DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.

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Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients

Cancers ◽

10.3390/cancers13030508 ◽

2021 ◽

Vol 13 (3) ◽

pp. 508

Author(s):

Emanuela Di Gregorio ◽

Gianmaria Miolo ◽

Asia Saorin ◽

Elena Muraro ◽

Michela Cangemi ◽

...

Keyword(s):

Amino Acids ◽

Overall Survival ◽

Clinical Outcome ◽

Malignant Pleural Mesothelioma ◽

Therapeutic Option ◽

Enrichment Analysis ◽

Metabolic Effects ◽

Pleural Mesothelioma ◽

Polyamine Biosynthesis ◽

The Individual

Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.

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Experimental study of the inhibition effect of CXCL12/CXCR4 in malignant pleural mesothelioma

Journal of Investigative Medicine ◽

10.1136/jim-2018-000839 ◽

2018 ◽

Vol 67 (2) ◽

pp. 338-345 ◽

Cited By ~ 2

Author(s):

Jianshuang Li ◽

Tong Li ◽

Shuo Li ◽

Lipeng Xie ◽

Yi-Lin Yang ◽

...

Keyword(s):

Treatment Group ◽

Malignant Pleural Mesothelioma ◽

Synergistic Effects ◽

Control Group ◽

Pleural Mesothelioma ◽

Gene Expressions ◽

Relationship Of ◽

The Relationship ◽

Cxcr4 Axis

Previous studies have demonstrated that CXCL12/CXCR4 axis is closely related to tumors such as malignant pleural mesothelioma (MPM). This research was conducted in order to detect whether CXCL12/CXCR4 inhibitors could restrain MPM and have a synergistic effect with chemotherapy, also to investigate the relationship of CXCL12/CXCR4 with other gene expressions in MPM. Forty mice were injected MPM cells and randomly divided into four groups: the PBS (control group), AMD3100 (CXCR4-CXCL12 antagonist), pemetrexed and AMD3100 plus pemetrexed. The mice were treated respectively for duration of 3 weeks. The size, bioluminescence and weight of tumors were measured. The differences between gene expressions in each group were analyzed. The tumor weights of each treatment group were lower than that of the control group (p<0.05). The bioluminescence of the tumor of the AMD3100 treatment group and the AMD3100 plus pemetrexed treatment group were lower than that of the control group (p<0.05), and AMD3100 was shown to have synergistic effects with pemetrexed (p<0.05). Among the 2.5 billion genes, several hundreds of genes expressed differently between groups. Results show that AMD3100 and pemetrexed can inhibit the growth of MPM in vivo, also that there is a better result if both are used together. Our findings suggest that CXCL12/CXCR4 axis affects a certain amount of gene expression in MPM.

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Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival

Molecular Oncology ◽

10.1002/1878-0261.12651 ◽

2020 ◽

Vol 14 (6) ◽

pp. 1207-1223 ◽

Cited By ~ 14

Author(s):

Lisa Quetel ◽

Clément Meiller ◽

Jean‐Baptiste Assié ◽

Yuna Blum ◽

Sandrine Imbeaud ◽

...

Keyword(s):

Overall Survival ◽

Malignant Pleural Mesothelioma ◽

Tumor Heterogeneity ◽

Genetic Alterations ◽

Pleural Mesothelioma

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ATIM-35. THE ASSOCIATIONS BETWEEN TOTAL LYMPHOCYTE COUNTS AFTER CONCOMITANT CHEMORADIATION WITH OVERALL SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.034 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi9-vi9

Author(s):

Stephen Ahn ◽

Jae-Sung Park ◽

Yong Kil Hong ◽

Seung Ho Yang ◽

Sin-Soo Jeun

Keyword(s):

Overall Survival ◽

Complete Blood Count ◽

Malignant Tumors ◽

P Value ◽

Newly Diagnosed ◽

Total Lymphocyte ◽

Concomitant Chemoradiation ◽

Newly Diagnosed Glioblastoma ◽

The Relationship

Abstract Several studies have been conducted to determine the relationship between post-treatment total lymphocyte count (TLC) and overall survival (OS) in patients with malignant tumors including glioblastomas (GBMs). In this retrospective study, whether patients with newly diagnosed GBM experience significant lymphopenia after concomitant chemoradiation (CCRT) was evaluated, and whether TLC after this treatment is associated with OS in the treated population was examined. Using electronic medical records, all patients newly diagnosed with GBM between 2008 and 2016 at Seoul St. Mary’s Hospital were retrospectively examined. The eligible criteria included the following: 1) craniotomy with surgical resection or biopsy, 2) completion of CCRT, 3) accessible baseline and/or follow-up complete blood count (CBC). Median TLC significantly decreased after completion of CCRT, compared to TLC at baseline (1,742 versus 1,319 cells/mm3, P-value < 0.001). Patients with TLC < 1,200 cells/mm3 at 4 weeks after the completion of CCRT showed shorter survival than those with TLC ≥ 1,200 cells/mm3 with median OS of 14.5 versus 21.0 months (P-value = 0.017). Also, in multivariate analysis for OS, TLC < 1,200 cells/mm3 at 4 weeks after the completion of CCRT (HR 1.97, 95% CI 1.61 – 2.25, P-value = 0.004) were significantly associated with shorter survival. The results from the present study indicate that treatment-related total lymphocyte counts after CCRT is associated with worse survival in patients with newly diagnosed GBM.

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Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.3190 ◽

2006 ◽

Vol 24 (9) ◽

pp. 1443-1448 ◽

Cited By ~ 173

Author(s):

Giovanni L. Ceresoli ◽

Paolo A. Zucali ◽

Adolfo G. Favaretto ◽

Francesco Grossi ◽

Paolo Bidoli ◽

...

Keyword(s):

Overall Survival ◽

Disease Control ◽

Phase Ii ◽

Malignant Pleural Mesothelioma ◽

Objective Response ◽

Dose Intensity ◽

Pleural Mesothelioma ◽

Standard Regimen ◽

Time Curve ◽

Grade 3

Purpose This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM). Patients and Methods Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2 and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12 supplementation. Pemetrexed was provided within the Expanded Access Program. Results A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible. Conclusion Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

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