bims-mesote 2024-02-25 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2024–02–25
seven papers selected by
Laura Mannarino, Humanitas Research

Safety of First-Line Nivolumab Plus Ipilimumab in Very Old (≥ 80 Years) Patients With Unresectable Malignant Pleural Mesothelioma: A Retrospective Single-Center Case Series.
CHST4 Gene as a Potential Predictor of Clinical Outcome in Malignant Pleural Mesothelioma.
The BAP1 nuclear deubiquitinase is involved in the nonhomologous end-joining pathway of double-strand DNA repair through interaction with DNA-PK.
Nivolumab in pretreated pleural mesothelioma: Results from an observational real-world study of patients treated within the AIFA 5% Fund.
Involvement of Palliative Care in Malignant Pleural Mesothelioma Patients and Associations with Survival and End-of-Life Outcomes.
Telomere length and TERT polymorphisms as biomarkers in asbestos-related diseases.
Clonal gene signatures predict prognosis in mesothelioma and lung adenocarcinoma.

Cureus. 2024 Jan;16(1): e52714

Safety of First-Line Nivolumab Plus Ipilimumab in Very Old (≥ 80 Years) Patients With Unresectable Malignant Pleural Mesothelioma: A Retrospective Single-Center Case Series.

Takayuki Shimamoto, Yoshie Morimoto, Naohiro Nitta, Rie Yoshida, Nozomi Tani.

  Nivolumab plus ipilimumab as the first-line treatment results in superior survival outcomes in patients with malignant pleural mesothelioma (MPM). However, its safety in old (≥ 80 years) patients with MPM has not been elucidated yet. Three male patients with MPM, aged 80-90 years, were treated with nivolumab plus ipilimumab as the first-line treatment in our hospital. All of them discontinued the treatment due to adverse events. The overall survival from treatment initiation was 2.5, 3.5, and 4.0 months, respectively. Nivolumab plus ipilimumab should be used cautiously in very old patients with MPM.

Keywords:  age; case series; malignant pleural mesothelioma; nivolumab plus ipilimumab; safety

DOI:  https://doi.org/10.7759/cureus.52714
Int J Mol Sci. 2024 Feb 14. pii: 2270. [Epub ahead of print]25(4):

CHST4 Gene as a Potential Predictor of Clinical Outcome in Malignant Pleural Mesothelioma.

Shoji Okado, Taketo Kato, Yuki Hanamatsu, Ryo Emoto, Yoshito Imamura, Hiroki Watanabe, Yuta Kawasumi, Yuka Kadomatsu, Harushi Ueno, Shota Nakamura, Tetsuya Mizuno, Tamotsu Takeuchi, Shigeyuki Matsui, Toyofumi Fengshi Chen-Yoshikawa.

  Malignant pleural mesothelioma (MPM) develops primarily from asbestos exposures and has a poor prognosis. In this study, The Cancer Genome Atlas was used to perform a comprehensive survival analysis, which identified the CHST4 gene as a potential predictor of favorable overall survival for patients with MPM. An enrichment analysis of favorable prognostic genes, including CHST4, showed immune-related ontological terms, whereas an analysis of unfavorable prognostic genes indicated cell-cycle-related terms. CHST4 mRNA expression in MPM was significantly correlated with Bindea immune-gene signatures. To validate the relationship between CHST4 expression and prognosis, we performed an immunohistochemical analysis of CHST4 protein expression in 23 surgical specimens from surgically treated patients with MPM who achieved macroscopic complete resection. The score calculated from the proportion and intensity staining was used to compare the intensity of CHST4 gene expression, which showed that CHST4 expression was stronger in patients with a better postoperative prognosis. The median overall postoperative survival was 107.8 months in the high-expression-score group and 38.0 months in the low-score group (p = 0.044, log-rank test). Survival after recurrence was also significantly improved by CHST4 expression. These results suggest that CHST4 is useful as a prognostic biomarker in MPM.

Keywords:  CHST4; FFPE; immunohistochemistry; malignant pleural mesothelioma; prognostic factor

DOI:  https://doi.org/10.3390/ijms25042270
Oncogene. 2024 Feb 21.

The BAP1 nuclear deubiquitinase is involved in the nonhomologous end-joining pathway of double-strand DNA repair through interaction with DNA-PK.

Hiroki Sato, Tatsuo Ito, Takuo Hayashi, Shigehisa Kitano, Hediye Erdjument-Bromage, Matthew J Bott, Shinichi Toyooka, Marjorie Zauderer, Marc Ladanyi.

