bims-mesote 2022-09-25 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–09–25
nine papers selected by
Laura Mannarino, Humanitas Research

Editorial: Novel agents and combinations for treatment of malignant pleural mesothelioma in pre-clinical models.
Malignant Pleural Mesothelioma: Current Understanding of the Immune Microenvironment and Treatments of a Rare Disease.
Immune cells in mesothelioma microenvironment simplistic marker of response to nivolumab plus ipilimumab?
Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma.
Incidence and Risk Factors of Chest Wall Metastasis at Biopsy Sites in Patients with Malignant Pleural Mesothelioma.
Genomic landscape of pleural and peritoneal mesothelioma tumours.
Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma.
Effects of tumor-infiltrating CD8+ T cells, PD1/PD-L1 axis, and expression patterns of HLA class I on the prognosis of patients with malignant pleural mesothelioma who underwent extra-pleural pneumonectomy.
Cytoreductive Surgical Treatment of Pleural Mesothelioma in a Porcine Model Using Magnetic-Resonance-Guided Focused Ultrasound Surgery (MRgFUS) and Radiofrequency Ablation (RFA).

Front Pharmacol. 2022 ;13 1015959

Editorial: Novel agents and combinations for treatment of malignant pleural mesothelioma in pre-clinical models.

Sze-Kwan Lam, Steven Eugene Mutsaers.



Keywords:  animal models; malignant pleural mesothelioma; novel combinations; novel therapies; review

DOI:  https://doi.org/10.3389/fphar.2022.1015959
Cancers (Basel). 2022 Sep 11. pii: 4415. [Epub ahead of print]14(18):

Malignant Pleural Mesothelioma: Current Understanding of the Immune Microenvironment and Treatments of a Rare Disease.

John Tedesco, Mark Jaradeh, Wickii T Vigneswaran.

  Malignant pleural mesothelioma is a rare disease with an annual incidence of around 3000 cases a year in the United States. Most cases are caused by asbestos exposure, with a latency period of up to 40 years. Pleural mesothelioma is an aggressive disease process with overall survival of roughly 6-12 months after the time of diagnosis. It is divided into three subtypes: epithelioid, mixed type, and sarcomatoid type, with the epithelioid subtype having the best overall survival. Often, the treatment is multimodality with surgery, chemotherapy, and radiation. The survival benefit is improved but remains marginal. New treatment options involving targeted immune therapies appear to offer some promise. The tumor microenvironment is the ecosystem within the tumor that interacts and influences the host immune system. Understanding this complex interaction and how the host immune system is involved in the progression of the disease process is important to define and guide potential treatment options for this devastating and rare disease.

Keywords:  immune microenvironment; mesothelioma; outcomes; pleura

DOI:  https://doi.org/10.3390/cancers14184415
Lung Cancer. 2022 Sep 05. pii: S0169-5002(22)00609-2. [Epub ahead of print]173 49-52

Immune cells in mesothelioma microenvironment simplistic marker of response to nivolumab plus ipilimumab?

Maria J Disselhorst, Yoni Lubeck, Vincent van der Noort, Josine Quispel-Janssen, Iris M Seignette, Joyce Sanders, Dennis Peters, Erik Hooijberg, Paul Baas.

   INTRODUCTION: Malignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better understanding of the tumor micro environment is needed. We investigated subgroups of immune cells in subsequent tumor biopsies of patients treated with ICI.
METHODS: Biopsies from MPM patients included in two clinical ICI trials (nivolumab alone and an ipilimumab/nivolumab combination) were examined. At baseline and after 6 weeks of treatment, pleural biopsies were taken to examine the tumor microenvironment (CD20+, CD4+, CD8+, FoxP3+ and PD-1+ ). Cell density was defined as the number of marker positive cells per mm2. Radiological responses were evaluated as partial response, stable disease or progressive disease according to modified RECIST criteria.
RESULTS: Thirty-four and 36 patients were included in the nivolumab and ipiliumumab/nivolumab trial respectively. In the nivolumab trial, no significant differences in cell densities were seen in baseline biopsies of patients with partial response versus progressive disease. In contrast, in the ipilimumab/nivolumab trial, a higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells at baseline was significantly correlated with partial responses. On-treatment biopsies of both trials did not show significant changes when compared to baseline biopsies.
CONCLUSION: Biopsies from patients responding to nivolumab plus ipilimumab treatment show a significant higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells, without a change after 6 weeks of treatment. This observation is a first step in exploring the tumor microenvironment as predictor of response in ICI treatment in MPM.

