bims-mesote 2024-03-03 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2024–03–03
seven papers selected by
Laura Mannarino, Humanitas Research

POLD1 Is Required for Cell Cycle Progression by Overcoming DNA Damage in Malignant Pleural Mesothelioma.
The genetic susceptibility in the development of malignant pleural mesothelioma: somatic and germline variants, clinicopathological features and implication in practical medical/surgical care: a narrative review.
The lncRNAs Gas5, MALAT1 and SNHG8 as diagnostic biomarkers for epithelial malignant pleural mesothelioma in Egyptian patients.
Comprehensive Review of Mesothelioma Cases: From Diagnosis to Therapeutic Strategies.
The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition.
The role of MicroRNAs as early biomarkers of asbestos-related lung cancer: A systematic review and meta-analysis.
Impact of Surgery on Disease Progression and Survival of Patients with Pleural Mesothelioma.

Cancer Genomics Proteomics. 2024 Mar-Apr;21(2):21(2): 158-165

POLD1 Is Required for Cell Cycle Progression by Overcoming DNA Damage in Malignant Pleural Mesothelioma.

Daiki Shimizu, Miku Ishibashi, Tadaaki Yamada, Yuki Toda, Shigekuni Hosogi, Eishi Ashihara.

   BACKGROUND/AIM: The prognosis of patients with malignant pleural mesothelioma (MPM) remains poor due to lack of effective therapeutic targets. DNA damage caused by long-time exposure to asbestos fibers has been associated with the development of MPM, with mutations at genes encoding DNA damage repair (DDR)-related molecules frequently expressed in patients with MPM. The present study was designed to identify novel therapeutic targets in MPM using large public databases, such as The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) focused on DDR pathways.
MATERIALS AND METHODS: The correlations between mRNA expression levels of DDR-related genes and overall survival (OS) were analyzed in mesothelioma patients in TCGA mesothelioma (TCGA-MESO) datasets. The anti-tumor effects of small interfering RNAs (siRNA) against DDR-related genes associated with OS were subsequently tested in MPM cell lines.
RESULTS: High levels of mRNA encoding DNA polymerase delta 1, catalytic subunit (POLD1) were significantly associated with reduced OS in patients with MPM (p<0.001, Log-rank test). In addition, siRNA targeting POLD1 (siPOLD1) caused cell cycle arrest at the G1/S checkpoint and induced apoptosis involving accumulation of DNA damage in MPM cell lines.
CONCLUSION: POLD1 plays essential roles in overcoming DNA damage and cell cycle progression at the G1/S checkpoint in MPM cells. These findings suggest that POLD1 may be a novel therapeutic target in MPM.

Keywords:  DNA damage; DNA polymerase δ; Malignant pleural mesothelioma; POLD1; The Cancer Genome Atlas; cell cycle

DOI:  https://doi.org/10.21873/cgp.20437
J Thorac Dis. 2024 Jan 30. 16(1): 671-687

The genetic susceptibility in the development of malignant pleural mesothelioma: somatic and germline variants, clinicopathological features and implication in practical medical/surgical care: a narrative review.

Maria Teresa Congedo, Elizabeth Casey West, Jessica Evangelista, Aubrey Anne Mattingly, Giuseppe Calabrese, Carolina Sassorossi, Adriana Nocera, Marco Chiappetta, Sara Flamini, Ludovico Abenavoli, Stefano Margaritora, Luigi Boccuto, Filippo Lococo.

