bims-mesote Biomed News
on Mesothelioma
Issue of 2025–01–12
nine papers selected by
Laura Mannarino, Humanitas Research
  1. Analysis of Pleiotropic Effects of Nivolumab in Patients with relapsed Pleural Mesothelioma: A Single center retrospective study.
  2. Correlation of Histologic Features with Gene Alterations in Pleural Mesothelioma.
  3. Prognostic Indicator for Pleural Mesothelioma.
  4. Social Determinants of Health Impact on Survival of Patients With Malignant Pleural Mesothelioma.
  5. A Perspective on the MARS2 Trial.
  6. Intracavitary cisplatin-fibrin followed by irradiation improved tumor control compared to the single treatments in a mesothelioma rat model.
  7. Treatment of Pleural Mesothelioma: ASCO Guideline Update.
  8. Modeling Malignant Mesothelioma in Genetically Engineered Mice.
  9. Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma.
  1. Oncology. 2025 Jan 08. 1-24
    Analysis of Pleiotropic Effects of Nivolumab in Patients with relapsed Pleural Mesothelioma: A Single center retrospective study.
    Tomoki Higashiyama, Kozo Kuribayashi, Hiroshi Doi, Aki Kubota, Taiichiro Otsuki, Yasuhiro Nakajima, Koji Mikami, Ryo Takahashi, Akifumi Nakamura, Daichi Fujimoto, Kazuhiro Kitajima, Toshiyuki Minami, Takashi Kijima.
       INTRODUCTION: In August 2018, the Japanese PMDA approved nivolumab, an immune checkpoint inhibitor (ICI), for previously treated, unresectable, advanced, or recurrent pleural mesothelioma (PM) based on the MERIT trial, a phase II study of 34 cases. However, concerns regarding limited evidence persist.
    METHODS: We retrospectively analyzed 83 patients with previously treated, unresectable, advanced, or recurrent malignant pleural mesothelioma (MPM) treated with nivolumab from August 2018 to May 2022. Efficacy was evaluated using overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) per modified RECIST criteria. Safety was assessed by treatment-related adverse events (TRAEs) according to CTCAE v5.0. PD-L1 expression was analyzed with the anti-PD-1 antibody (22C3).
    RESULTS: The median age was 73 years. Histological subtypes included epithelioid (60), sarcomatoid (15), biphasic (6), and unknown (2). Lines of treatment were 2nd (62), 3rd (13), and 4th or later (8). Partial response (PR) was seen in 16 patients, stable disease (SD) in 30, progressive disease (PD) in 29, and not evaluable (NE) in 8, with an ORR of 19.3% and a disease control rate of 55.4%. Median PFS and OS were 5.1 and 12.4 months, respectively. TRAEs occurred in 45 patients (54.2%), with grade ≥3 in 6 (7.2%) and one treatment-related death. PFS correlated with male gender, TRAEs, and good performance status (PS: 0-1), while OS correlated with PS.
    CONCLUSION: Nivolumab demonstrated efficacy and safety in clinical practice, supporting its use in patients with good PS, even in later lines.
    DOI:  https://doi.org/10.1159/000543414
  2. Mod Pathol. 2025 Jan 07. pii: S0893-3952(25)00002-X. [Epub ahead of print] 100706
    Correlation of Histologic Features with Gene Alterations in Pleural Mesothelioma.
    Rachel E Fanaroff, Soo-Ryum Yang, Kay See Tan, Prasad S Adusumilli, Francis Bodd, Anita Bowman, Jason Chang, Michael D Offin, Allison Reiner, Natasha Rekhtman, Valerie W Rusch, William D Travis, Marjorie G Zauderer, Marc Ladanyi, Jennifer L Sauter.
      Histologic features, including architectural patterns, cytologic features, and 2021 World Health Organization nuclear grade have been shown to have prognostic significance in epithelioid diffuse pleural mesothelioma (DPM). Biphasic and sarcomatoid DPM, regardless of morphology, have worse outcomes. These prognostic findings are well-established but correlation of architectural patterns, cytologic features, and nuclear grade with genetic alterations has not been well studied. To investigate relationships between histologic findings and genomic alterations, 128 treatment-naïve DPM specimens (70% epithelioid, 23% biphasic and 6.3% sarcomatoid) with next generation sequencing data were retrospectively reviewed. Alterations in BAP1 were the most common genomic alteration (n=62, 48%), followed by CDKN2A (n=49, 38%) and NF2 (n=38, 30%). NF2 alterations were significantly more frequent in biphasic DPM (53% in biphasic versus 25% in sarcomatoid and 22% in epithelioid; p=0.005). In epithelioid DPM, TP53 alterations were associated with presence of prognostically unfavorable histology, including micropapillary or solid architecture, pleomorphic features and high nuclear grade. Tumors with low tumor infiltrating lymphocytes had a higher rate of BAP1 alterations compared to tumors with higher levels of tumor infiltrating lymphocytes (67% versus 30%; p=0.002). The findings of this study enhance our understanding of the relationships among prognostically significant histologic and molecular features of DPM and provide preliminary data to support increased integration of these findings in clinical diagnosis of pleural mesothelioma.
