bims-mesote 2022-10-30 papers

Issue of 2022–10–30
four papers selected by
Laura Mannarino, Humanitas Research

Oncol Lett. 2022 Nov;24(5): 402

Sarcomatoid malignant pleural mesothelioma treated with nivolumab: A case series.

Kentaro Hashimoto, Hiroaki Ozasa, Akihiko Yoshizawa, Hiroshi Yoshida, Tatsuya Ogimoto, Kazutaka Hosoya, Masatoshi Yamazoe, Hitomi Ajimizu, Tomoko Funazo, Hironori Yoshida, Yuichi Sakamori, Toyohiro Hirai.

Immune checkpoint therapy (ICT) with nivolumab has been widely used to treat malignant pleural mesothelioma (MPM) since clinical trials confirmed its efficacy. However, only a few clinical trials have been conducted for the treatment of sarcomatoid MPM, which is a rare histological type of MPM. Additionally, clinical reports of sarcomatoid MPM are scarce. Therefore, the benefits and risks of nivolumab treatment for sarcomatoid MPM remain unclear. The present report describes the treatment of 3 cases of sarcomatoid MPM (all 3 were men) with nivolumab monotherapy. In all three cases, nivolumab was effective despite variations in the duration of treatment, although side effects were observed in 2 patients. Programmed death ligand 1 (PD-L1) expression was positive in all 3 cases. In particular, the patient with the highest PD-L1 expression had the most rapid response of the 3 patients, and the effect lasted as long as those of the other 2, despite receiving the smallest number of doses of nivolumab. It has been reported that sarcomatoid MPM tends to respond poorly to chemotherapy and express higher levels of PD-L1 than epithelial MPM; thus, ICT may be necessary in these cases. This case series suggests that ICT with nivolumab is a promising treatment option for sarcomatoid MPM.

Keywords: ICT; PD-1 inhibitor; PD-L1 expression; effectiveness; immune-related adverse events

DOI: https://doi.org/10.3892/ol.2022.13522

Front Oncol. 2022 ;12 1014749

The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling.

Arivazhagan Roshini, Chandra Goparaju, Somanath Kundu, Mohan S Nandhu, Sharon L Longo, John A Longo, Joan Chou, Frank A Middleton, Harvey I Pass, Mariano S Viapiano.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.

Keywords: PI3k signaling; antibody therapy; extracellular matrix; fibulin family; mesothelioma; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2022.1014749

Int J Cancer. 2022 Oct 28.

Blood cell DNA methylation biomarkers in preclinical malignant pleural mesothelioma: the EPIC prospective cohort.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive non-invasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM pre-diagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within five years from enrolment (n=36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex, PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than five years before diagnosis [AUC (area under the curve) < 5 years=0.89; AUC 5-10 years=0.80; AUC >10 years=0.75; baseline AUC range=0.63-0.67)]. DNAm changes as non-invasive biomarkers in pre-diagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk in order to possibly adopt more intensive monitoring for early disease identification.

Keywords: DNA methylation; cancer biomarkers; mesothelioma; prospective nested case-control study

DOI: https://doi.org/10.1002/ijc.34339

Med Lav. 2022 Oct 24. 113(5): e2022047

Incidence of malignant mesothelioma and asbestos exposure in the Emilia-Romagna region, Italy.

Lucia Mangone, Cinzia Storchi, Carmine Pinto, Paolo Giorgi Rossi, Isabella Bisceglia, Antonio Romanelli.

BACKGROUND: The aim of this study is to describe the incidence of malignant mesothelioma (MM) and asbestos exposure in an Italian region in the period 1996-June 2021.
METHODS: The study included cases with microscopic confirmation and those with instrumental confirmation. For each case, information on sex, age, tumour site, morphology and date of diagnosis was collected, along with details of exposure to asbestos.
RESULTS: 3,097 cases of MM (2,233 males and 864 females) were registered: 90.8% with microscopic confirmation. A total of 2,840 cases involved the pleura (92%), 230 cases the peritoneum (7%), and a small number of cases the pericardium and testis (9 and 18, respectively). Most cases (78.0%) occurred after 65 years of age, while only 1.5% concerned individuals with age < 45 years. The standardized incidence rate for the entire period (adjusted to the 2000 Italian standard population and calculated per 100,000 person-years) was equal to 3.9 in males and 1.4 in females, and the trend showed an increase with age in both sexes. Concerning asbestos exposure, 79.7% of cases were exposed (86.7% males and 60.1% females). In 70.3%, exposure was occupational (83.4% males and 33.2% females), while 20.7% of females and 0.8% of males had familial exposure. Building construction, rolling stock manufacture/repair and metalworking were the most prevalent economic activities associated with occupational exposure.
CONCLUSIONS: This study offers an overview of MM in an Italian region characterized by high incidence and high exposure due to its particular production activities.

DOI: https://doi.org/10.23749/mdl.v113i5.13312