   Background and Objective: Malignant pleural mesothelioma (MPM) is a very aggressive primary tumor of the pleura whose main risk factor is exposure to asbestos. However, only a minority of exposed people develops MPM and the incidence of MPM cases without an apparent association with asbestos exposure has been increasing in recent years, suggesting that genetic predisposing factors may play a crucial role. In addition, several studies reported familial cases of MPM, suggesting that heredity may be an important and underestimated feature in MPM development. Several candidate genes have been associated with a predisposition to MPM and most of them play a role in DNA repair mechanisms: overall, approximately 20% of MPM cases may be related to genetic predisposition. A particular category of patients with high susceptibility to MPM is represented by carriers of pathogenic variants in the BAP1 gene. Germline variants in BAP1 predispose to the development of MPM following an autosomal dominant pattern of inheritance in the familial cases. MPMs in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. In the present narrative review, we presented a comprehensive overview of genetic susceptibility in the development of MPM.
Methods: The narrative review is based on a selective literature carried out in PubMed in 2023. Inclusion criteria were original articles in English language, and clinical trials (randomized, prospective, or retrospective).
Key Content and Findings: We summarized the somatic and germline variants and the differences in terms of clinicopathological features and prognosis between gene-related MPM (GR-MPM) and asbestos-related MPM (AR-MPM). We also discussed the indications for screening, genetic testing, and surveillance of patients with BAP1 germline variants.
Conclusions: In this narrative review, we have emphasized that the BAP1 gene's harmful germline variations are inherited in an autosomal dominant manner in familial cases. MPMs in individuals with these variations are less severe, and their medical care necessitates a collaborative effort. Additionally, we have outlined the current therapeutic prospects for MPM, including the possibility of gene-specific therapy, which is currently promising but still requires clinical validation.

Keywords:  BRCA1 associated protein 1 (BAP1); Malignant pleural mesothelioma (MPM); genetic counseling; genetic susceptibility; pleural tumors

DOI:  https://doi.org/10.21037/jtd-23-611
Sci Rep. 2024 02 27. 14(1): 4823

The lncRNAs Gas5, MALAT1 and SNHG8 as diagnostic biomarkers for epithelial malignant pleural mesothelioma in Egyptian patients.

Dina Mohamed Elkahwagy, Caroline Joseph Kiriacos, Mohamed Emam Sobeih, Ola M Reda Khorshid, Manar Mansour.

  Long noncoding RNAs have been shown to be involved in a myriad of physiological and pathological pathways. To date, malignant pleural mesothelioma (MPM) is considered an extremely aggressive cancer. One reason for this is the late diagnosis of the disease, which can occur within 30-40 years of asbestos exposure. There is an immense need for the development of new, sensitive, inexpensive and easy methods for the early detection of this disease other than invasive methods such as biopsy. The aim of this study was to determine the expression of circulating lncRNAs in mesothelioma patient plasma to identify potential biomarkers. Ten previously identified lncRNAs that were shown to be aberrantly expressed in mesothelioma tissues were selected as candidates for subsequent validation. The expression of the ten selected candidate lncRNAs was verified via quantitative PCR (qPCR) in human plasma samples from mesothelioma patients versus healthy controls. The expression levels of circulating GAS5, SNHG8 and MALAT1 were significantly greater in plasma samples from patients than in those from controls. The ROC analysis of both MALAT1 and SNHG8 revealed 88.89% sensitivity and 66.67% specificity. The sensitivity of these markers was greater than that of GAS5 (sensitivity 72.22% and specificity 66.67%). The regression model for GAS5 was statistically significant, while that for SNHG8 and MALAT1 was not significant due to the small sample size. The area under the curve (AUC) of the three ROC curves was acceptable and significant: 0.7519 for GAS5, 0.7352 for SNHG8 and 0.7185 for MALAT1. This finding confirmed their ability to be used as markers. The three lncRNAs were not affected by age, sex or smoking status. The three lncRNAs showed great potential as independent predictive diagnostic biomarkers. Although the prediction model for MALAT1 did not significantly differ, MALAT1 was significantly expressed in patients more than in controls (p = 0.0266), and the recorded sensitivity and specificity were greater than those of GAS5.

