bims-mesote 2022-01-23 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–01–23
seven papers selected by
Laura Mannarino, Humanitas Research

Malignant pleural mesothelioma patients' experience by gender: findings from a cross-sectional UK-national questionnaire.
Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment.
Changes in body composition in patients with malignant pleural mesothelioma and the relationship with activity levels and dietary intake.
Surgical strategy for malignant pleural mesothelioma: the superiority of pleurectomy/decortication.
CircPLK1 Acts as a Carcinogenic Driver to Promote the Development of Malignant Pleural Mesothelioma by Governing the miR-1294/HMGA1 Pathway.
Sarcomatoid mesothelioma originating from mesothelioma in situ: are methylthioadenosine phosphorylase loss and CDKN2A homozygous deletion poor prognostic factors for preinvasive mesothelioma?
Metabolomics of a cell line-derived xenograft model reveals circulating metabolic signatures for malignant mesothelioma.

BMJ Open Respir Res. 2022 Jan;pii: e001050. [Epub ahead of print]9(1):

Malignant pleural mesothelioma patients' experience by gender: findings from a cross-sectional UK-national questionnaire.

Michaela Senek, Steve Robertson, Liz Darlison, Lorraine Creech, Angela Tod.

   OBJECTIVES: Malignant mesothelioma is an aggressive malignancy of mesothelial surfaces, most commonly those of the pleura. The aim of this study was to understand, using a national questionnaire, the gendered care experiences of patients with malignant pleural mesothelioma (MPM).Patients were asked about their experience of the diagnostic process, about information clarity, health care professionals' knowledge, general practitioner support and overall satisfaction with care received.
SETTING: Recruitment of patients was carried out in three UK countries (England, Wales and Scotland) via mesothelioma clinical nurse specialists.
PARTICIPANTS: In total, 503 patients completed the questionnaire. 460 had MPM, the remainder had other types of mesothelioma. In accord with the study protocol, only the MPM patients were included in this study.Primary and secondary measures were: (1) time from symptom to diagnosis, (2) satisfaction with the diagnosis and treatment, and (3) quality of life and well-being.
RESULTS: There were gender differences in time from symptom to diagnosis. The time from symptom to diagnosis was significantly longer for women than men (median=152 days vs men=92 days, p=0.01). Lack of a verified source of exposure to asbestos was a hindrance to private treatment access for women (95% of those that access private treatment are men). Patients were five times more likely to be satisfied if they thought that the doctors knew enough about their condition (OR=4.4, p=0.001) and nearly three times more likely to be satisfied if information was presented in a sensitive way (OR=2.8,p=0.01).
CONCLUSIONS: This study has several implications for clinical practice. Our findings suggest that the diagnostic time in women might be reduced by reviewing diagnostic processes including occupational history taking, and by revising the occupational risk of mesothelioma categorisation.

Keywords:  asbestos induced lung disease; lung cancer; mesothelioma

DOI:  https://doi.org/10.1136/bmjresp-2021-001050
Eur J Cancer. 2022 Jan 12. pii: S0959-8049(21)01304-6. [Epub ahead of print]163 44-54

Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment.

Marika Sculco, Marta La Vecchia, Anna Aspesi, Giulia Pinton, Michela G Clavenna, Elisabetta Casalone, Alessandra Allione, Federica Grosso, Roberta Libener, Alberto Muzio, Ottavio Rena, Guido Baietto, Sara Parini, Renzo Boldorini, Daniela Giachino, Mauro Papotti, Giorgio V Scagliotti, Enrica Migliore, Dario Mirabelli, Laura Moro, Corrado Magnani, Daniela Ferrante, Giuseppe Matullo, Irma Dianzani.

   INTRODUCTION: Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions.
AIM: This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments.
METHODS: NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair.
RESULTS: We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat).
CONCLUSIONS: Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality.

Keywords:  DNA repair genes; Germline variants; Mesothelioma; Synthetic lethality; Tazemetostat

DOI:  https://doi.org/10.1016/j.ejca.2021.12.023
Eur J Clin Nutr. 2022 Jan 17.

Changes in body composition in patients with malignant pleural mesothelioma and the relationship with activity levels and dietary intake.

Emily Jeffery, Y C Gary Lee, Robert U Newton, Philippa Lyons-Wall, Joanne McVeigh, Deirdre B Fitzgerald, Leon Straker, Carolyn J Peddle-McIntyre.

