MTAP IHC in peritoneal mesothelioma.

Keywords:  CDKN2A; CNV; FISH; MTAP; biomarkers; immunohistochemistry; mesothelioma

DOI:  https://doi.org/10.1111/his.15502
F1000Res. 2025 ;14 481

Methodology for generating chorioallantoic membrane patient-derived xenograft (CAM-PDX) models of pleural mesothelioma and performing preclinical imaging for the translation of cancer studies and drug screening.

Jan Schulze, Sarah Barnett, Liam Shaw, Anne Herrmann, Harish Poptani, Doris M Rassl, Alexander Haragan, Michael Shackcloth, Joseph J Sacco, Judy M Coulson.

   Background: Pleural mesothelioma is a cancer of the lung lining associated with asbestos exposure. Platinum/pemetrexed chemotherapy has been used for many years but provides little benefit and, despite recent immunotherapy advances, prognosis remains poor underpinning the need for development of novel therapeutics or drug repurposing. Fertilized hens' eggs provide a rapid and cost-effective alternative to murine models of pleural mesothelioma which are commonly used in preclinical studies, with chorioallantoic membrane (CAM) xenografts being a partial replacement for mouse flank xenografts. Here we describe methods to generate mesothelioma patient-derived xenografts on the CAM (CAM-PDX), and to subsequently assess these PDX nodules by preclinical imaging and histology.
Methods: Fragments of surplus mesothelioma tissue obtained from patient biopsies were implanted onto the CAM on embryonic day 7 (E7), fresh or following cryopreservation, with the established PDX dissected on E14 and fixed for histological/immunohistochemical analysis. The optimal freezing method was determined by comparing tissue integrity and cellular content of cryopreserved tissue fragments with paired fresh samples via histological/immunohistochemical analyses. [ 18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was used to assess viability of PDXs in ovo.
Results: Methodologies for processing, cryopreservation, re-animation, and engraftment of mesothelioma tissue fragments were established. Cryopreservation of biopsy samples and parallel processing of contiguous sections allows for assessment of mesothelioma cellularity. CAM-PDXs, generated from fresh or slow-frozen tissue, were well vascularized whilst maintaining the architecture and cellular composition of the patient tissue. Furthermore, uptake of [ 18F]-FDG following intravenous injection could be visualized and quantified.
Conclusions: The CAM is a rapid platform for engrafting patient-derived tissue, maintaining elements of the tumor microenvironment and recapitulating heterogeneity observed in mesothelioma. Combining the CAM-PDX model and FDG-PET/CT provides a quantitative in vivo platform for pre-screening of novel treatment strategies and drug combinations, with the potential for development of patient tumor avatars for predicting clinical response.

Keywords:  3Rs; Chorioallantoic membrane; PDX; PET/CT imaging; histology; immunohistochemistry; pleural mesothelioma; preclinical model

DOI:  https://doi.org/10.12688/f1000research.163596.1
J Thorac Oncol. 2025 Jun 25. pii: S1556-0864(25)00806-8. [Epub ahead of print]

Immune Composition and Immunotherapy Outcomes of Mesothelioma with BAP1, CDKN2A, MTAP, and NF2 Alterations.

Ibiayi Dagogo-Jack, Owen Mitchell, Elizabeth Codd, Annie Li, Dawn Mitchell, Samantha E Flynn, Nanna Sivamanoharan, Patrick Reeves, Mark Poznansky, Ivan Valiev, Artem Kosmin, Beow Y Yeap, Grace Hambelton, A John Iafrate, Jochen K Lennerz, Yin P Hung, Hedy Kindler.