    Keywords:  BAP1; CDKN2A; NF2; SETD2; TP53; biphasic; diffuse pleural mesothelioma; epithelioid; histopathology; molecular profiling; next generation sequencing; sarcomatoid
    DOI:  https://doi.org/10.1016/j.modpat.2025.100706
  3. Ann Thorac Surg Short Rep. 2024 Dec;2(4): 597-602
    Prognostic Indicator for Pleural Mesothelioma.
    Masaya Yotsukura, Yukihiro Yoshida, Kazuo Nakagawa, Shun-Ichi Watanabe.
       Background: In malignant pleural mesothelioma), it is difficult to evaluate the degree of tumor progression using imaging findings. It is essential to develop an objective index that is independent of imaging findings and useful for assessing the degree of tumor progression and indications for surgery.
    Methods: We retrospectively evaluated the data of 79 patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy or pleurectomy/decortication at our institution between 1999 and 2022. The postoperative prognosis was evaluated based on clinical factors.
    Results: Of the 79 patients, extrapleural pneumonectomy was performed in 41 (51.9%), and pleurectomy/decortication was performed in 38 (48.1%). Univariate analyses identified that percent predicted forced vital capacity (FVC) < 80% (P < .01), rind-like growth pattern on computed tomography (P < .01), Glasgow Prognostic Score ≥ 1 (P < .01), and pathologic stage ≥ II (P < .01) were poor prognostic factors for overall survival. In the multivariate analysis, percent predicted FVC <80% (hazard ratio, 2.76; 95% CI, 1.23-6.18, P = .01) was found to be the only poor prognostic factor for overall survival after surgery. Pathologic stage was a less significant prognostic factor (hazard ratio, 1.83; 95% CI, 0.95-3.53, P = .07). Two-year overall survival in patients with percent predicted FVC ≥80% and <80% was 76.6% ± 6.6% and 16.6% ± 7.5%, respectively.
    Conclusions: FVC is a strong predictor of postoperative survival in patients with malignant pleural mesothelioma independent of imaging findings. FVC is useful for assessing tumor invasion and would help determining surgical indication.
    DOI:  https://doi.org/10.1016/j.atssr.2024.05.011
  4. Ann Thorac Surg Short Rep. 2023 Dec;1(4): 548-552
    Social Determinants of Health Impact on Survival of Patients With Malignant Pleural Mesothelioma.
    Ahmed Alnajar, Samuel A Kareff, Syed S Razi, J Sunil Rao, Dao M Nguyen, Nestor Villamizar, Estelamari Rodriguez.
       Background: Patients with malignant pleural mesothelioma (MPM) have a high mortality risk, even after optimal management and accounting for differences in comorbidities. We aimed to assess the overall survival of patients with operable MPM based on social determinants of health (SDH). We hypothesized that an SDH score can predict patients with poorer overall survival despite optimal management.
    Methods: This study used a retrospective analysis of the National Cancer Database from 2004 to 2017. Adult patients with clinical stage I-IIIA MPM were included. Based on patients' personal and geographic characteristics, we constructed an SDH score index that identifies patients of socioeconomic disadvantage by the following variables: income, education, geography, and hospital types within 250 miles. We performed a survival analysis using the Kaplan-Meier method as well as univariable and multivariable Cox regression models.
    Results: Higher composite SDH scores demonstrated worse outcomes. Overall increased disadvantage increased the risk of mortality by 21% (hazard ratio [HR], 1.21; CI, 1.12-1.30), with a higher increase of 57% for score ≥2 (HR,1.57; CI, 1.36-1.81). After accounting for age, stage, comorbidities, multimodal therapy, and hospital volume and type, the SDH score index remained statistically significant, with a 29% increased risk of mortality for score ≥2 compared with ≤1 (HR, 1.29; CI, 1.10-1.50). Curative surgery with chemotherapy reduced mortality risk by 29% (HR, 0.71; CI, 0.62-0.81) after adjustment for patients' SDH scores and other relevant factors.
