bims-mesote 2021-10-17 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2021–10–17
nine papers selected by
Laura Mannarino, Humanitas Research

The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM).
[New MAA: First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma].
Upregulation of Thymidylate Synthase Induces Pemetrexed Resistance in Malignant Pleural Mesothelioma.
Brief Report: Meningiomas in Patients with Malignant Pleural Mesothelioma Harboring Germline BAP1 Mutations.
Computed Tomography and Spirometry Can Predict Unresectability in Malignant Pleural Mesothelioma.
Thoracic mesenchymal malignant tumors and programed cell death ligand-1 status: Clinicopathologic and prognostic analysis of eight pulmonary sarcomatoid carcinomas and eightmalignant mesotheliomas.
Recent progress and perspectives on the mechanisms underlying Asbestos toxicity.
The Epidemiologic Characteristics of Malignant Mesothelioma Cases in Korea: Findings of the Asbestos Injury Relief System from 2011-2015.
Brief Report: Molecular characterization of peritoneal mesotheliomas.

Int J Mol Sci. 2021 Sep 23. pii: 10225. [Epub ahead of print]22(19):

The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM).

Man Lee Yuen, Ling Zhuang, Emma M Rath, Takun Yu, Ben Johnson, Kadir Harun Sarun, Yiwei Wang, Steven Kao, Anthony Linton, Candice Julie Clarke, Brian C McCaughan, Ken Takahashi, Kenneth Lee, Yuen Yee Cheng.

  Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective treatment options. Focal adhesion kinase (FAK) inhibitors have been shown to efficiently suppress MPM cell growth initially, with limited utility in the current clinical setting. In this study, we utilised a large collection of MPM cell lines and MPM tissue samples to study the role of E-cadherin (CDH1) and microRNA on the efficacy of FAK inhibitors in MPM. The immunohistochemistry (IHC) results showed that the majority of MPM FFPE samples exhibited either the absence of, or very low, E-cadherin protein expression in MPM tissue. We showed that MPM cells with high CDH1 mRNA levels exhibited resistance to the FAK inhibitor PND-1186. In summary, MPM cells that did not express CDH1 mRNA were sensitive to PND-1186, and MPM cells that retained CDH1 mRNA were resistant. A cell cycle analysis showed that PND-1186 induced cell cycle disruption by inducing the G2/M arrest of MPM cells. A protein-protein interaction study showed that EGFR is linked to the FAK pathway, and a target scan of the microRNAs revealed that microRNAs (miR-17, miR221, miR-222, miR137, and miR148) interact with EGFR 3'UTR. Transfection of MPM cells with these microRNAs sensitised the CHD1-expressing FAK-inhibitor-resistant MPM cells to the FAK inhibitor.

Keywords:  E-cadherin; FAK inhibitor; drug resistant; malignant pleural mesothelioma (MPM); microRNA

DOI:  https://doi.org/10.3390/ijms221910225
Bull Cancer. 2021 Oct 12. pii: S0007-4551(21)00374-X. [Epub ahead of print]

[New MAA: First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma].

Quentin Laune, Solenn Brosseau.



Keywords:  First-line; Immunotherapy; Immunothérapie; Mésothéliome pleural malin; Nivolumab plus ipilimumab; Pleural mesothelioma; Première ligne

DOI:  https://doi.org/10.1016/j.bulcan.2021.07.010
Front Pharmacol. 2021 ;12 718675

Upregulation of Thymidylate Synthase Induces Pemetrexed Resistance in Malignant Pleural Mesothelioma.

Yuzo Sato, Masaru Tomita, Tomoyoshi Soga, Atsushi Ochiai, Hideki Makinoshima.