   BACKGROUND: First-line mesothelioma treatment paradigms prioritize histology without integrating molecular features. Findings from other thoracic cancers suggest that tumor immune microenvironment (TME) composition and immunotherapy efficacy are informed by genomic profile. Mesothelioma studies exploring the relationship between molecular alterations, immune infiltrate, and immunotherapy outcomes are needed.
METHODS: Exome and transcriptomic sequencing and multiplex immunofluorescence were performed on pleural and peritoneal mesotheliomas annotated for BAP1, CDKN2A, MTAP, and NF2 (merlin) status to infer immune cell abundance and TME composition. Progression-free survival (PFS) and overall survival (OS) on ipilimumab + nivolumab was retrospectively determined according to molecular profile.
RESULTS: Transcriptional analysis segregated 113 mesothelioma specimens (n=85 epithelioid, n=28 non-epithelioid) into four predefined TME groups: fibrotic (n=14), immune desert (n=52), immune-enriched fibrotic (n=13), and immune-enriched non-fibrotic (n=34). The composition of the immune infiltrate was similar when tumors with BAP1 alterations were compared to BAP1 wildtype tumors. In contrast, specimens with MTAP or CDKN2A loss had global decrease in immune populations with predominance of the immune desert phenotype. There was non-significant increase in T lymphocytes in NF2-altered tumors. Multiplex immunofluorescence similarly demonstrated increased T lymphoid infiltrate in mesotheliomas with merlin loss, including regulatory T cells. On ipilimumab + nivolumab, patients with BAP1 alterations had improved survival whereas those with NF2 and CDKN2A alterations had shorter survival.
CONCLUSIONS: Composition of the immune infiltrate may be distinct for mesotheliomas with loss of 9p21 genes (i.e., MTAP, CDKN2A) and NF2 alterations. Overall immune infiltrate abundance did not align with immunotherapy outcomes. Future immunotherapy biomarker development strategies should consider molecular background and functional characterization of mesothelioma tumor-immune interactions.

Keywords:  BAP1; CDKN2A; MTAP; Mesothelioma; NF2

DOI:  https://doi.org/10.1016/j.jtho.2025.06.018
J Surg Res. 2025 Jun 26. pii: S0022-4804(25)00309-9. [Epub ahead of print]312 111-118

Different Diseases, Different Outcomes: A Comparative Study of Peritoneal and Pleural Subtypes.

Christina S Boutros, Erik L Risa, Boxiang Jiang, Jillian Sinopoli, Leonidas Tapias, Philip A Linden, Christopher W Towe.

   INTRODUCTION: Peritoneal and pleural mesotheliomas have often been grouped together in studies, with limited exploration of their distinct characteristics. We conducted an analysis of demographics, clinical features, treatment types, and overall survival in these two mesothelioma subtypes.
METHODS: We queried the 2021 iteration of the National Cancer Database for adult patients with mesothelioma, and categorized patients by the primary site (pleural versus peritoneal). Patients with a primary site other than pleural or peritoneal were excluded. Clinical and demographic characteristics were compared between the groups. Overall survival was evaluated using Kaplan-Meier analysis and multivariable Cox regression.
RESULTS: We identified 40,488 adults with pleural (88.1%) or peritoneal (11.9%) mesothelioma. Patients with pleural mesothelioma were older (73.1 versus 61.8 y, P < 0.001), predominantly male (77.3% versus 53.3%, P < 0.001), and more likely to have a Charlson-Deyo Comorbidity Index >2 (11.3% versus 8.5%, P < 0.001). In contrast, patients with peritoneal mesothelioma were treated more frequently at academic centers (46.5% versus 34.8%, P < 0.001) and were more likely to receive surgery (50.5% versus 23.8%, P < 0.001) and chemotherapy (67.3% versus. 52.4%, P < 0.001). Metastatic disease was more common in peritoneal mesothelioma (34% versus 20%, P < 0.001). Median survival was longer for peritoneal mesothelioma (20.9 versus 9.9 mo, P < 0.001). After adjustment for confounders, peritoneal mesothelioma remained associated with improved survival (odds ratio 0.73, 95% confidence interval 0.69-0.76).
CONCLUSIONS: Peritoneal mesothelioma differs significantly from pleural mesothelioma in demographics, treatment patterns, and outcomes, with better overall survival despite higher rates of metastasis. Recognizing these distinctions is crucial for optimizing clinical management and research.

Keywords:  Mesothelioma; Outcomes; Peritoneal; Pleural

DOI:  https://doi.org/10.1016/j.jss.2025.05.022