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Cortes-Dericks L, Galetta D. An Overview of Cellular and Molecular Determinants Regulating Chemoresistance in Pleural Mesothelioma. Cancers (Basel) 2025; 17:979. [PMID: 40149313 PMCID: PMC11940806 DOI: 10.3390/cancers17060979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
Malignant pleural mesothelioma (PM) is a highly aggressive disease of the lung pleura associated with poor prognosis. Despite advances in improving the clinical management of this malignancy, there is no effective chemotherapy for refractory or relapsing PM. The acquisition of resistance to standard and targeted therapy in this disease is a foremost concern; therefore, a deeper understanding of the complex factors surrounding the emergence of drug resistance is deemed necessary. In this review, we will present broad insights into various cellular and molecular concepts, accounting for the recalcitrance of PM to chemotherapy, including signaling networks regulating drug tolerance, drug resistance-associated proteins, genes, and miRNAs, as well as the critical role of cancer stem cells. Identification of the biological determinants and their associated mechanisms may provide a framework for the development of appropriate treatment.
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Affiliation(s)
| | - Domenico Galetta
- Division of Thoracic Surgery, San Giovanni Bosco Hospital, 10154 Turin, Italy;
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2
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Suraya R, Nagano T, Tachihara M. Recent Advances in Mesothelioma Treatment: Immunotherapy, Advanced Cell Therapy, and Other Innovative Therapeutic Modalities. Cancers (Basel) 2025; 17:694. [PMID: 40002287 PMCID: PMC11853238 DOI: 10.3390/cancers17040694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 02/27/2025] Open
Abstract
Mesothelioma is a highly malignant condition arising from the pleura and peritoneum that is closely related to asbestos exposure. The prognosis for this condition has traditionally been poor due to the difficulty physicians have faced in diagnosing and treating this disease, even in its early phase. Fortunately, recent advances in both the molecular understanding of the development of this disease and innovative and novel treatment modalities have accelerated the discovery of new ways to treat mesothelioma. In this review, we first summarize the mechanism of mesothelioma pathophysiology and then relate it to emerging treatment modalities. These include immunotherapy or immune checkpoint inhibitors (ICIs), molecular targeted therapies, and cell-based therapies (such as CAR-T cells or dendritic cells). The scientific basis for the utilization of these treatment modalities, alongside the current clinical evidence for each option, will be explored in detail later on. The hope is that this review can elucidate how these emerging therapeutic options work clinically to help accelerate further developments in novel mesothelioma treatment modalities.
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Affiliation(s)
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (R.S.); (M.T.)
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Kraft A, Kirschner MB, Orlowski V, Ronner M, Bodmer C, Boeva V, Opitz I, Meerang M. Exploring RNA cargo in extracellular vesicles for pleural mesothelioma detection. BMC Cancer 2025; 25:212. [PMID: 39920655 PMCID: PMC11804012 DOI: 10.1186/s12885-025-13617-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 01/30/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Pleural Mesothelioma (PM) is a highly aggressive cancer, for which effective early detection remains a challenge due to limited screening options and low sensitivity of biomarkers discovered so far. While extracellular vesicles (EVs) have emerged as promising candidates for blood-based biomarkers, their role in PM has not been studied yet. In this study, we characterized the transcriptomic profile of EVs secreted by PM primary cells and explored their potential as a biomarker source for PM detection. METHODS We collected cell culture supernatant from early-passage PM cell cultures derived from the pleural effusion of 4 PM patients. EVs were isolated from the supernatant using Qiagen exoEasy Maxi kit. RNA isolation from EVs was done using the mirVana PARIS kit. Finally, single-end RNA sequencing was done with Illumina Novaseq 6000. RESULTS We identified a range of RNA species expressed in EVs secreted by PM cells, including protein-coding RNA (80%), long non-coding RNA (13%), pseudogenes (4.5%), and short non-coding RNA (1.6%). We detected a subset of genes associated with the previously identified epithelioid (32 genes) and sarcomatoid molecular components (36 genes) in PM-EVs. To investigate whether these markers could serve as biomarkers for PM detection in blood, we compared the RNA content of PM-EVs with the cargo of EVs isolated from the plasma of healthy donors (publicly available data). Majority of upregulated genes in PM-EVs were protein-coding and long non-coding RNAs. Interestingly, 25 of them were the sarcomatoid and epithelioid marker genes. Finally, functional analysis revealed that the PM-EV RNA cargo was associated with Epithelial-Mesenchymal transition, glycolysis, and hypoxia. CONCLUSIONS This is the first study to characterize the transcriptomic profile of EVs secreted by PM primary cell cultures, demonstrating their potential as biomarker source for early detection. Further investigation of the functional role of PM-EVs will provide new insights into disease biology and therapeutic avenues.
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Affiliation(s)
- Agnieszka Kraft
- Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
- Institute for Machine Learning, Department of Computer Science, ETH Zurich, Zurich, Switzerland
- Swiss Institute of Bioinformatics (SIB), Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Michaela B Kirschner
- Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Vanessa Orlowski
- Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Manuel Ronner
- Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Caroline Bodmer
- Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Valentina Boeva
- Institute for Machine Learning, Department of Computer Science, ETH Zurich, Zurich, Switzerland
- Swiss Institute of Bioinformatics (SIB), Zurich, Switzerland
- ETH AI Center, ETH Zurich, Zurich, Switzerland
- UMR 8104, UMR-S1016, Cochin InstituteCNRSParis Descartes University, Inserm U1016, 75014, Paris, France
| | - Isabelle Opitz
- Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Mayura Meerang
- Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
- University of Zurich, Zurich, Switzerland.
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Erickson SM, Manning BM, Kumar A, Patel MR. Engineered Cellular Therapies for the Treatment of Thoracic Cancers. Cancers (Basel) 2024; 17:35. [PMID: 39796666 PMCID: PMC11718842 DOI: 10.3390/cancers17010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/16/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Thoracic malignancies (lung cancers and malignant pleural mesothelioma) are prevalent worldwide and are associated with high morbidity and mortality. Effective treatments are needed for patients with advanced disease. Cell therapies are a promising approach to the treatment of advanced cancers that make use of immune effector cells that have the ability to mediate antitumor immune responses. In this review, we discuss the prospect of chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells, and tumor-infiltrating lymphocytes (TILs) as treatments for thoracic malignancies. CAR-T cells and TILs have proven successful in several hematologic cancers and advanced melanoma, respectively, but outside of melanoma, results have thus far been unsuccessful in most other solid tumors. NK cells and TCR-T cells are additional cell therapy platforms with their own unique advantages and challenges. Obstacles that must be overcome to develop effective cell therapy for these malignancies include selecting an appropriate target antigen, combating immunosuppressive cells and signaling molecules present in the tumor microenvironment, persistence, and delivering a sufficient quantity of antitumor immune cells to the tumor. Induced pluripotent stem cells (iPSCs) offer great promise as a source for both NK and T cell-based therapies due to their unlimited expansion potential. Here, we review clinical trial data, as well as recent basic scientific advances that offer insight into how we may overcome these obstacles, and provide an overview of ongoing trials testing novel strategies to overcome these obstacles.