BACKGROUND: Skeletal muscle loss is common in advanced cancer and is associated with negative outcomes. In malignant pleural mesothelioma (MPM), no study has reported body composition changes or factors associated with these changes. This study aimed to describe changes in body composition over time and its relationship with activity levels, dietary intake and survival.
METHODS: The study was a secondary analysis of data collected from a longitudinal observational study of patients with MPM. Participants completed 3-month assessments for up to 18 months. Participants with two dual-energy x-ray absorptiometry (DXA) scans were included. Changes in appendicular skeletal muscle mass (ASM) and total fat mass were used to categorise participants into phenotypes. Activity levels were measured with an ActiGraph GT3X+ accelerometer and energy and protein intake was measured with a 3-day food record and 24-h recall.
RESULTS: Eighteen participants were included (89% men, mean age 68.9 ± 7.1 years). Median time between DXA was 91 [IQR 84-118] days. Compared to participants with ASM maintenance (n = 9), fewer participants with ASM loss (n = 9) survived ≥12 months from follow-up (p = 0.002). Participants with ASM loss increased sedentary time (p = 0.028) and decreased light activity (p = 0.028) and step count (p = 0.008). Activity levels did not change in participants with ASM maintenance (p > 0.05). Energy and protein intake did not change in either group (p > 0.05).
CONCLUSIONS: Muscle loss was associated with poorer survival and decreased activity levels. Interventions that improve physical activity or muscle mass could benefit patients with MPM.

DOI: https://doi.org/10.1038/s41430-021-01062-6
Surg Today. 2022 Jan 19.

Surgical strategy for malignant pleural mesothelioma: the superiority of pleurectomy/decortication.

Masatoshi Kanayama, Masataka Mori, Hiroki Matsumiya, Akihiro Taira, Shinji Shinohara, Masaru Takenaka, Koji Kuroda, Fumihiro Tanaka.

   PURPOSE: Both extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are used for the surgical treatment of malignant pleural mesothelioma (MPM). This study aimed to compare the operative and clinical outcomes and survival between EPP and P/D.
METHODS: We performed a retrospective analysis of the surgical and clinical data of 40 patients who underwent either EPP (n = 18) or P/D (n = 22) for MPM at our institution between January 2000 and December 2018.
RESULTS: In comparison to EPP, P/D was associated with a higher intraoperative bleeding volume (1175 vs 1805 ml, p = 0.0020) and greater duration of postoperative thoracic drainage (3 vs 16 days, p < 0.0001). Adjuvant chemotherapy was more common after P/D (81.8%) than after EPP (33.3%; p = 0.0024). For epithelioid-type MPM, overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients who underwent P/D in comparison to those who underwent EPP (p = 0.040 and p = 0.015, respectively), with no difference for the biphasic and sarcomatoid types of MPM. A Cox proportional hazards regression model identified P/D as a significant favorable prognostic factor for OS [hazard ratio (HR), 0.391; 95% confidence interval (CI), 0.175-0.871; p = 0.022] and RFS (HR, 0.418; 95% CI, 0.190-0.920; p = 0.030).
CONCLUSIONS: Based on our findings, P/D may be superior to EPP for improving the prognosis of patients with resectable epithelioid-type MPM.

Keywords:  Extrapleural pneumonectomy; Mesothelioma; Pleurectomy/decortication

DOI:  https://doi.org/10.1007/s00595-021-02437-9
Biochem Genet. 2022 Jan 20.

CircPLK1 Acts as a Carcinogenic Driver to Promote the Development of Malignant Pleural Mesothelioma by Governing the miR-1294/HMGA1 Pathway.

Qi Zhang, Zhiqiang Wang, Huarong Cai, Dongming Guo, Wei Xu, Shi Bu, Yuequan Jiang.

  The deregulation of circular RNAs (circRNAs) is involved in cancer development. CircRNA polo-like kinase 1 (circPLK1) was reported to promote breast cancer development. However, the role of circPLK1 in malignant pleural mesothelioma (MPM) is unclear. The expression of circPLK1, miR-1294, and high mobility group AT-hook 1 (HMGA1) mRNA was measured by quantitative real-time PCR (qPCR). Cell viability was detected by CCK-8 assay. Colony formation ability was monitored by colony formation assay. Cell proliferation was detected by EdU assay. Cell migration and cell invasion were monitored by transwell assay. Cancer cell stemness was investigated by sphere formation assay. The protein levels of marker proteins and HMGA1 expression were measured by western blot analysis. The binding relationship between miR-1294 and circPLK1 or HMGA1 was validated by pull-down assay, dual-luciferase reporter assay or RIP assy. Animal study was performed to disclose the role of circPLK1 in vivo. Exosomes were identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). CircPLK1 was upregulated in MPM tumor tissues and cell lines. CircPLK1 knockdown suppressed the proliferation, migration, invasion and stemness of MPM cells. CircPLK1 contained a binding site for miR-1294 and thus bound to miR-1294 to sequester its expression. Inhibition of miR-1294 reversed the effects of circPLK1 knockdown. HMGA1 was a target of miR-1294, and circPLK1 bound to miR-1294 to increase the expression of HMGA1. MiR-1294 restoration also suppressed the proliferation, migration, invasion and stemness of MPM cells, while these effects were abolished by HMGA1 overexpression. In addition, circPLK1 knockdown inhibited tumor growth in vivo. CircPLK1 was overexpressed in exosomes derived from serum of MPM patients. CircPLK1 knockdown inhibited MPM cell proliferation, migration, invasion and stemness by targeting the miR-1294/HMGA1 pathway.