Keywords:  Immune checkpoint inhibitor; Malignant pleural mesothelioma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.lungcan.2022.08.019
Cells. 2022 Sep 19. pii: 2924. [Epub ahead of print]11(18):

Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma.

Umair Ali Khan Saddozai, Fengling Wang, Saadullah Khattak, Muhammad Usman Akbar, Muhammad Badar, Nazeer Hussain Khan, Lu Zhang, Wan Zhu, Longxiang Xie, Yongqiang Li, Xinying Ji, Xiangqian Guo.

  Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.

Keywords:  gene expression; mesothelioma; molecular subtype; subtype-specific treatment

DOI:  https://doi.org/10.3390/cells11182924
Cancers (Basel). 2022 Sep 07. pii: 4356. [Epub ahead of print]14(18):

Incidence and Risk Factors of Chest Wall Metastasis at Biopsy Sites in Patients with Malignant Pleural Mesothelioma.

Masaki Hashimoto, Michiko Yuki, Kazuhiro Kitajima, Akihiro Fukuda, Toru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Seiji Matsumoto, Nobuyuki Kondo, Ayuko Sato, Koichiro Yamakado, Tohru Tsujimura, Seiki Hasegawa.

  To investigate the incidence and risk factors of chest wall metastasis (CWM) at biopsy sites in patients with malignant pleural mesothelioma (MPM). This retrospective cohort study was conducted in 262 consecutive MPM patients who underwent multimodal treatment in which including neoadjuvant chemotherapy (NAC) and curative-intent surgery, from August 2009 to March 2021. CWM was evaluated radiologically (r-CWM) and pathologically (p-CWM). We also investigated the risk factors of p-CWM and the consistency between r-CWM and p-CWM. Of 262 patients, 25 patients were excluded from analysis due to missing data or impossibility of evaluation. Of the eligible 237 patients, pleural biopsy was performed via video-assisted thoracoscopic surgery in 197 (83.1%) and medical thoracoscopy in 40 (16.9%). Pleurodesis was performed after pleural biopsy in 74 patients (31.2%). All patients received NAC followed by curative-intent surgery. Radiological examination showed r-CWM in 43 patients (18.1%), while pathological examination showed p-CWM in 135 patients (57.0%). The incidence of p-CWM was significantly higher in the patients who received pleurodesis after pleural biopsy (77.0% vs. 47.9%, <0.001). Multivariate logistic regression analysis for p-CWM revealed that pleurodesis is an independent risk factor of p-CWM (adjusted hazard ratio, 3.46; 95% confidence interval, 1.84-6.52, <0.001). CWM at the biopsy site was pathologically proven in more than half of the patients (57.0%) who received NAC followed by curative-intent surgery, which was higher than the numbers diagnosed by radiological examinations (p-CWM: 57.0% vs. r-CWM: 18.1%). Pleurodesis after pleural biopsy is an independent risk factor of p-CWM.

Keywords:  chest wall metastasis; malignant pleural mesothelioma; pleural biopsy; pleurodesis

DOI:  https://doi.org/10.3390/cancers14184356
Br J Cancer. 2022 Sep 22.

Genomic landscape of pleural and peritoneal mesothelioma tumours.

Stefanie Hiltbrunner, Zoe Fleischmann, Ethan S Sokol, Martin Zoche, Emanuela Felley-Bosco, Alessandra Curioni-Fontecedro.