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Affiliation(s)
- Spencer M. Erickson
- Internal Medicine Residency Program, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Benjamin M. Manning
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA (A.K.)
| | - Akhilesh Kumar
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA (A.K.)
| | - Manish R. Patel
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA (A.K.)
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5
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Chow KVC, Turner C, Hughes B, Lwin Z, Chan B. Real-world outcomes for patients with pleural mesothelioma: A multisite retrospective cohort study. Asia Pac J Clin Oncol 2024; 20:723-730. [PMID: 39495618 DOI: 10.1111/ajco.14098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 06/07/2024] [Indexed: 11/06/2024]
Abstract
AIM To evaluate the real-world treatment patterns and outcomes for patients with pleural mesothelioma (PM) in the era of immunotherapy. METHODS This retrospective audit included patients with PM diagnosed within three tertiary referral centers in Queensland, Australia from January 2017 to July 2023. Patient and treatment characteristics and outcomes were recorded. Data was analyzed using descriptive statistics and the Kaplan-Meier survival method. RESULTS A total of 90 patients were included: 84% were male, the median age was 75 years (range 70-79) and 85% had baseline Eastern Group Cooperative Group of 0-1. Subtypes included 54% epithelioid, 17% biphasic, 12% sarcomatoid, and 17% unspecified/unknown. First-line treatment was received by 57/90 patients (63%) and 33/90 patients (37%) received the best supportive care (BSC). Chemotherapy was most used (63%) overall, but first-line immunotherapy was more commonly used since ipilimumab/nivolumab was reimbursed by the Australian Pharmaceutical Benefits Scheme in July 2021. After first-line treatment, only 40% received second-line treatment and 60% received BSC. 12-month overall survival (OS) and progression-free survival for all patients were 53% (95% confidence interval [CI]: 43-65) and 25% (95% CI 15-40) respectively. 12-month OS was 72%, 64%, and 29% for immunotherapy, chemotherapy, and BSC, respectively. There was no significant difference in survival between chemotherapy and immunotherapy (hazard ratio 1.28, 95% CI: 0.65-2.5, p = 0.5). CONCLUSION In our unselected real-world cohort, both chemotherapy and immunotherapy are active against PM, but the prognosis remains guarded. There remains a need for better treatment options, especially in the first-line setting. Enrolment in clinical trials is crucial to improving outcomes in this debilitating disease.
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Affiliation(s)
- Kar Ven Cavan Chow
- The Adem Crosby Cancer Centre, Department of Medical Oncology, Sunshine Coast Hospital and Health Service, Sunshine Coast, Australia
- School of Medicine, The University of Queensland, Herston, Australia
| | - Cassie Turner
- The Adem Crosby Cancer Centre, Department of Medical Oncology, Sunshine Coast Hospital and Health Service, Sunshine Coast, Australia
- School of Medicine, The University of Queensland, Herston, Australia
- Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Australia
| | - Brett Hughes
- School of Medicine, The University of Queensland, Herston, Australia
- Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Australia
- Department of Medical Oncology, The Prince Charles Hospital, Chermside, Australia
| | - Zarnie Lwin
- School of Medicine, The University of Queensland, Herston, Australia
- Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Australia
- Department of Medical Oncology, The Prince Charles Hospital, Chermside, Australia
| | - Bryan Chan
- The Adem Crosby Cancer Centre, Department of Medical Oncology, Sunshine Coast Hospital and Health Service, Sunshine Coast, Australia
- School of Medicine, The University of Queensland, Herston, Australia
- School of Medicine and Dentistry, Griffith University, Gold Coast, Australia
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Khosla D, Singh PK, Chhabria BA, Kataria V, Singh N, Kapoor R. Malignant pleural mesothelioma: The disdained member of thoracic oncology! World J Exp Med 2024; 14:91739. [PMID: 39312698 PMCID: PMC11372740 DOI: 10.5493/wjem.v14.i3.91739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 07/17/2024] [Accepted: 07/30/2024] [Indexed: 08/29/2024] Open
Abstract
Pleural mesothelioma is a very aggressive malignancy that arises from the pleural mesothelial cell lining and is linked strongly to prior asbestos exposure. The ban on asbestos has helped to lower the incidence, but in developing countries like India, it is expected to rise. It has an extended latency period usually progressing over decades and presents with nonspecific symptoms. It has a median survival ranging between 10-22 months. The diagnosis of malignant pleural mesothelioma is challenging and is done using computed tomography (CT), magnetic resonance imaging, or positron emission tomography-CT, with the last two predicting the resectability of the tumor better than CT alone. A pleural biopsy along with an array of immunohistochemical markers, such as p16, BRCA1 associated protein 1, and claudin-4, are required for a definitive diagnosis. Several genetic alterations have prognostic significance as well. The current histological subtype identification is indispensable for decision making because of the new therapeutic avenues being explored. The combination of nivolumab and ipilimumab-based immunotherapy outperformed platinum and pemetrexed-based chemotherapy in terms of survival benefit and improved quality of life especially for non-epithelioid subtypes. However, the latter continues to be a robust treatment option for patients with the epithelioid subtype. Surgery is recommended for resectable cases with radiotherapy being indicated in neoadjuvant, adjuvant, and palliative settings along with systemic treatment. This review article provides an overview of epidemiology, etiology, clinical manifestations, diagnostic approaches (including immunohistochemical and genetic markers), staging, and multidisciplinary approaches to current treatment for malignant pleural mesothelioma using surgery, chemotherapy, immunotherapy, and radiotherapy. It also sheds light on some recent studies (EMPHACIS, CALGB30901, Checkmate-743, etc.) that have led to significant developments in recent years with clinically meaningful results.