    Conclusions: Various SDH factors affect survival outcomes independently of treatment modality and patient characteristics. This SDH composite score could help identify patients with socioeconomic disadvantages at risk for suboptimal survival outcomes.
    DOI:  https://doi.org/10.1016/j.atssr.2023.05.020
  5. J Thorac Oncol. 2025 Jan 08. pii: S1556-0864(24)02533-4. [Epub ahead of print]
    A Perspective on the MARS2 Trial.
    Eric Lim, Isabelle Opitz, Gavitt Woodard, Raphael Bueno, Marc de Perrot, Raja Flores, Ritu Gill, David Jablons, Harvey Pass.
       INTRODUCTION: The phase 3 randomized controlled trial of extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (PM) (MARS2) reported "extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable PM, compared with chemotherapy alone." These results have led to considerable discourse regarding the future role of surgery for PM, and there has not been unanimity in the mesothelioma surgical community regarding the trial interpretation. This "perspective" evaluates MARS2 using internationally renowned PM experts who either agreed with the trial interpretation or who found issues with its conduct which may have influenced the results.
    METHODS: A facilitator (HP) worked with team leaders (GW, IO) to assemble individuals offering opinions regarding the trial and its conclusions. Arguments agreeing or not agreeing with the trial interpretation were written only after publication of the full trial. Once both arguments were received by the facilitator, the individual team manuscripts were combined and sent to each team allowing editing for changes in perceived factual errors.
    FINDINGS: Insightful arguments include (but were not limited to) the difficulties yet advantages of randomization, quality assurance, selection of histologic subtypes, the timing of randomization, use of preoperative staging, statistical methods, and reasons for surgical mortality.
    CONCLUSIONS: The decision to operate for PM in the future will continue to be defined by consensus guidelines and health payer willingness, and the interpretation of MARS2 may play an important role in modulating the role of surgery in the future.
    Keywords:  Chemotherapy; MARS2; Mesothelioma; Pleurectomy; Randomization
    DOI:  https://doi.org/10.1016/j.jtho.2024.12.014
  6. JTCVS Open. 2024 Dec;22 491-503
    Intracavitary cisplatin-fibrin followed by irradiation improved tumor control compared to the single treatments in a mesothelioma rat model.
    Michaela B Kirschner, Mayura Meerang, Vanessa Orlowski, Katarzyna Furrer, Fabienne Tschanz, Ivo Grgic, Virginia Cecconi, Maries van den Broek, Matthias Guckenberger, Martin Pruschy, Olivia Lauk, Isabelle Opitz.
       Objective: To test the safety and efficacy of combination treatment for pleural mesothelioma (PM) with intracavitary cisplatin-fibrin (cis-fib) plus hemithoracic irradiation (IR) applied after lung-sparing surgery in an orthotopic immunocompetent rat model.
    Methods: We randomized male F344 rats into 5 groups: cis-fib (n = 9), 10 Gy IR (n = 6), 20 Gy IR (n = 9), cis-fib+10 Gy IR (n = 6), and cis-fib+20 Gy IR (n = 9). Subpleural tumor implantation was performed on day 0 with 1 million syngeneic rat mesothelioma cells (IL45-luciferase). Tumors were resected on day 9, followed by treatment with intracavitary cis-fib or vehicle control (NaCl-fib). On day 12, computed tomography-guided local irradiation in a single high dose of the former tumor region was applied.
    Results: We observed only short-term side effects related to 20 Gy radiotherapy. Compared to 20 Gy, 10 Gy IR did not show an impact on tumor growth. At 3 days after treatment with 20 Gy IR (day 15 of the experiment), we detected significantly smaller tumors in the cis-fib+IR group compared to IR alone (mean tumor growth, 252% vs 539%; P = .04). On day 21, there was a significant difference in tumor growth between cis-fib-treated and cis-fib+IR- treated tumors (mean tumor growth, 2295% vs 660%; P = .01).
    Conclusions: Localized treatment after tumor resection in PM aims to improve local tumor control. Irradiation applied in combination with intracavitary cis-fib in rats is safe up to a dosage of 20 Gy and shows an additive effect on tumor growth delay compared to the single treatments.
    Keywords:  chemotherapy; intracavitary therapy; pleural mesothelioma; radiosensitization; radiotherapy
    DOI:  https://doi.org/10.1016/j.xjon.2024.07.024
  7. J Clin Oncol. 2025 Jan 08. JCO2402425
    Treatment of Pleural Mesothelioma: ASCO Guideline Update.
