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

2020 ◽  
Vol 14 (6) ◽  
pp. 1207-1223 ◽  
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

scholarly journals Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Clément Meiller ◽  
François Montagne ◽  
Theo Z. Hirsch ◽  
Stefano Caruso ◽  
Julien de Wolf ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Malignant Pleural Mesothelioma ◽  
Tumor Heterogeneity ◽  
Immunological Synapse ◽  
Side Wall ◽  
Molecular Classification ◽  
Suppressor Gene ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Methylome Analysis

Abstract Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

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

Cancers ◽  
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.

scholarly journals Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2454
Author(s):  
Federica Torricelli ◽  
Filippo Lococo ◽  
Teresa Severina Di Stefano ◽  
Eugenia Lorenzini ◽  
Simonetta Piana ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Deep Sequencing ◽  
Validation Cohort ◽  
Genetic Alterations ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Specific Subset ◽  
Validation Set ◽  
Custom Panel ◽  
Deep Sequencing Analysis

Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients’ survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients’ risk stratification.

Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma

2006 ◽  
Vol 24 (9) ◽  
pp. 1443-1448 ◽  
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.

scholarly journals OA13.03 Long-Term Overall Survival for Patients with Malignant Pleural Mesothelioma on Pembrolizumab Enrolled in KEYNOTE-028

2017 ◽  
Vol 12 (1) ◽  
pp. S294 ◽  
Author(s):  
Evan Alley ◽  
Juanita Lopez ◽  
Armando Santoro ◽  
Anne Morosky ◽  
Sanatan Saraf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma

scholarly journals External validation of prognostic indices for overall survival of malignant pleural mesothelioma

Lung Cancer ◽  
2017 ◽  
Vol 113 ◽  
pp. 88-92 ◽  
Author(s):  
Yuki Kataoka ◽  
Yosuke Yamamoto ◽  
Taiichiro Otsuki ◽  
Sawako Kaku ◽  
Nobuko Maehashi-Wada ◽  
...  
Keyword(s):  
Overall Survival ◽  
Malignant Pleural Mesothelioma ◽  
External Validation ◽  
Pleural Mesothelioma ◽  
Prognostic Indices

scholarly journals Malignant Pleural Mesothelioma Outcomes in the Era of Combined Platinum and Folate Antimetabolite Chemotherapy

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Mathieu D. Saint-Pierre ◽  
Christopher Pease ◽  
Hamid Mithoowani ◽  
Tinghua Zhang ◽  
Garth A. Nicholas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
Performance Status ◽  
Treatment Modalities ◽  
Pleural Mesothelioma ◽  
Cox Models ◽  
Platinum Based Chemotherapy ◽  
Before And After ◽  
Incremental Improvement

Introduction. Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. Palliative platinum-based chemotherapy may help to improve symptoms and prolong life. Since 2004, the platinum is commonly partnered with a folate antimetabolite. We performed a review investigating if survival had significantly changed before and after the arrival of folate antimetabolites in clinical practice. Methods. All MPM patients from January 1991 to June 2012 were identified. Data collected included age, gender, asbestos exposure, presenting signs/symptoms, performance status, histology, stage, bloodwork, treatment modalities including chemotherapy, and date of death or last follow-up. The primary endpoint was overall survival. Cox models were applied to determine variables associated with survival. Results. There were 245 patients identified. Median overall survival for all patients was 9.4 months. After multivariate analysis, performance status, stage, histology, leucocytosis, and thrombophilia remained independently associated with survival. Among all patients who received chemotherapy, there was no difference in overall survival between the periods before and after folate antimetabolite approval: 14.2 versus 13.2 months (P=0.35). Specifically receiving combined platinum-based/folate antimetabolite chemotherapy did not improve overall survival compared to all other chemotherapy regimens: 14.1 versus 13.6 months (P=0.97). Conclusions. In this review, we did not observe an incremental improvement in overall survival after folate antimetabolites became available.

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