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Affiliation(s)
- Divya Khosla
- Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Pawan Kumar Singh
- Department of Pulmonary and Critical Care Medicine, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak 124001, India
| | - Bharath A Chhabria
- Department of Pulmonary and Critical Care Medicine, Ramaiah Memorial Hospital, Bengaluru 560054, India
| | - Vaishali Kataria
- Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Navneet Singh
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rakesh Kapoor
- Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
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Sørensen JB, Baas P, Szépligeti SK, Pedersen AB, Johnsen SP, Carroll R, Schoemaker MJ, Rault C, Daumont MJ, Ehrenstein V. Patient characteristics, treatment patterns, and survival outcomes for patients with malignant pleural mesothelioma in Denmark between 2011 and 2018: a nationwide population-based cohort study. Acta Oncol 2024; 63:649-657. [PMID: 39114950 PMCID: PMC11332510 DOI: 10.2340/1651-226x.2024.34802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/31/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy with poor prognosis and limited treatment options. Immunotherapy shows potential for improved outcomes; however, real-world evidence on its use will take time to accumulate. This study examined patient characteristics, treatment patterns, overall survival (OS), and predictors of mortality among patients diagnosed with MPM in Denmark prior to the introduction of newer treatments. METHODS This historical cohort study based on routinely collected Danish National Registry data included adults newly diagnosed with MPM between 01 January 2011 and 31 May 2018. Summary statistics were used to describe patient characteristics and initial treatment. OS was estimated using Kaplan-Meier methods; Cox regression was used to compare patient mortality against the (age/sex-matched) general population and to investigate mortality predictors. RESULTS Overall, 880 patients were included; 44% had advanced MPM, 37% had non-advanced MPM, and 19% had unknown MPM stage. Median age at diagnosis was 71.9 years, and 82% of the patients were male. Within 180 days of diagnosis, no treatment was recorded for 215 patients (54%) with advanced MPM and 150 (46%) with non-advanced MPM. Median time-to-initial treatment (interquartile range) was 47 days (31-111) overall, 40 days (28-77) in patients with advanced MPM, and 53 days (35-121) with non-advanced MPM. Median OS was 13.7 months overall (non-advanced MPM: 18.0 months vs. advanced MPM: 10.0 months). Predictors of higher mortality were older age at diagnosis, histology, and advanced MPM stage. INTERPRETATION These findings provide a baseline upon which to evaluate MPM epidemiology as newer treatments are adopted in routine practice.
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Affiliation(s)
| | - Paul Baas
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Alma B Pedersen
- Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Søren P Johnsen
- Danish Center for Health Services Research, Department for Clinical Medicine, Aalborg University Aalborg, Denmark
| | - Robert Carroll
- Centre for Observational Research and Data Science, Bristol Myers Squibb, Uxbridge, UK
| | | | | | - Melinda J Daumont
- Worldwide Health Economics & Outcomes Research, Bristol Myers Squibb, Braine-L'Alleud, Belgium
| | - Vera Ehrenstein
- Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
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8
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Layer JP, Fischer P, Dejonckheere CS, Sarria GR, Mispelbaum R, Hattenhauer T, Wiegreffe S, Glasmacher AR, Layer K, Nour Y, Caglayan L, Grau F, Müdder T, Köksal M, Scafa D, Giordano FA, Lopez-Pastorini A, Stoelben E, Schmeel LC, Leitzen C. Safety and efficacy of helical tomotherapy following lung-sparing surgery in locally advanced malignant pleural mesothelioma. Strahlenther Onkol 2024; 200:605-613. [PMID: 37993554 PMCID: PMC11186888 DOI: 10.1007/s00066-023-02174-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/22/2023] [Indexed: 11/24/2023]
Abstract
PURPOSE To assess the value of radiation therapy (RT) with helical tomotherapy (HT) in the management of locally advanced malignant pleural mesothelioma (MPM) receiving no or lung-sparing surgery. METHODS Consecutive MPM cases not undergoing extrapleural pneumonectomy and receiving intensity-modulated (IM) HT were retrospectively evaluated for local control, distant control, progression-free survival (PFS), and overall survival (OS). Impact of age, systemic treatment, RT dose, and recurrence patterns was analyzed by univariate and multivariate analysis. As a secondary endpoint, reported toxicity was assessed. RESULTS A total of 34 localized MPM cases undergoing IMHT were identified, of which follow-up data were available for 31 patients. Grade 3 side effects were experienced by 26.7% of patients and there were no grade 4 or 5 events observed. Median PFS was 19 months. Median OS was 20 months and the rates for 1‑ and 2‑year OS were 86.2 and 41.4%, respectively. OS was significantly superior for patients receiving adjuvant chemotherapy (p = 0.008). CONCLUSION IMHT of locally advanced MPM after lung-sparing surgery is safe and feasible, resulting in satisfactory local control and survival. Adjuvant chemotherapy significantly improves OS. Randomized clinical trials incorporating modern RT techniques as a component of trimodal treatment are warranted to establish an evidence-based standard of care pattern for locally advanced MPM.
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Affiliation(s)
- Julian P Layer
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany.
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany.
| | - Pascal Fischer
- Department of Thoracic Surgery, St. Hildegardis Hospital, Augustinerinnen Krankenhäuser gGmbH, Cologne, Germany
| | - Cas S Dejonckheere
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Gustavo R Sarria
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Rebekka Mispelbaum
- Department of Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany
| | - Tessa Hattenhauer
- Department of Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, Bonn, Germany
| | - Shari Wiegreffe
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Andrea R Glasmacher
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Katharina Layer
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Youness Nour
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Lara Caglayan
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Franziska Grau
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Thomas Müdder
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Mümtaz Köksal
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Davide Scafa
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
| | - Frank A Giordano
- Department of Radiation Oncology, University Medical Center Mannheim, Mannheim, Germany
- DKFZ-Hector Cancer Institute of the University Medical Center Mannheim, Mannheim, Germany
| | - Alberto Lopez-Pastorini
- Department of Thoracic Surgery, St. Hildegardis Hospital, Augustinerinnen Krankenhäuser gGmbH, Cologne, Germany
| | - Erich Stoelben
- Department of Thoracic Surgery, St. Hildegardis Hospital, Augustinerinnen Krankenhäuser gGmbH, Cologne, Germany
| | | | - Christina Leitzen
- Department of Radiation Oncology, University Hospital Bonn/Venusberg-Campus 1, 53127, Bonn, Germany
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Neilly MD, Pearson J, Thu AW, MacRae C, Blyth KG. Contemporary management of mesothelioma. Breathe (Sheff) 2024; 20:230175. [PMID: 39015660 PMCID: PMC11250169 DOI: 10.1183/20734735.0175-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 05/12/2024] [Indexed: 07/18/2024] Open
Abstract
Pleural mesothelioma (PM) is an aggressive asbestos-associated thoracic malignancy with a median survival of 12-18 months. Due to continued asbestos use in many nations, global incidence is rising. Causes due to non-occupational, environmental exposure are also rising in many countries despite utilisation bans. For many years, platinum--pemetrexed chemotherapy was the solitary licensed therapy, but first-line combination immune checkpoint blockade has recently demonstrated improved outcomes, with both regimes tested in predominantly late-stage cohorts. In the second-line setting, single-agent nivolumab has been shown to extend survival and is now available for routine use in some regions, while second-line chemotherapy has no proven role and opportunities for clinical trials should be maximised in relapsed disease. Surgery for "technically resectable" disease has been offered for decades in many expert centres, but the recent results from the phase III MARS2 trial have challenged this approach. There remains no robustly proven standard of care for early-stage PM. The clinical trial landscape for PM is complex and increasingly diverse, making further development of specialist PM multidisciplinary teams an important priority in all countries. The observation of improving outcomes in centres that have adopted this service model emphasises the importance of high-quality diagnostics and equitable access to therapies and trials. Novel therapies targeting a range of aberrations are being evaluated; however, a better understanding of the molecular drivers and their associated vulnerabilities is required to identify and prioritise treatment targets.