BACKGROUND: Malignant pleural and peritoneal mesotheliomas are rare malignancies with unacceptable poor prognoses and limited treatment options. The genomic landscape is mainly characterised by the loss of tumour suppressor genes and mutations in DNA repair genes. Currently, data from next-generation sequencing (NGS) of mesothelioma tumours is restricted to a limited number of cases; moreover, data comparing molecular features of mesothelioma from the pleural and peritoneal origin with NGS are lacking.
METHODS: We analysed 1113 pleural mesothelioma and 355 peritoneal mesothelioma samples. All tumours were sequenced with the FoundationOne® or FoundationOne®CDx assay for detection of substitutions, insertion-deletions, copy-number alterations and selected rearrangements in at least 324 cancer genes.
RESULTS: This analysis revealed alterations in 19 genes with an overall prevalence of at least 2%. Alterations in BAP1, CDKN2A, CDKN2B, NF2, MTAP, TP53 and SETD2 occurred with a prevalence of at least 10%. Peritoneal, compared to pleural mesothelioma, was characterised by a lower prevalence of alterations in CDKN2A, CDKN2B and MTAP. Moreover, we could define four distinct subgroups according to alterations in BAP1 and CDKN2A/B. Alterations in Hedgehog pathway-related genes (PTCH1/2 and SUFU) and Hippo pathway-related gene (NF2) as well as KRAS, EGFR, PDGFRA/B, ERBB2 and FGFR3 were detected in both cohorts.
CONCLUSION: Here, we report the molecular aberrations from the largest cohort of patients with mesothelioma. This analysis identified a proportion of patients with targetable alterations and suggests that molecular profiling can identify new treatment options for patients with mesothelioma.

DOI: https://doi.org/10.1038/s41416-022-01979-0
Diagnostics (Basel). 2022 Sep 12. pii: 2210. [Epub ahead of print]12(9):

Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma.

Zhenhua Lu, Wenlong Zhang, Ke Huang, Mucheng Zhu, Xiaoting Gu, Defang Wei, Mingxuan Shi, Yaqiong Chen, Huihui Wang.

  In previous studies, non-invasive diagnostic biomarkers showed great benefit in the early-stage diagnosis of malignant pleural mesothelioma (MPM). However, the accuracy of different biomarkers was controversial. In this study, meta-analysis and bioinformatics analysis were conducted to compare the accuracy of the following three biomarkers and explore the relationship between the gene expression levels and MPM. A systematic search of meta-analysis was conducted using PubMed, EMBASE and Cochrane Library to identify relevant studies from the inception to March 2021. QUADAS-2 for Quality Assessment of Diagnostic Accuracy Studies was used to evaluate the quality of eligible studies. The meta-analysis was performed utilizing Stata 15.0 and Review Manager 5.4 software. The meta-analysis results showed that 31 studies that involved 8750 participants were included. The pooled sensitivity and specificity (SPE) were 0.90 (95% CI: 0.74, 0.97) and 0.91 (95% CI: 0.84, 0.95) for Fibulin-3, 0.66 (95% CI, 0.51-0.78) and 0.91 (95% CI, 0.82-0.96) for mesothelin (MSLN), 0.68 (95% CI: 0.63,0.73) and 0.86 (95% CI: 0.82,0.90) for soluble mesothelin-related peptides (SMRP), and 0.74 (95% CI, 0.66-0.80) and 0.89 (95% CI, 0.85-0.91) for MSLN + SMRP + Fibulin-3. Compared with the other two biomarkers, Fibulin-3 may be more appropriate to be one of the indicators for combined diagnosis. Bioinformatics analysis showed that the low expression level of the MSLN gene was significantly related to longer survival time and better prognosis of MPM patients. However, considering the limitation in the quality and sample size of the included research, further studies are required.

Keywords:  MPM; bioinformatics analysis; biomarkers; meta-analysis; prognosis

DOI:  https://doi.org/10.3390/diagnostics12092210
Cancer Immunol Immunother. 2022 Sep 17.

Effects of tumor-infiltrating CD8+ T cells, PD1/PD-L1 axis, and expression patterns of HLA class I on the prognosis of patients with malignant pleural mesothelioma who underwent extra-pleural pneumonectomy.

Riki Okita, Yuka Mimura-Kimura, Nobutaka Kawamoto, Naoki Yamamoto, Masashi Umeda, Masanori Okada, Hidetoshi Inokawa, Yusuke Mimura, Tomoyuki Murakami, Masao Nakata, Kazunori Okabe.