Keywords:  Biomarker; Blood; Cancer; Circulating; Early detection; Marker; Mesothelioma; Plasma; Screening; lncRNA; qPCR

DOI:  https://doi.org/10.1038/s41598-024-55083-9
Cureus. 2024 Jan;16(1): e52859

Comprehensive Review of Mesothelioma Cases: From Diagnosis to Therapeutic Strategies.

Abeer Qasim, Sai Vishnu Vardhan Allu, Patrik Schmidt, Harsh R Parikh, Sarah Moore, Laura Yapor, Maryam Soliman.

  Mesothelioma is a rare and aggressive malignancy typically associated with asbestos exposure. We present the clinical and diagnostic journey of a 63-year-old male carpenter, who presented with concerning symptoms of shortness of breath and total right lung "white-out" on imaging. Comprehensive medical evaluation revealed the presence of malignant pleural mesothelioma. This study underscores the importance of considering mesothelioma as a potential diagnosis in individuals with occupational asbestos exposure and highlights patterns in diagnosing and managing this devastating disease. Early recognition and intervention are essential in improving outcomes for patients diagnosed with mesothelioma.

Keywords:  biopsy; epitheloid asbestos exposure; malignant; mesothelioma; pleural mesothelioma

DOI:  https://doi.org/10.7759/cureus.52859
Transl Oncol. 2024 Feb 26. pii: S1936-5233(23)00243-7. [Epub ahead of print]43 101857

The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition.

Claudia Kalla, German Ott, Francesca Finotello, Karolina Niewola-Staszkowska, Giusy Di Conza, Michael Lahn, Lars van der Veen, Julia Schüler, Roger Falkenstern-Ge, Joanna Kopecka, Chiara Riganti.

  Targeting aberrantly expressed kinases in malignant pleural mesothelioma (MPM) is a promising therapeutic strategy. We here investigated the effect of the novel and highly selective Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib (IOA-244) on MPM cells and on the immune cells in MPM microenvironment. To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). In a co-culture model of patient-derived MPM cells, autologous peripheral blood mononuclear cells and fibroblasts, the tumor cell viability and changes in immune cell composition were investigated after treatment of roginolisib with nivolumab and cisplatin. PI3K-δ was detected in 66/89 (74%) MPM tumors and was associated with reduced overall survival (12 vs. 25 months, P=0.0452). Roginolisib induced apoptosis in MPM cells and enhanced the anti-tumor efficacy of AKT and mTOR kinase inhibitors by suppressing PI3K-δ/AKT/mTOR and ERK1/2 signaling. Furthermore, the combination of roginolisib with chemotherapy and immunotherapy re-balanced the immune cell composition, increasing effector T-cells and reducing immune suppressive cells. Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin. These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen.

Keywords:  PI3/AKT/mTOR inhibition; Phosphoinositide 3-kinase delta (PI3K-δ); apoptosis; combinatorial therapy; malignant pleural mesothelioma; tumor induced-immunosuppression

DOI:  https://doi.org/10.1016/j.tranon.2023.101857
Pulmonology. 2024 Feb 23. pii: S2531-0437(24)00015-1. [Epub ahead of print]

The role of MicroRNAs as early biomarkers of asbestos-related lung cancer: A systematic review and meta-analysis.

D Mukhopadhyay, P Cocco, S Orrù, R Cherchi, S De Matteis.