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Affiliation(s)
- Mark D.J. Neilly
- Glasgow Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Jennifer Pearson
- Glasgow Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Akari Win Thu
- Glasgow Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Carolyn MacRae
- Glasgow Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK
| | - Kevin G. Blyth
- Glasgow Pleural Disease Unit, Queen Elizabeth University Hospital, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Institute, Glasgow, UK
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Hocking AJ, Mortimer LA, Farrall AL, Russell PA, Klebe S. Establishing mesothelioma patient-derived organoid models from malignant pleural effusions. Lung Cancer 2024; 191:107542. [PMID: 38555809 DOI: 10.1016/j.lungcan.2024.107542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 03/19/2024] [Accepted: 03/25/2024] [Indexed: 04/02/2024]
Abstract
OBJECTIVES Pleural mesothelioma is a cancer arising in the cells that line the lungs and chest wall with poor survival and poor response to first-line therapy. Organoid models of cancer can faithfully recapitulate the genetic and histopathological characteristics of individualized tumors and have potential to be used for precision medicine, however methods of establishing patient-derived mesothelioma organoids have not been well established in the published literature. MATERIALS AND METHODS Long-term mesothelioma patient-derived organoids were established from ten malignant pleural effusion fluids. Mesothelioma patient-derived organoids were compared to the corresponding biopsy tissue specimens using immunohistochemistry labelling for select diagnostic markers and the TruSight Oncology-500 sequencing assay. Cell viability in response to the chemotherapeutic drug cisplatin was assessed. RESULTS We established five mesothelioma patient-derived organoid cultures from ten malignant pleural effusion fluids collected from nine individuals with pleural mesothelioma. Mesothelioma patient-derived organoids typically reflected the histopathological and genomic features of patients' matched biopsy specimens and displayed cytotoxic sensitivity to cisplatin in vitro. CONCLUSION This is the first study of its kind to establish long-term mesothelioma organoid cultures from malignant pleural effusions and report on their utility to test individuals' chemotherapeutic sensitivities ex vivo.
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Affiliation(s)
- Ashleigh J Hocking
- College of Medicine and Public Health, Flinders University, Adelaide, Australia.
| | - Lauren A Mortimer
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Alexandra L Farrall
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Prudence A Russell
- LifeStrands Genomics and TissuPath Pathology, Mount Waverley, Victoria, Australia
| | - Sonja Klebe
- College of Medicine and Public Health, Flinders University, Adelaide, Australia; Anatomical Pathology, SA Pathology, Flinders Medical Centre, Bedford Park, Australia
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Jones TE, Geisler DL, Baskota SU, Ohori NP, Cuda J, Khader SN. Reliably making the primary diagnosis of mesothelioma utilizing serous fluid cytology specimens: an institutional experience. J Am Soc Cytopathol 2024; 13:174-182. [PMID: 38514361 DOI: 10.1016/j.jasc.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 02/05/2024] [Accepted: 02/26/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION The diagnosis of mesothelioma has historically been challenging, especially on serous fluid cytology (SFC). Distinguishing between reactive and neoplastic mesothelial cells can be difficult on cytomorphology alone. However, additional ancillary tests, such as BRCA1 associated protein-1 immunohistochemistry and fluorescence in situ hybridization for cyclin-dependent kinase inhibitor 2A deletion, can provide a sensitive and highly specific method of proving malignancy. MATERIALS AND METHODS SFC specimens diagnosed as mesothelioma, suspicious for mesothelioma (SM), and atypical mesothelial cells (AMCs) since 2012 were identified by querying the laboratory information system. Clinical data and pathologic parameters were gathered. RESULTS One hundred ten cases of mesothelioma, SM, and AMC were identified. Of these, 61 cases had a definitive diagnosis of mesothelioma on SFC. Average age at SFC diagnosis was 67 years (26-87 years), with most patients being male (67%). Out of the 61 cases, 11 cases (18%) had an initial diagnosis of mesothelioma made on SFC specimens, with 5 of these 11 cases being in patients that never received a histologic diagnosis of mesothelioma. Ancillary studies were utilized in all 11 cases. An initial diagnosis of metastatic mesothelioma was made on SFC in 9 cases (15%). For 6 of these 9 cases, the SFC diagnosis was the sole diagnosis of metastatic mesothelioma without a companion histologic diagnosis. In addition, 15 cases were diagnosed as SM, with 11 of these cases following a definitive mesothelioma diagnosis. Thirty-four cases were diagnosed as AMC, with 27 cases following a definitive mesothelioma diagnosis. CONCLUSIONS The diagnosis of mesothelioma can be reliably made on SFC with the appropriate cytomorphology criteria and/or confirmatory ancillary testing.
