bims-mesote 2023-01-29 papers

Issue of 2023–01–29
five papers selected by
Laura Mannarino, Humanitas Research

Cureus. 2023 Jan;15(1): e33965

Pleural Mesothelioma: A Rapid Evolution of an Indolent Disease.

Miguel Romano, Pedro Pinto, Raquel Afonso, Joana Fontes, Manuel Ferreira.

Mesothelioma is a rare and insidious neoplasm and is characterized by its highly malignant and aggressive nature. The most common etiology is asbestos exposure, but there are some reports without known asbestos exposure and other factors leading to malignant pleural mesothelioma (MPM). Here, we present the case of a 58-year-old woman with pleuritic chest pain, dyspnea, and fever on presentation to the emergency department (ED), which caused several admissions to the ED in 20 days. The patient was then admitted to the internal medicine department with a diagnosis of community-acquired pneumonia with parapneumonic effusion. During hospitalization, a positron emission tomography (PET) scan, thoracic computed tomography (CT), and pleural biopsy were performed and a final diagnosis of malignant epithelioid pleural mesothelioma was made. Six weeks after the onset of symptoms, the patient presented with an exponential disease progression, dying two months after the diagnosis, despite the initiation of chemotherapy. MPM remains a diagnostic and therapeutic challenge with a very poor prognosis. However, studies show that mesothelioma patients who undergo treatment live at least twice as long as patients who do not receive treatment. This case report is particularly significant because, although it was epithelioid mesothelioma, multiple solid masses were noted on CT and the patient exhibited rapid disease progression, dying a few weeks after starting treatment.

Keywords: diagnosis; epithelioid mesothelioma; malignant pleural mesothelioma (mpm); oncology; pneumology; prognosis; treatment

DOI: https://doi.org/10.7759/cureus.33965

Gigascience. 2022 Dec 28. pii: giac128. [Epub ahead of print]12

A molecular phenotypic map of malignant pleural mesothelioma.

Alex Di Genova, Lise Mangiante, Alexandra Sexton-Oates, Catherine Voegele, Lynnette Fernandez-Cuesta, Nicolas Alcala, Matthieu Foll.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare understudied cancer associated with exposure to asbestos. So far, MPM patients have benefited marginally from the genomics medicine revolution due to the limited size or breadth of existing molecular studies. In the context of the MESOMICS project, we have performed the most comprehensive molecular characterization of MPM to date, with the underlying dataset made of the largest whole-genome sequencing series yet reported, together with transcriptome sequencing and methylation arrays for 120 MPM patients.
RESULTS: We first provide comprehensive quality controls for all samples, of both raw and processed data. Due to the difficulty in collecting specimens from such rare tumors, a part of the cohort does not include matched normal material. We provide a detailed analysis of data processing of these tumor-only samples, showing that all somatic alteration calls match very stringent criteria of precision and recall. Finally, integrating our data with previously published multiomic MPM datasets (n = 374 in total), we provide an extensive molecular phenotype map of MPM based on the multitask theory. The generated map can be interactively explored and interrogated on the UCSC TumorMap portal (https://tumormap.ucsc.edu/?p=RCG_MESOMICS/MPM_Archetypes ).
CONCLUSIONS: This new high-quality MPM multiomics dataset, together with the state-of-art bioinformatics and interactive visualization tools we provide, will support the development of precision medicine in MPM that is particularly challenging to implement in rare cancers due to limited molecular studies.

Keywords: DNA methylation; cancer tasks; genomics; malignant pleural mesothelioma; quality control; transcriptomics; tumor map

DOI: https://doi.org/10.1093/gigascience/giac128

J Pharm Policy Pract. 2023 Jan 25. 16(1): 16

Alvopem® (pemetrexed) safety assessment in patients with non-small cell lung cancer or malignant pleural mesothelioma: a post-marketing surveillance.

Sharareh Seifi, Babak Salimi, Zahra Esfahani Monfared, Cyrus Sabahi, Hamidreza Kafi, Adnan Khosravi.

BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide in both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority (~ 85%) of lung cancers. This post-marketing surveillance (PMS) study aimed to evaluate the safety of Pemetrexed (Alvopem®, NanoAlvand, Iran) in Iranian patients with lung cancer or mesothelioma.
METHODS: The present study is an observational, single-center, open-label, and post-authorization study. All eligible non-squamous NSCLC and malignant pleural mesothelioma (MPM) patients who received pemetrexed based on the physicians' decision, were enrolled.
RESULTS: A total of 199 patients with non-squamous NSCLC [186 patients (93.47%) or MPM (12 patients (6.03%)] were enrolled from March 2016 to February 2020. The most common reported adverse event (AE) was anemia (89.39%), followed by neutropenia (28.79%) and leukopenia (24.75%). The most important grade 3 AEs were anemia and neutropenia, with the incidence rate of 3.54% and 7.58%, respectively. No grade 4 AEs were reported. Moreover, the results of our study showed negative statistically significant correlations between patients' age and mean neutrophil count (r = - 0.17; P = 0.0156) and hemoglobin (r = - 0.16; P = 0.0201) in all six visits.
CONCLUSIONS: The results of this open-label, observational PMS showed that Pemetrexed (Alvopem®) is safe in patients with non-squamous NSCLC patients receiving pemetrexed-containing regimens.
TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT04843007) in April 13th, 2021.

Keywords: Non-small cell lung cancer; Observational study; Pemetrexed; Post-marketing surveillance; Safety

DOI: https://doi.org/10.1186/s40545-023-00524-5

Front Immunol. 2022 ;13 1026185

Deep dive into the immune response against murine mesothelioma permits design of novel anti-mesothelioma therapeutics.

Esther Stern, Stefano Caruso, Clément Meiller, Inbal Mishalian, Theo Z Hirsch, Quentin Bayard, Carmit T Tadmor, Hanna Wald, Didier Jean, Ori Wald.

Given the need to improve the efficacy of standard-of-care immunotherapy (anti-CTLA-4 + anti-PD-1) in human malignant pleural mesothelioma (hMPM), we thoroughly characterized the immunobiology of the AB12 murine mesothelioma (MM) model, aiming to increase its accuracy in predicting the response of hMPM to immunotherapy and in designing novel anti-hMPM treatments. Specifically, we used immunologic, transcriptomic and survival analyses, to synchronize the MM tumor growth phases and immune evolution with the histo-molecular and immunological characteristics of hMPM while also determining the anti-MM efficacy of standard-of-care anti-hMPM immunotherapy as a benchmark that novel therapeutics should meet. We report that early-, intermediate- and advanced- AB12 tumors are characterized by a bell-shaped anti-tumor response that peaks in intermediate tumors and decays in advanced tumors. We further show that intermediate- and advanced- tumors match with immune active ("hot") and immune inactive ("cold") hMPM respectively, and that they respond to immunotherapy in a manner that corresponds well with its performance in real-life settings. Finally, we show that in advanced tumors, addition of cisplatin to anti CTLA-4 + anti PD-1 can extend mice survival and invigorate the decaying anti-tumor response. Therefore, we highlight this triple combination as a worthy candidate to improve clinical outcomes in hMPM.

Keywords: animal models; immunomodulation; immunotherapy; lung neoplasms; thoracic cancer

DOI: https://doi.org/10.3389/fimmu.2022.1026185

J Exp Clin Cancer Res. 2023 Jan 23. 42(1): 27

Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin.

Alexander Ries, Daniela Flehberger, Astrid Slany, Christine Pirker, Johanna C Mader, Thomas Mohr, Karin Schelch, Katharina Sinn, Berta Mosleh, Mir Alireza Hoda, Balazs Dome, Helmut Dolznig, Georg Krupitza, Leonhard Müllauer, Christopher Gerner, Walter Berger, Michael Grusch.

BACKGROUND: Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, PM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several malignancies. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on PM cells.
METHODS: Meso-CAFs were isolated from surgical specimens of PM patients and analyzed by array comparative genomic hybridization, next generation sequencing, transcriptomics and proteomics. Human PM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, as well as the response to small molecule inhibitors, cisplatin and pemetrexed treatment was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis.
RESULTS: Meso-CAFs show a normal diploid genotype without gene copy number aberrations typical for PM cells. They express CAF markers and lack PM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in significantly increased proliferation and migration of PM cells. A similar effect on PM cell growth and migration was induced by Meso-CAF-conditioned medium. Inhibition of c-Met with crizotinib, PI3K with LY-2940002 or WNT signaling with WNT-C59 significantly impaired the Meso-CAF-mediated growth stimulation of PM cells in co-culture at concentrations not affecting the PM cells alone. Meso-CAFs did not provide protection of PM cells against cisplatin but showed significant protection against the EGFR inhibitor erlotinib.
CONCLUSIONS: Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on PM cell growth and migration, two key characteristics of PM aggressiveness, indicating a major role of Meso-CAFs in driving PM progression. Moreover, we identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for novel therapeutic strategies against PM.

Keywords: C-Met; Cancer-associated fibroblasts; Cisplatin; Co-cultures; HGF; PI3K; Pemetrexed; Pleural mesothelioma; Tumor microenvironment; WNT

DOI: https://doi.org/10.1186/s13046-022-02582-0