  Malignant pleural mesothelioma (MPM) is an invasive malignancy that develops in the pleural cavity, and antifolates are used as chemotherapeutics for treating. The majority of antifolates, including pemetrexed (PMX), inhibit enzymes involved in purine and pyrimidine synthesis. MPM patients frequently develop drug resistance in clinical practice, however the associated drug-resistance mechanism is not well understood. This study was aimed to elucidate the mechanism underlying resistance to PMX in MPM cell lines. We found that among the differentially expressed genes associated with drug resistance (determined by RNA sequencing), TYMS expression was higher in the established resistant cell lines than in the parental cell lines. Knocking down TYMS expression significantly reduced drug resistance in the resistant cell lines. Conversely, TYMS overexpression significantly increased drug resistance in the parental cells. Metabolomics analysis revealed that the levels of dTMP were higher in the resistant cell lines than in the parental cell lines; however, resistant cells showed no changes in dTTP levels after PMX treatment. We found that the nucleic acid-biosynthetic pathway is important for predicting the efficacy of PMX in MPM cells. The results of chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays suggested that H3K27 acetylation in the 5'-UTR of TYMS may promote its expression in drug-resistant cells. Our findings indicate that the intracellular levels of dTMP are potential biomarkers for the effective treatment of patients with MPM and suggest the importance of regulatory mechanisms of TYMS expression in the disease.

Keywords:  H3K27ac; drug-resistance; mesothelioma; thymidylate synthase; tumor metabolism

DOI:  https://doi.org/10.3389/fphar.2021.718675
J Thorac Oncol. 2021 Oct 07. pii: S1556-0864(21)03202-0. [Epub ahead of print]

Brief Report: Meningiomas in Patients with Malignant Pleural Mesothelioma Harboring Germline BAP1 Mutations.

Zishuo I Hu, Markku Miettinen, Martha Quezado, Alexandra P Lebensohn, Kenneth Aldape, Maria Agra, Cathy Wagner, Yvonne Mallory, Raffit Hassan, Azam Ghafoor.



Keywords:  BAP1; meningioma; mesothelioma

DOI:  https://doi.org/10.1016/j.jtho.2021.08.765
J Clin Med. 2021 Sep 26. pii: 4407. [Epub ahead of print]10(19):

Computed Tomography and Spirometry Can Predict Unresectability in Malignant Pleural Mesothelioma.

Alice Bellini, Andrea Dell'Amore, Chiara Giraudo, Antonella Modugno, Nicol Bernardinello, Stefano Terzi, Giovanni Zambello, Giulia Pasello, Andrea Zuin, Federico Rea.

  Preoperative identification of unresectable pleural mesothelioma could spare unnecessary surgical intervention and accelerate the initiation of medical treatments. The aim of this study is to determine predictors of unresectability, testing our impression that the contraction of the ipsilateral hemithorax is often associated with exploratory thoracotomy. Between 1994 and 2020, 291 patients undergoing intended macroscopic complete resection for mesothelioma after chemotherapy were retrospectively investigated. Eligible patients (n = 58) presented a preoperative 3 mm slice-thickness chest computed tomography without pleural effusion or hydropneumothorax. Lung volumes (segmented using a semi-automated method), modified-Response Evaluation Criteria in Solid Tumors (RECIST) measurements, and spirometries were collected after chemotherapy. Multivariable analysis was performed to determine the predictors of unresectability. An unresectable disease was found at the time of operation in 25.9% cases. By multivariable analysis, the total lung capacity (p = 0.03) and the disease burden (p = 0.02) were found to be predictors of unresectability; cut-off values were <77.5% and >120.5 mm, respectively. Lung volumes were not confirmed to be associated with unresectability at multivariable analysis, probably due to the correlation with the disease burden (p < 0.001; r = -0.4). Our study suggests that disease burden and total lung capacity could predict MPM unresectability, helping surgeons in recommending surgery or not in a multimodality setting.

Keywords:  RECIST; mesothelioma; thoracic surgery

DOI:  https://doi.org/10.3390/jcm10194407
Thorac Cancer. 2021 Oct 15.

Thoracic mesenchymal malignant tumors and programed cell death ligand-1 status: Clinicopathologic and prognostic analysis of eight pulmonary sarcomatoid carcinomas and eightmalignant mesotheliomas.