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Affiliation(s)
- Terri E Jones
- Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | - Daniel L Geisler
- Department of Pathology, UPMC East, University of Pittsburgh Medical Center, Monroeville, Pennsylvania
| | - Swikrity Upadhyay Baskota
- Department of Pathology and Laboratory Medicine, University of California Davis Health System, Sacramento, California
| | - N Paul Ohori
- Department of Pathology, Presbyterian-Shadyside Hospitals, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Jacqueline Cuda
- Department of Pathology, Presbyterian-Shadyside Hospitals, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Samer N Khader
- Department of Pathology, Presbyterian-Shadyside Hospitals, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Miller LJ, Holmes IM, Lew M. An Updated Contextual Approach to Mesothelial Proliferations in Pleural Effusion Cytology Leveraging Morphology, Ancillary Studies, and Novel Biomarkers. Arch Pathol Lab Med 2024; 148:409-418. [PMID: 37622452 DOI: 10.5858/arpa.2023-0049-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2023] [Indexed: 08/26/2023]
Abstract
CONTEXT.— Pleural effusions are common cytologic specimens that can be leveraged to make diagnoses of malignancy that drive appropriate patient management. However, the overlap in morphologic features of reactive mesothelial proliferations, mesotheliomas, and adenocarcinomas can create diagnostic pitfalls in the cytologic evaluation of pleural fluids. OBJECTIVE.— To review the morphologic spectrum of benign and malignant mesothelial proliferations in pleural effusions, as well as relevant clinicoradiologic contexts and ancillary tests. DATA SOURCES.— Existing scientific and clinical literature as of January 2023. CONCLUSIONS.— We can leverage the knowledge of several overlapping morphologic features, clinicoradiologic scenarios, and immunohistochemical studies to enhance the diagnostic accuracy of pleural effusion cytology to appropriately delineate cases of adenocarcinoma, reactive mesothelial proliferation, and mesothelioma. Earlier diagnosis through cytology, particularly in cases of mesothelioma, may positively impact patient treatment options and prognosis.
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Affiliation(s)
- Lauren J Miller
- From the Department of Pathology, University of Michigan Hospital and Health System, Ann Arbor
| | - Isabella M Holmes
- From the Department of Pathology, University of Michigan Hospital and Health System, Ann Arbor
| | - Madelyn Lew
- From the Department of Pathology, University of Michigan Hospital and Health System, Ann Arbor
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Martella S, Aiello MM, Bertaglia V, Cau R, Denaro N, Cadoni A, Novello S, Scartozzi M, Novello G, Soto Parra HJ, Saba L, Solinas C, Porcu M. Malignant Pleural Mesothelioma: Staging and Radiological Response Criteria in Patients Treated with Immune Checkpoint Inhibitors. Target Oncol 2024; 19:13-28. [PMID: 38063957 DOI: 10.1007/s11523-023-01017-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2023] [Indexed: 02/01/2024]
Abstract
Malignant pleural mesothelioma (MPM) is a rare and challenging cancer associated with asbestos fiber exposure, which offers limited treatment options. Historically, platinum-based chemotherapy has been the primary approach, but recent developments have introduced immunotherapy as a promising alternative for the treatment of this disease. Nevertheless, the unique growth patterns and occasionally ambiguous progressive characteristics of MPM make the interpretation of radiological assessments complex. Immunotherapy further complicates matters by introducing unconventional treatment response patterns such as hyperprogression and pseudoprogression. Consequently, there is a growing imperative to integrate the standard RECIST criteria with the mesothelioma-specific mRECIST criteria (version 1.1), as outlined in iRECIST. This comprehensive review is driven by the intent to provide a valuable resource for radiologists and clinicians engaged in the diagnosis, treatment, and monitoring of MPM in the era of immunotherapy. Specifically, the current imaging methods employed for staging and follow-up will be exposed and discussed, with a focus on the technical specificities and the mRECIST 1.1 methodology. Furthermore, we will provide a discussion about major clinical trials related to the use of immunotherapy in MPM patients. Finally, the latest advancements in radiomics, the applications of artificial intelligence in MPM, and their potential impact on clinical practice for prognosis and therapy, are discussed.
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Affiliation(s)
- Serafina Martella
- Department of Medical Oncology, University Hospital Policlinico San Marco, Catania, Italy
| | - Marco Maria Aiello
- Department of Medical Oncology, University Hospital Policlinico San Marco, Catania, Italy
| | - Valentina Bertaglia
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Turin, Italy
| | - Riccardo Cau
- Department of Radiology, AOU Cagliari, S.S: 554, km 4,500, CAP: 09042, Monserrato (CA), Italy
| | - Nerina Denaro
- Department of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Andrea Cadoni
- Department of Medical Oncology, AOU Cagliari, Monserrato (CA), Italy
| | - Silvia Novello
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Turin, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, AOU Cagliari, Monserrato (CA), Italy
| | - Giuseppe Novello
- Department of Medical Oncology, University Hospital Policlinico San Marco, Catania, Italy
| | - Hector Josè Soto Parra
- Department of Medical Oncology, University Hospital Policlinico San Marco, Catania, Italy
| | - Luca Saba
- Department of Radiology, AOU Cagliari, S.S: 554, km 4,500, CAP: 09042, Monserrato (CA), Italy
| | - Cinzia Solinas
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Turin, Italy
| | - Michele Porcu
- Department of Radiology, AOU Cagliari, S.S: 554, km 4,500, CAP: 09042, Monserrato (CA), Italy.
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Smith S, Kao S. PEMMELA: a promising regimen at the expense of toxicity. Lancet Oncol 2023; 24:1161-1162. [PMID: 37844596 DOI: 10.1016/s1470-2045(23)00512-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/18/2023]
Affiliation(s)
- Samuel Smith
- St Vincent's Hospital Melbourne Melbourne, VIC, Australia
| | - Steven Kao
- Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia.
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15
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Schelch K, Emminger D, Zitta B, Johnson TG, Kopatz V, Eder S, Ries A, Stefanelli A, Heffeter P, Hoda MA, Hoetzenecker K, Dome B, Berger W, Reid G, Grusch M. Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo. Cancer Lett 2023; 574:216395. [PMID: 37730104 DOI: 10.1016/j.canlet.2023.216395] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/31/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023]
Abstract
Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.