BRCA1-associated protein 1 (BAP1) has emerged as a major tumor suppressor gene in diverse cancer types, notably in malignant pleural mesothelioma (DPM), and has also been identified as a germline cancer predisposition gene for DPM and other select cancers. However, its role in the response to DNA damage has remained unclear. Here, we show that BAP1 inactivation is associated with increased DNA damage both in Met-5A human mesothelial cells and human DPM cell lines. Through proteomic analyses, we identified PRKDC as an interaction partner of BAP1 protein complexes in DPM cells and 293 T human embryonic kidney cells. PRKDC encodes the catalytic subunit of DNA protein kinase (DNA-PKcs) which functions in the nonhomologous end-joining (NHEJ) pathway of DNA repair. Double-stranded DNA damage resulted in prominent nuclear expression of BAP1 in DPM cells and phosphorylation of BAP1 at serine 395. A plasmid-based NHEJ assay confirmed a significant effect of BAP1 knockdown on cellular NHEJ activity. Combination treatment with X-ray irradiation and gemcitabine (as a radiosensitizer) strongly suppressed the growth of BAP1-deficient cells. Our results suggest reciprocal positive interactions between BAP1 and DNA-PKcs, based on phosphorylation of BAP1 by the latter and deubiquitination of DNA-PKcs by BAP1. Thus, functional interaction of BAP1 with DNA-PKcs supports a role for BAP1 in NHEJ DNA repair and may provide the basis for new therapeutic strategies and new insights into its role as a tumor suppressor.

DOI: https://doi.org/10.1038/s41388-024-02966-w
Tumori. 2024 Feb 19. 3008916241229287

Nivolumab in pretreated pleural mesothelioma: Results from an observational real-world study of patients treated within the AIFA 5% Fund.

Luigi Cerbone, Sara Delfanti, Stefania Crivellari, Antonina Maria De Angelis, Laura Mazzeo, Claudia Proto, Mario Occhipinti, Giuseppe Lo Russo, Chiara Dellepiane, Federica Biello, Irene Alabiso, Francesco Verderame, Roberta Gauna, Irene De Simone, Federica Cuppone, Sandra Petraglia, Giulia Pasello, Giovanni Luca Ceresoli, Marina Chiara Garassino, Valter Torri, Federica Grosso.

   BACKGROUND: Pleural mesothelioma is a rare cancer with a dismal prognosis and few therapeutic options, especially in the pretreated setting. Immunotherapy with checkpoint inhibitors as single agents yielded interesting results in refractory pleural mesothelioma, achieving a response rate between 10-20%, median progression-free survival of 2-5 months and median overall survival of 7-13 months.
PATIENTS AND METHODS: A retrospective, multi-institutional study of pleural mesothelioma patients treated with nivolumab in second and further line was performed. The endpoints of the study are response rate, disease control rate, progression free survival and overall survival.
RESULTS: Sixty-five patients with pleural mesothelioma treated with nivolumab in second and further line were enrolled at seven Italian institutions. The response rate was 8%, disease control rate was 37%, median progression free survival was 5.7 months (95% CI: 2.9-9.0) and median overall survival was 11.1 (95% CI 6.2-19.9) months. A higher neutrophils and neutrophils to lymphocytes ratio at baseline were associated with worse prognosis.
CONCLUSION: Nivolumab as a single agent is fairly active in a cohort of unselected pretreated pleural mesothelioma patients. Further investigations on clinical and translational factors are needed to define which patient might benefit most from nivolumab treatment in pleural mesothelioma.

Keywords:  immunotherapy; mesothelioma; nivolumab; real life studies; thoracic oncology

DOI:  https://doi.org/10.1177/03008916241229287
Curr Oncol. 2024 Feb 14. 31(2): 1028-1034

Involvement of Palliative Care in Malignant Pleural Mesothelioma Patients and Associations with Survival and End-of-Life Outcomes.

Andrew Baird, Abdullah Nasser, Peter Tanuseputro, Colleen Webber, Paul Wheatley-Price, Camille Munro.

  Malignant pleural mesothelioma is a rare, aggressive, and incurable cancer with a poor prognosis and high symptom burden. For these patients, little is known about the impact of palliative care consultation on outcomes such as mortality, hospital admissions, or emergency department visits. The aim of this study is to determine if referral to supportive and palliative care in patients with malignant pleural mesothelioma is associated with survival and decreased hospital admissions and emergency department visits. This is a retrospective chart review. Study participants include all malignant pleural mesothelioma patients seen at The Ottawa Hospital-an acute care tertiary center-between January 2002 and March 2019. In total, 223 patients were included in the study. The mean age at diagnosis was 72.4 years and 82.5% were male. Of the patients diagnosed between 2002 and 2010, only 11 (9.6%) were referred to palliative care. By comparison, of those diagnosed between 2011 and 2019, 49 (45.4%) were referred to palliative care. Median time from diagnosis to referral was 4.1 months. There was no significant difference in the median survival of patients referred for palliative care compared to those who did not receive palliative care (p = 0.46). We found no association between receiving palliative care and the mean number of hospital admissions (1.04 vs. 0.91) from diagnosis to death, and an increase in mean number of emergency department visits in the palliative care group (2.30 vs. 1.18). Although there was increased utilization of palliative care services, more than half of the MPM patients did not receive palliative care despite their limited survival. There was an increase in emergency department visits in the palliative care group; this may represent an increase in the symptom burden (i.e., indication bias) in those referred to palliative care.