Keywords:  HMGA1; Malignant pleural mesothelioma; circPLK1; miR-1294

DOI:  https://doi.org/10.1007/s10528-022-10186-8
Virchows Arch. 2022 Jan 19.

Sarcomatoid mesothelioma originating from mesothelioma in situ: are methylthioadenosine phosphorylase loss and CDKN2A homozygous deletion poor prognostic factors for preinvasive mesothelioma?

Megumi Nishikubo, Naoe Jimbo, Yugo Tanaka, Motoko Tachihara, Tomoo Itoh, Yoshimasa Maniwa.

  The diagnosis of mesothelioma in situ (MIS) is challenging with conventional diagnostic approaches. Although recent advances in genomic-based assays have made it possible to diagnose MIS, the prognosis, treatment indications, and prognostic factors remain unclear. Previous reports have shown that MIS progresses to invasive mesothelioma; however, to the best of our knowledge, progression to sarcomatoid mesothelioma has not yet been reported. A 73-year-old man was diagnosed with MIS associated with methylthioadenosine phosphorylase (MTAP) loss and a CDKN2A homozygous deletion. Strikingly, pathological examination revealed that the MIS lesion had progressed to sarcomatoid mesothelioma. In analyses of previously reported cases and our case, MIS with a CDKN2A homozygous deletion or MTAP loss progressed to invasive mesothelioma earlier than that without them, indicating that a CDKN2A homozygous deletion and MTAP loss could be poor prognostic factors. Genomic analyses might be useful for predicting the prognosis of MIS and contributing to an optimal treatment.

Keywords:  CDKN2A; Malignant mesothelioma in situ (MIS); Methylthioadenosine phosphorylase (MTAP); Sarcomatoid malignant mesothelioma

DOI:  https://doi.org/10.1007/s00428-022-03281-z
PeerJ. 2022 ;10 e12568

Metabolomics of a cell line-derived xenograft model reveals circulating metabolic signatures for malignant mesothelioma.

Yun Gao, Ziyi Dai, Chenxi Yang, Ding Wang, Zhenying Guo, Weimin Mao, Zhongjian Chen.

   Background: Malignant mesothelioma (MM) is a rare and highly aggressive cancer. Despite advances in multidisciplinary treatments for cancer, the prognosis for MM remains poor with no effective diagnostic biomarkers currently available. The aim of this study was to identify plasma metabolic biomarkers for better MM diagnosis and prognosis by use of a MM cell line-derived xenograft (CDX) model.
Methods: The MM CDX model was confirmed by hematoxylin and eosin staining and immunohistochemistry. Twenty female nude mice were randomly divided into two groups, 10 for the MM CDX model and 10 controls. Plasma samples were collected two weeks after tumor cell implantation. Gas chromatography-mass spectrometry analysis was conducted. Both univariate and multivariate statistics were used to select potential metabolic biomarkers. Hierarchical clustering analysis, metabolic pathway analysis, and receiver operating characteristic (ROC) analysis were performed. Additionally, bioinformatics analysis was used to investigate differential genes between tumor and normal tissues, and survival-associated genes.
Results: The MM CDX model was successfully established. With VIP > 1.0 and P-value < 0.05, a total of 23 differential metabolites were annotated, in which isoleucine, 5-dihydrocortisol, and indole-3-acetamide had the highest diagnostic values based on ROC analysis. These were mainly enriched in pathways for starch and sucrose metabolism, pentose and glucuronate interconversions, galactose metabolism, steroid hormone biosynthesis, as well as phenylalanine, tyrosine and tryptophan biosynthesis. Further, down-regulation was observed for amino acids, especially isoleucine, which is consistent with up-regulation of amino acid transporter genes SLC7A5 and SLC1A3 in MM. Overall survival was also negatively associated with SLC1A5, SLC7A5, and SLC1A3.
Conclusion: We found several altered plasma metabolites in the MM CDX model. The importance of specific metabolic pathways, for example amino acid metabolism, is herein highlighted, although further investigation is warranted.

Keywords:  Amino acid metabolism; Cell line-derived xenograft; GC-MS; Malignant mesothelioma; Metabolomics

DOI:  https://doi.org/10.7717/peerj.12568