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Affiliation(s)
- Karin Schelch
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria; Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Asbestos and Dust Diseases Research Institute, Gate 3 Hospital Rd, Concord, 2139, Sydney, NSW, Australia
| | - Dominik Emminger
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Benjamin Zitta
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Thomas G Johnson
- Asbestos and Dust Diseases Research Institute, Gate 3 Hospital Rd, Concord, 2139, Sydney, NSW, Australia; The University of Sydney, Camperdown, 2006, Sydney, NSW, Australia
| | - Verena Kopatz
- Department of Radiation Oncology, Applied and Translational Radiobiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Sebastian Eder
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Alexander Ries
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Alessia Stefanelli
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Petra Heffeter
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Mir A Hoda
- Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Balazs Dome
- Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; National Koranyi Institute of Pulmonology, Korányi Frigyes u. 1, 1122 Budapest, Hungary; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, 1122 Budapest, Hungary
| | - Walter Berger
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Glen Reid
- Department of Pathology, Dunedin School of Medicine and the Maurice Wilkins Centre, 56 Hanover Street, Central Dunedin, Dunedin 9016, New Zealand
| | - Michael Grusch
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
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16
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Rondon L, Fu R, Patel MR. Success of Checkpoint Blockade Paves the Way for Novel Immune Therapy in Malignant Pleural Mesothelioma. Cancers (Basel) 2023; 15:2940. [PMID: 37296902 PMCID: PMC10251855 DOI: 10.3390/cancers15112940] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/18/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is a malignancy associated with asbestos exposure and is typically categorized as an orphan disease. Recent developments in immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies, specifically with agents nivolumab and ipilimumab, have demonstrated an improvement in overall survival over the previous standard chemotherapy leading to their FDA-approval as first-line therapy for unresectable disease. For quite some time, it has been known that these proteins are not the only ones that function as immune checkpoints in human biology, and the hypothesis that MPM is an immunogenic disease has led to an expanding number of studies investigating alternative checkpoint inhibitors and novel immunotherapy for this malignancy. Early trials are also supporting the notion that therapies that target biological molecules on T cells, cancer cells, or that trigger the antitumor activity of other immune cells may represent the future of MPM treatment. Moreover, mesothelin-targeted therapies are thriving in the field, with forthcoming results from multiple trials signaling an improvement in overall survival when combined with other immunotherapy agents. The following manuscript will review the current state of immune therapy for MPM, explore the knowledge gaps in the field, and discuss ongoing novel immunotherapeutic research in early clinical trials.
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Affiliation(s)
- Lizbeth Rondon
- Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55404, USA; (L.R.); (R.F.)
| | - Roberto Fu
- Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55404, USA; (L.R.); (R.F.)
| | - Manish R. Patel
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
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17
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Bonde A, Singh R, Prasad SR, Kamireddy D, Aggarwal A, Ramani N, Saboo S, Shanbhogue K, Dasyam AK, Katabathina VS. Mesotheliomas and Benign Mesothelial Tumors: Update on Pathologic and Imaging Findings. Radiographics 2023; 43:e220128. [PMID: 36757881 DOI: 10.1148/rg.220128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
A diverse spectrum of benign entities and malignant neoplasms originate from the monotonous mesothelium that lines the serosal membranes of the pleural, pericardial, and peritoneal cavities. The mesothelium of myriad sites shows a common origin from the lateral plate mesoderm; primary mesothelial tumors thus demonstrate similar pathogenesis, imaging findings, and treatment options. Significant changes have been made in the 2021 World Health Organization (WHO) classification schemata of the pleural and pericardial tumors on the basis of recent advances in pathology and genetics. While malignant mesotheliomas are biologically aggressive malignancies that occur primarily in patients exposed to asbestos with attendant poor survival rates, well-differentiated papillary mesothelial tumors and adenomatoid tumors charter a benign clinical course with an excellent prognosis. Mesothelioma in situ is a newly characterized entity represented by recurrent unexplained pleural effusions without any identifiable mass at imaging or thoracoscopy. Immunohistochemical markers based on BAP1, MTAP, CDKN2A, and TRAF7 gene mutations help differentiate diffuse mesotheliomas from benign mesothelial proliferations and localized mesotheliomas. Cross-sectional imaging modalities, including US, CT, MRI, and fluorine 18-fluorodeoxyglucose (FDG) PET/CT, permit diagnosis and play a major role in staging and assessing surgical resectability. Imaging studies are invaluable in providing noninvasive and quantitative assessment of tumor response in patients with unresectable disease. Owing to significant overlap in patient characteristics and pathomorphology, accurate diagnosis based on advanced histopathology techniques and genetic abnormalities is imperative for optimal management and prognostication. While patients with nonepithelioid pleural mesotheliomas benefit from immunotherapy, novel targeted therapies for CDKN2A-, NF2-, and BAP1-altered mesotheliomas are under consideration. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.
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Affiliation(s)
- Apurva Bonde
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Ramandeep Singh
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Srinivasa R Prasad
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Dhiraj Kamireddy
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Aarushi Aggarwal
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Nisha Ramani
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Sachin Saboo
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Krishna Shanbhogue
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Anil K Dasyam
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
| | - Venkata S Katabathina
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (A.B., D.K., A.A., S.S., V.S.K.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (R.S.); Departments of Radiology (S.R.P.) and Pathology (N.R.), University of Texas M. D. Anderson Cancer Center, Houston, Tex; Department of Radiology, NYU Medical Center, New York, NY (K.S.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (A.K.D.)
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Prognostic Value of EMT Gene Signature in Malignant Mesothelioma. Int J Mol Sci 2023; 24:ijms24054264. [PMID: 36901697 PMCID: PMC10001510 DOI: 10.3390/ijms24054264] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 02/07/2023] [Accepted: 02/17/2023] [Indexed: 02/23/2023] Open
Abstract
Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial-mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-β signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-β1/TGFBR1 pathway.
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Meirson T, Nardone V, Pentimalli F, Markel G, Bomze D, D'Apolito M, Correale P, Giordano A, Pirtoli L, Porta C, Gray SG, Mutti L. Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology. J Transl Med 2022; 20:593. [PMID: 36514092 DOI: 10.1186/s12967-022-03744-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 10/29/2022] [Indexed: 12/15/2022] Open
Abstract
In this commentary, using existing clinical trial data and FDA approvals we propose that there is currently a critical need for an appropriate balancing between the financial impact of new cancer drugs and their actual benefit for patients. By adopting "pleural mesothelioma" as our clinical model we summarize the most relevant pertinent and available literature on this topic, and use an analysis of the reliability of the trials submitted for registration and/or recently published as a case in point to raise concerns with respect to appropriate trial design, biomarker based stratification and to highlight the ongoing need for balancing the benefit/cost ratio for both patients and healthcare providers.