  Programmed cell death protein-1 (PD1), PD1 ligand 1 (PD-L1), and human leukocyte antigen (HLA) class I molecule play pivotal roles in T cell-induced anti-tumor immunity; however, the clinical impact of these parameters in resected malignant pleural mesothelioma (MPM) cases is unknown. We immunohistochemically evaluated the tumor infiltrated lymphocytes (TILs), PD1/PD-L1 axis, and expression of HLA class I in resected specimens from 58 patients with MPM who underwent extra-pleural pneumonectomy (EPP). Higher infiltration of CD3-TIL, CD8-TIL, and PD1-TIL, loss of HLA class I, and overexpression of PD-L1 by tumor cells (PD-L1 TC) or immune cells (PD-L1 IC) were observed in 34 (58.6%), 27 (46.6%), 41 (70.7%), 45 (77.6%), 29 (50.0%), and 33 (56.4%) of 58 cases, respectively. Interestingly, the CD3-TIL score positively correlated with PD-L1 TC and PD1-TIL scores. HLA class I expression level was inversely correlated with the expression levels of PD-L1 TC and PD-L1 IC. Multivariate analysis showed that age, histology, and node metastasis were independent prognostic factors for 5-year overall survival (OS) and loss of HLA class I coincided with a positive prognosis (p = 0.011). The concomitant lack of infiltrating CD8+ T cells with no loss of HLA class I predicted worse 5-year OS (p = 0.007). Moreover, cluster classifications among multiple immunoparameters showed that categories among CD3/PD-L1 TC/HLA class I (p = 0.043), CD8/PD1/HLA class I (p = 0.032), CD8/PD-L1 TC/HLA class I (p = 0.011), and PD1/PD-L1 TC/HLA class I (p = 0.032) predicted 5-year OS in EPP cases for MPM. These immunoparameters could guide surgical indications for patients with MPM.

Keywords:  Human leukocyte antigen class I (HLA class I); Malignant pleural mesothelioma (MPM); Prognostic factor; Programmed cell death protein-1/programmed cell death protein-1 ligand 1 axis (PD1/PD-L1 axis); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/s00262-022-03292-4
Tomography. 2022 Sep 03. 8(5): 2232-2242

Cytoreductive Surgical Treatment of Pleural Mesothelioma in a Porcine Model Using Magnetic-Resonance-Guided Focused Ultrasound Surgery (MRgFUS) and Radiofrequency Ablation (RFA).

Marcia Costa, Carolina Fernandes, Matt Eames, Arik Hananel, John P Mugler, Jhosep Huaromo, Jack B Yang, Jaime Mata.

  A combination of surgery and chemotherapy is the most effective treatment available for Malignant Pleural Mesothelioma (MPM). However, both cause significant collateral damage and cannot eliminate residual microscopic disease. This investigation aimed to compare and determine the feasibility of utilizing Radiofrequency Ablation (RFA) and Magnetic-Resonance-guided Focused Ultrasound Surgery (MRgFUS) as alternative treatments for MPM. A large animal tumor model was developed in 13 Yorkshire female pigs using the MSTO211H cell line. Two pigs were initially used to determine the cyclosporine dose required for immunosuppression and tumor development. Subsequently, 11 other pigs underwent tumor development. Of these 11, 2 died during cell inoculation. Small tumor masses and adhesions were present in the other 9, indicating mesothelioma development. Five pigs then received RFA treatment, and 4 pigs received MRgFUS treatment. Tumor model development and effect of the two treatments were examined using MRI and by necropsy. RFA and MRgFUS both successfully ablated approximately the same sized area in the same treatment time. This study demonstrates that RFA and MRgFUS are feasible for tumor debulking, and while MRgFUS requires more pretreatment planning compared to RFA, MRgFUS is a completely noninvasive procedure.

Keywords:  high-intensity focused ultrasound; magnetic resonance imaging; mesothelioma; radiofrequency ablation

DOI:  https://doi.org/10.3390/tomography8050187