    Hedy L Kindler, Nofisat Ismaila, Lyudmila Bazhenova, Quincy Chu, Jane E Churpek, Ibiayi Dagogo-Jack, Darren S Bryan, Michael W Drazer, Patrick Forde, Aliya N Husain, Jennifer L Sauter, Valerie Rusch, Penelope A Bradbury, B C John Cho, Marc de Perrot, Azam Ghafoor, David L Graham, Ola Khorshid, Alexandra Lebensohn, Julie White, Raffit Hassan.
       PURPOSE: To provide evidence-based recommendations to practicing physicians and others on the management of pleural mesothelioma (PM).
    METHODS: ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pathology, cancer genetics, and advocacy experts to conduct an updated literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2016 through 2024. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.
    RESULTS: The literature search identified 110 additional relevant studies to inform the evidence base for this guideline.
    RECOMMENDATIONS: Evidence-based recommendations were developed for surgical cytoreduction, immunotherapy, chemotherapy, pathology, and germline testing in patients with PM.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
    DOI:  https://doi.org/10.1200/JCO-24-02425
  8. Curr Protoc. 2025 Jan;5(1): e70086
    Modeling Malignant Mesothelioma in Genetically Engineered Mice.
    Yuwaraj Kadariya, Eleonora Sementino, Xiang Hua, Dietmar J Kappes, Joseph R Testa.
      Mesothelioma is a lethal cancer of the serosal lining of the body cavities. Risk factors include environmental and genetic factors. Asbestos exposure is considered the principal environmental risk factor, but other carcinogenic mineral fibers, such as erionite, also have a causal role. Pathogenic germline (heritable) mutations of specific genes, especially BAP1, are thought to predispose the individual to mesothelioma in about 10% of cases. Somatic mutations and deletions of specific tumor suppressor genes, particularly BAP1, CDKN2A/B, and NF2, occur frequently in human mesothelioma, and asbestos-exposed mice with heterozygous deletions of any one of these genes have been shown to develop mesothelioma more often and at an accelerated rate than in control animals. Autochthonous mesothelioma mouse models, which are genetically engineered to carry multiple genetic lesions matching those observed in the human disease counterpart, closely resemble the disease phenotype and the extensive inflammatory responses that characterize human mesothelioma. Because autochthonous mice do not require asbestos exposure and form tumors rapidly, these models are invaluable for assessing novel therapeutic strategies in an immunocompetent setting. The overlapping genetic, epigenetic, and immune environments of the tumors observed in these genetically engineered mouse models (GEMMs) and human primary mesothelioma specimens support the clinical relevance of these preclinical models. This article presents protocols for studies of asbestos-induced mesothelioma in GEMMs and non-carcinogenic conditional knockout models of mesothelioma, including an example of a preclinical application. These models are invaluable for understanding the biological underpinnings of mesothelioma and for testing new therapeutics and chemoprevention or interception agents. © 2025 Wiley Periodicals LLC. Basic Protocol 1: Generation of a genetically engineered mouse model (GEMM) with a germline Bap1 knockout allele Basic Protocol 2: Generation of GEMMs with germline Bap1 knock-in alleles Basic Protocol 3: Asbestos carcinogenicity investigations with GEMMs Basic Protocol 4: Preclinical chemoprevention and chemotherapy studies using a GEMM with asbestos-induced mesothelioma Basic Protocol 5: Generation of a GEMM with conditional knockout of Bap1 Basic Protocol 6: Generation of a conditional knockout model of mesothelioma.
    Keywords:  asbestos carcinogenicity; conditional knockout mice; intraperitoneal tumors; intrapleural tumors; mesothelioma
    DOI:  https://doi.org/10.1002/cpz1.70086
  9. iScience. 2025 Jan 17. 28(1): 111525
    Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma.
    Josephine Carpentier, Marta Freitas, Valle Morales, Katiuscia Bianchi, John Bomalaski, Peter Szlosarek, Sarah A Martin.
      Pleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive therapeutic strategy. We investigated whether combinatory treatment composed of ADI-PEG20 and polyamine inhibitors constitutes a promising novel therapeutic strategy to overcome ADI-PEG20 resistance in mesothelioma patients. Treatment of ADI-PEG20-resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20-resistant cell lines were highly sensitive to the spermidine-analog GC7. We observed a synergistic effect of GC7 and ADI-PEG20 in both ADI-PEG20-sensitive and ADI-PEG20-resistant cell lines. Metabolomic analysis revealed that sensitivity to GC7 is due to inhibition of the Tricarboxylic (TCA) cycle. Significantly, combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. Taken together, we have identified the therapeutic potential of combinatorial treatment of ADI-PEG20 with GC7 for mesothelioma management.
    Keywords:  Biological sciences; Cancer; Cancer systems biology; Natural sciences; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111525
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