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Affiliation(s)
- Tomer Meirson
- Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, 49100, Petah Tikva, Israel
| | - Valerio Nardone
- Department of Precision Oncology, University Hospital of Campania L. Vanvitelli, Naples, Italy
| | - Francesca Pentimalli
- Dipartimento di Medicina e Chirurgia, Libera Università Mediterranea "Giuseppe Degennaro", Bari, Italy
| | - Gal Markel
- Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, 49100, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - David Bomze
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Maria D'Apolito
- Unit of Medical Oncology, Oncology Department, Grand Metropolitan Hospital Bianchi Melacrino Morelli, Reggio Calabria, Italy
| | - Pierpaolo Correale
- Unit of Medical Oncology, Oncology Department, Grand Metropolitan Hospital Bianchi Melacrino Morelli, Reggio Calabria, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.,Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Luigi Pirtoli
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Camillo Porta
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro" and A.O.U. Consorziale Policlinico di Bari, Bari, Italy.
| | - Steven G Gray
- Thoracic Oncology Research Group, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.
| | - Luciano Mutti
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA. .,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy.
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Canova S, Ceresoli G, Grosso F, Zucali P, Gelsomino F, Pasello G, Mencoboni M, Rulli E, Galli F, De Simone I, Carlucci L, De Angelis A, Belletti M, Bonomi M, D’Aveni A, Perrino M, Bono F, Cortinovis D, Canova S, Colonese F, Abbate M, Sala L, Sala E, Perez Gila M, Bono F, Pagni F, Ceresoli G, D’Aveni A, Bonomi M, Grosso F, De Angelis A, Ugo F, Belletti M, Zucali P, Perrino M, De Vincenzo F, Santoro A, Gelsomino F, Ardizzoni A, Pasello G, Frega S, Mencoboni M, Carlucci L, De Simone I, D’Incalci M, Galli F, Poli D, Rulli E, Torri V. Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma. ESMO Open 2022; 7:100644. [PMID: 36463732 PMCID: PMC9808442 DOI: 10.1016/j.esmoop.2022.100644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 09/15/2022] [Accepted: 10/26/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Malignant pleural mesothelioma (MPM) is a cancer with a high mortality rate and few therapeutic options. After platinum-pemetrexed combination, no further promising drug seems to be effective. Immune checkpoint inhibitors may have some activity in pretreated patients and no data are available in this population about durvalumab. MATERIALS AND METHODS DIADEM was a multicenter, open-label, single-arm, phase II trial aimed at evaluating the efficacy and safety of durvalumab. Patients with locally advanced/metastatic MPM who progressed after platinum-pemetrexed chemotherapy were enrolled to receive durvalumab (1500 mg, intravenously Q4W) for 12 months or until evidence of disease progression or unacceptable toxicity. The primary endpoint was the proportion of patients alive and free from progression at 16 weeks (PFS16wks) calculated from treatment initiation. Secondary endpoints were progression-free survival, overall survival, overall response rate, and safety. RESULTS Sixty-nine patients with a median age of 69 years (range 44-82 years) were enrolled; 62 patients (89.9%) had epithelioid histotype. As first-line treatment, all patients received platinum derivatives-pemetrexed combination (60.9% with carboplatin and 39.1% with cisplatin). As of March 2021, the median follow-up was 9.2 months (interquartile range 5.2-11.1 months). Six patients (8.7%) completed the 12-month treatment; 60 patients discontinued, of whom 42 for progressive disease, and 4 died. Seventeen patients (28.3%; 95% confidence interval 17.5% to 41.4%) were alive or free from progression at 16 weeks. Eleven patients (18.6%) had a grade 3 or 4 treatment-related adverse event (AE), and one (1.4%) had a grade ≥3 immune-related, treatment-related AE. There was one drug-related death. CONCLUSION Durvalumab alone in pretreated non-selected MPM did not reach a meaningful clinical activity, showing any new major safety issue signals.
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Affiliation(s)
- S. Canova
- ASST H S Gerardo, SC Medical Oncology, Monza
| | - G.L. Ceresoli
- Humanitas Gavazzeni, Bergamo,Department of Oncology, Saronno Hospital, ASST Valle Olona, Saronno (VA)
| | - F. Grosso
- Mesothelioma Unit, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria
| | - P.A. Zucali
- Department of Oncology, IRCCS Humanitas Research Hospital, Rozzano,Department of Biomedical Sciences, Humanitas University, Rozzano
| | - F. Gelsomino
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna
| | - G. Pasello
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova,Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova
| | | | - E. Rulli
- Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan
| | - F. Galli
- Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan
| | - I. De Simone
- Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan
| | - L. Carlucci
- Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan
| | - A. De Angelis
- Mesothelioma Unit, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria
| | - M. Belletti
- Mesothelioma Unit, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria
| | - M. Bonomi
- Humanitas Gavazzeni, Bergamo,Department of Oncology, ASST Cremona, Cremona, Italy
| | - A. D’Aveni
- Humanitas Gavazzeni, Bergamo,Department of Oncology, Saronno Hospital, ASST Valle Olona, Saronno (VA)
| | - M. Perrino
- Department of Oncology, IRCCS Humanitas Research Hospital, Rozzano
| | - F. Bono
- ASST H S Gerardo, SC Medical Oncology, Monza
| | - D.L. Cortinovis
- ASST H S Gerardo, SC Medical Oncology, Monza,Correspondence to: Dr Diego Luigi Cortinovis, ASST-Monza San Gerardo Hospital, SC Medical Oncology, Monza, Via Pergolesi 33 20900 Monza, Italy. Tel: +39-0392339575; Fax: +39-0392332284
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21
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Handra CM, Chirila M, Smarandescu RA, Ghita I. Near Missed Case of Occupational Pleural Malignant Mesothelioma, a Case Report and Latest Therapeutic Options. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:14763. [PMID: 36429481 PMCID: PMC9690238 DOI: 10.3390/ijerph192214763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/02/2022] [Accepted: 11/07/2022] [Indexed: 06/16/2023]
Abstract
Asbestos use started to be gradually banned in Europe from 1991 onwards, and there are currently strict occupational exposure limits for asbestos. However, malignant mesothelioma has a long latency time (in some cases up to 50-60 years), so the risks related to asbestos exposure should not be forgotten. Considering the increased risk of lung cancer following the inhalation of asbestos fibers, lifetime health monitoring should be considered in people occupationally exposed to asbestos, with an emphasis on the respiratory system. An assessment of their occupational history should be performed rigorously, especially in the areas with a history of asbestos production/use, as this is a key element for an early diagnosis and appropriate treatment. This case report presents a near-missed case of occupational pleural malignant mesothelioma. The latency time between the first asbestos exposure and the diagnosis of occupational pleural malignant mesothelioma was 49 years. The accurate diagnosis was made two years after the first symptoms appeared.