   BACKGROUND: Asbestos is still the leading cause of occupational cancer mortality worldwide. Asbestos-related lung cancer (LC) and malignant pleural mesothelioma (MPM) prognosis is still poor especially at advanced stage, so early diagnosis biomarkers are needed. MicroRNAs (miRNAs) have been proposed as potential early diagnostic biomarkers of asbestos-related LC and MPM.
AIM: To evaluate the role of miRNAs as diagnostic and prognostic biomarkers of asbestos-related LC and MPM by performing a literature systematic review and meta-analysis.
METHODS: MEDLINE, EMBASE via Ovid, PUBMED and Cochrane library databases were systematically searched up to April 2023 to identify relevant articles. A grey literature search was also conducted using the Google Scholar platform. MeSH and free text terms for 'asbestos', 'occupational exposure', 'lung cancer', 'mesothelioma' and 'miRNAs' were used to search the literature. Our systematic review protocol was registered in the PROSPERO database. Study quality was assessed via the Newcastle-Ottawa Scale.
RESULTS: From the search, 331 articles were retrieved, and, after applying our selection criteria, and exclusion of one study for poor quality, 27 studies were included in the review. Most of the studies were hospital-based case-control, conducted in Europe, and evaluated MPM among men only. MiRNAs expression was measured mainly in plasma or serum. MiR-126, miR-132-3p, and miR-103a-3p were the most promising diagnostic biomarkers for MPM, and we estimated a pooled area under the curve (AUC) of 85 %, 73 %, and 50 %, respectively. In relation to MPM prognosis, miR-197‑3p resulted associated with increased survival time. MiR-126, alone and combined with miR-222, was confirmed associated also to LC diagnosis, together with miR-1254 and miR-574-5p; no miRNA was found associated to LC prognosis.
CONCLUSION: Based on our systematic literature review there is suggestive evidence that the expression of specific miRNAs in the blood serum or plasma are associated with asbestos-related LC and MPM diagnosis and prognosis. Further large longitudinal studies are urgently needed to validate these findings and elucidate the underlying mechanisms given the potential important implications for patients' survival.

Keywords:  Asbestos; Biomarkers; Lung cancer; Mesothelioma; Occupational health; miRNA

DOI:  https://doi.org/10.1016/j.pulmoe.2024.02.002
Ann Thorac Surg. 2024 Feb 28. pii: S0003-4975(24)00126-7. [Epub ahead of print]

Impact of Surgery on Disease Progression and Survival of Patients with Pleural Mesothelioma.

Akifumi Nakamura, Masaki Hashimoto, Ayumi Kuroda, Seiji Matsumoto, Nobuyuki Kondo, Kazuhiro Kitajima, Toshiyuki Minami, Kozo Kuribayashi, Takashi Kijima, Seiki Hasegawa.

BACKGROUND: The effects of surgery on the survival of patients with pleural mesothelioma remain poorly understood. We compared the therapeutic outcomes of patients receiving neoadjuvant chemotherapy followed by surgery or refusing surgery for pleural mesothelioma.
METHODS: This retrospective study included consecutive patients who were eligible for curative-intent surgery after three cycles of neoadjuvant chemotherapy with platinum plus pemetrexed at our hospital during January 2011-December 2021. Patients were divided into two groups. The surgery group comprised patients who underwent curative-intent surgery for pleural mesothelioma. The refusal of surgery group comprised patients who were medically eligible for surgery but refused to consent to surgery. Overall survival and progression-free survival were calculated using the Kaplan-Meier method with the generalized Wilcoxon test.
RESULTS: Of the 296 eligible patients for the study, 272 and 24 underwent and refused surgery, respectively. During the surgery, 204 (75.0%), 43 (15.8%), and 25 (9.2%) patients underwent pleurectomy/decortication, extrapleural pneumonectomy, and exploratory thoracotomy, respectively. The median follow-up length was 28.4 months. The median overall survival periods were 40.7 (95% confidence interval [CI]: 32.2--45.6) and 23.6 (95% CI: 15.2-43.0) months for surgery and refusal of surgery, respectively (P = 0.03). The median progression-free survival periods were 20.2 (95% CI: 17.0-22.5) and 12.9 (95% CI: 8.3-16.8) months for surgery and refusal of surgery, respectively (P < 0.001).
CONCLUSIONS: Overall survival and progression-free survival were significantly better in surgery than in refusal of surgery. Surgery may improve the survival outcomes of patients with pleural mesothelioma.

DOI: https://doi.org/10.1016/j.athoracsur.2024.02.022