Keywords:  emergency departments; mesothelioma; palliative care; patient admission; survival

DOI:  https://doi.org/10.3390/curroncol31020076
Radiol Oncol. 2024 Mar 01. 58(1): 87-98

Telomere length and TERT polymorphisms as biomarkers in asbestos-related diseases.

Ana Mervic, Katja Goricar, Tanja Blagus, Alenka Franko, Katarina Trebusak-Podkrajsek, Metoda Dodic Fikfak, Vita Dolzan, Viljem Kovac.

   BACKGROUND: Asbestos exposure has been proposed as a risk factor for shorter telomere length. The aim of our study was to investigate whether telomere length in leukocytes and hTERT genetic polymorphisms may serve as potential biomarkers for the risk of developing asbestos-related diseases and as biomarkers of progression and chemotherapy response rate in malignant mesothelioma (MM).
SUBJECTS AND METHODS: We conducted two retrospective studies. In the first study, a case-control study, telomere length and hTERT polymorphisms were determined in patients with MM, subjects with pleural plaques and controls without the asbestos related disease, who were occupationally exposed to asbestos. In the second study, a longitudinal observational study, telomere length was also determined in samples from MM patients before and after chemotherapy. Telomere length was determined by monochromatic multiplex quantitative polymerase chain reaction (PCR), while competitive allele-specific PCR was used to genotype hTERT rs10069690, rs2736100 and rs2736098. Logistic regression and survival analysis were used in statistical analysis.
RESULTS: Patients with MM had shorter telomere length than subjects with pleural plaques (p < 0.001). After adjustment for age, rs2736098 CT, and rs10069690 TT and CT+TT genotypes were significantly associated with a higher risk of MM (padj = 0.023; padj = 0.026 and padj = 0.017), while rs2736100 AA and CA+AA genotypes conferred to a lower risk for MM compared to all other subjects (padj = 0.017, and padj = 0.026). Telomere length was not associated with a response to chemotherapy (p > 0.05) or time to disease progression (p > 0.05). Carriers of one or two polymorphic rs10069690 T alleles had a good response to chemotherapy (p = 0.039, and p = 0.048), these associations remained statistically significant after adjustment for age (padj = 0.019; padj = 0.017). Carriers of two polymorphic rs2736100 A alleles had a longer time to disease progression (p = 0.038).
CONCLUSIONS: Shorter telomere length and hTERT polymorphisms may serve as a biomarker for the risk of developing MM. Additionally, rs10069690 and rs2736100 polymorphisms, but not telomere length, were associated with a chemotherapy response or MM progression.

Keywords:  asbestos; hTERT polymorphisms; malignant mesothelioma; telomere length

DOI:  https://doi.org/10.2478/raon-2024-0009
NPJ Precis Oncol. 2024 Feb 23. 8(1): 47

Clonal gene signatures predict prognosis in mesothelioma and lung adenocarcinoma.

Yupei Lin, Bryan M Burt, Hyun-Sung Lee, Thinh T Nguyen, Hee-Jin Jang, Claire Lee, Wei Hong, Robert Taylor Ripley, Christopher I Amos, Chao Cheng.

Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By integrating this dataset with the Cancer Genome Atlas MPM RNA-seq data, we selected 29 prognostic genes displaying high variability across different tumors but low ITH, which named PRACME (Prognostic Risk Associated Clonal Mesothelioma Expression). We evaluated PRACME in two independent MPM datasets and demonstrated its prognostic values. Patients with high signature scores are associated with poor prognosis after adjusting established clinical factors. Interestingly, the PRACME and the ORACLE signatures defined respectively from MPM and lung adenocarcinoma cross-predict prognosis between the two cancer types. Further investigation indicated that the cross-prediction ability might be explained by the high similarity between the two cancer types in their genomic regions with copy number variation, which host many clonal genes. Overall, our clonal signature PRACME provided prognostic stratification in MPM and this study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.

DOI: https://doi.org/10.1038/s41698-024-00531-y