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Affiliation(s)
- Claudia-Mariana Handra
- Occupational Health Department, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Marinela Chirila
- Faculty of Pharmacy, Titu Maiorescu University, 040441 Bucharest, Romania
| | - Raluca-Andreea Smarandescu
- Occupational Health Department, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Isabel Ghita
- Pharmacy and Pharmacology Department, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Cimen F, Agackiran Y, Düzgün S, Aloglu M, Senturk A, Atikcan S. Factors affecting the life expectancy in malignant pleural mesothelioma: Our 10 years of studies and experience. Medicine (Baltimore) 2022; 101:e30711. [PMID: 36181042 PMCID: PMC9524951 DOI: 10.1097/md.0000000000030711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. In our study, we aimed to investigate the specific clinical, laboratory, and radiological features of the tumor and the prognostic effect of SUVmax (maximum standardized uptake values) according to PET/CT (positron emission tomography). Demographic, therapeutic, clinical, and survival information of patients diagnosed with histologically-validated pleural mesothelioma in our hospital between January 2010 to December 2019 will be retrospectively scanned from the hospital records. A total of 116 patients, 61 men (52.6%), and 55 women (47.4%), were analyzed. Thirty five patients (30.2%) were over the age of 65. Percentage of patients over 65 years of age, neutrophil count, and PET SUV Max values, asbestos exposure and pleural thickening rate were significantly higher in the deceased patients' group than in the living patients' group (P = .042, P = .039, P = .002, P = .004, P = .037). T stage (tumor stage), N stage (lymph nodes stage), metastasis stage, and Grade distribution were significantly higher in the deceased patients' group than in the living patients' group (P < .000, P < .000, P = .003, P < .000). The rates of chemotherapy and surgical treatment, right lung location, and epithelioid pathology were significantly lower in the deceased patients' group compared to the living patients' group (P = .016, P = .030, P = .018, P = .008). The mean follow-up time was 13 months. Key determinants of survival in MPM include age, male gender, neutrophil increase, pleural thickening, high PET SUV max values, stage, histological type, asbestos exposure, and treatment regimen.
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Affiliation(s)
- Filiz Cimen
- University of Health Sciences, Atatürk Chest Diseases and Thoracic Surgery Education and Research Hospital, Department of Pulmonology, Ankara, Turkey
- *Correspondence: Filiz Cimen, University of Health Sciences, Atatürk Chest Diseases and Thoracic Surgery Education and Research Hospital, Department of Pulmonology, 06290, Ankara, Turkey (e-mail: )
| | - Yetkin Agackiran
- University of Health Sciences, Atatürk Chest Diseases and Thoracic Surgery Education and Research Hospital, Department of Pathology, Ankara, Turkey
| | - Sevim Düzgün
- University of Health Sciences, Atatürk Chest Diseases and Thoracic Surgery Education and Research Hospital, Department of Pulmonology, Ankara, Turkey
| | - Melike Aloglu
- University of Health Sciences, Atatürk Chest Diseases and Thoracic Surgery Education and Research Hospital, Department of Pulmonology, Ankara, Turkey
| | - Aysegül Senturk
- University of Health Sciences, Atatürk Chest Diseases and Thoracic Surgery Education and Research Hospital, Department of Pulmonology, Ankara, Turkey
| | - Sükran Atikcan
- University of Health Sciences, Atatürk Chest Diseases and Thoracic Surgery Education and Research Hospital, Department of Pulmonology, Ankara, Turkey
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The silent malignant mesothelioma epidemic: a call to action. Lancet Oncol 2022. [DOI: 10.1016/s1470-2045(22)00269-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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24
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Hagiyama M, Mimae T, Wada A, Takeuchi F, Yoneshige A, Inoue T, Kotoku N, Hamada H, Sekido Y, Okada M, Ito A. Possible Therapeutic Utility of anti-Cell Adhesion Molecule 1 Antibodies for Malignant Pleural Mesothelioma. Front Cell Dev Biol 2022; 10:945007. [PMID: 35903548 PMCID: PMC9315061 DOI: 10.3389/fcell.2022.945007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 06/23/2022] [Indexed: 11/15/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive malignant tumor, and the effective therapeutic drugs are limited. Thus, the establishment of novel therapeutic method is desired. Considerable proportion of MPMs are shown to express cell adhesion molecule 1 (CADM1), and to use CADM1 to bind to and proliferate on the pleural mesothelial surface, suggesting that CADM1 is a possible therapeutic target. Here, anti-CADM1 ectodomain chicken monoclonal antibodies, 3E1 and 9D2, were examined for their possible therapeutic utility. The full-length form of CADM1 was expressed in eight out of twelve human MPM cell lines. MPM cell lines were cultured on a confluent monolayer of mesothelial MeT-5A cells in the presence of 9D2, the neutralizing antibody. 9D2 suppressed the cell growth of CADM1-positive MPM cells with the loss and aggregation of CADM1 molecules on the MPM cell membrane, but not of CADM1-negative MPM cells. Co-addition of 3E1, lacking the neutralizing action, enhanced the growth-suppressive effect of 9D2. The two antibodies were tested as drug delivery vectors. 3E1 was converted into a humanized antibody (h3E1) and conjugated with monomethyl auristatin E (MMAE), a tubulin polymerization inhibitor. When the resulting h3E1–MMAE antibody-drug conjugate (ADC) was added to the standard cultures of CADM1-positive MPM cells, it suppressed the cell growth in a dose-dependent manner. Co-addition of 9D2 enhanced the growth-suppressive effect of h3E1–MMAE ADC. Anti-CADM1 ectodomain antibodies were suggested to serve as both antibody drugs and drug vectors in the treatment of MPM.
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Affiliation(s)
- Man Hagiyama
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takahiro Mimae
- Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan
| | - Akihiro Wada
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Fuka Takeuchi
- Division of Molecular Pathology, Graduate School of Medical Science, Kindai University, Osaka, Japan
| | - Azusa Yoneshige
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takao Inoue
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Naoyuki Kotoku
- College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yoshitaka Sekido
- Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Morihito Okada
- Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan
| | - Akihiko Ito
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
- Division of Molecular Pathology, Graduate School of Medical Science, Kindai University, Osaka, Japan
- *Correspondence: Akihiko Ito,
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Kindler HL. Systemic Therapy for Mesothelioma: Turning the Corner. JCO Oncol Pract 2021; 18:e843-e845. [PMID: 34932380 DOI: 10.1200/op.21.00785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Hedy Lee Kindler
- Section of Hematology/Oncology, University of Chicago, Chicago, IL
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Affiliation(s)
- Amit A Kulkarni
- Section of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School Minneapolis, MN
| | - Robert A Kratzke
- Section of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School Minneapolis, MN
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