Kanji Otsubo, Hiroki Sakai, Hiroyuki Kimura, Tomoyuki Miyazawa, Hideki Marushima, Koji Kojima, Naoki Furuya, Masamichi Mineshita, Motohiro Chosokabe, Junki Koike, Hisashi Saji.

   BACKGROUND: The current study aimed to evaluate the significance of clinicopathological factors, particularly the immunohistochemistry of programed cell death ligand-1 (PD-L1), in eight cases each of pulmonary sarcomatoid carcinoma (PSC) and malignant pleural mesothelioma (MPM) at our hospital.
METHODS: From January 2004 to December 2020, a total of 16 consecutive patients (eight with PSC and eight with MPM diagnosed via surgical resection or biopsy) were included in this study. After retrospectively reviewing the patient characteristics, the associations between PD-L1 status and age, sex, stage, histological type, and prognosis were investigated.
RESULTS: PD-L1-positive staining was observed in four (50%) PSC cases and one (12.5%) MPM case. Among the four PD-L1-positive PSC cases, two showed high PD-L1 expression in the vimentin-positive sarcomatoid compartment. Moreover, among those with PSC, two survived for about 10 years, whereas the others died within 5 years. No clear correlation was found between PD-L1 expression and prognosis. Among the patients with MPM, four survived for more than 2 years, with the longest being 9 years. Among MPM cases who received nivolumab, one patient with positive PD-L1 staining in the sarcomatoid survived, whereas the other with negative PD-L1 staining did not.
CONCLUSION: The present study showed that sarcomatoid carcinoma had a higher PD-L1 expression compared to non-small-cell lung cancer and that both PSC and MPM tended to exhibit PD-L1 positivity in the sarcomatoid compartment. Moreover, while immune checkpoint inhibitors may somewhat prolong the prognosis of both tumors, further studies with a larger cohort are necessary to confirm our results.

Keywords:  immune checkpoint inhibitor; malignant pulmonary methotelioma; programed cell death ligand-1; pulmonary sarcomatoid carcinoma

DOI:  https://doi.org/10.1111/1759-7714.14177
Genes Environ. 2021 Oct 12. 43(1): 46

Recent progress and perspectives on the mechanisms underlying Asbestos toxicity.

Akio Kuroda.

  Most cases of mesothelioma are known to result from exposure to asbestos fibers in the environment or occupational ambient air. The following questions regarding asbestos toxicity remain partially unanswered: (i) why asbestos entering the alveoli during respiration exerts toxicity in the pleura; and (ii) how asbestos causes mesothelioma, even though human mesothelial cells are easily killed upon exposure to asbestos. As for the latter question, it is now thought that the frustrated phagocytosis of asbestos fibers by macrophages prolongs inflammatory responses and gives rise to a "mutagenic microenvironment" around mesothelial cells, resulting in their malignant transformation. Based on epidemiological and genetic studies, a carcinogenic model has been proposed in which BRCA1-associated protein 1 mutations are able to suppress cell death in mesothelial cells and increase genomic instability in the mutagenic microenvironment. This leads to additional mutations, such as CDKN2A [p16], NF2, TP53, LATS2, and SETD2, which are associated with mesothelioma carcinogenesis. Regarding the former question, the receptors involved in the intracellular uptake of asbestos and the mechanism of transfer of inhaled asbestos from the alveoli to the pleura are yet to be elucidated. Further studies using live-cell imaging techniques will be critical to fully understanding the mechanisms underlying asbestos toxicity.

Keywords:  Asbestos; BAP1; Carcinogenesis; Live-cell imaging; Mesothelioma; Mutagenic microenvironment; Toxicity

DOI:  https://doi.org/10.1186/s41021-021-00215-0
Int J Environ Res Public Health. 2021 Sep 23. pii: 10007. [Epub ahead of print]18(19):

The Epidemiologic Characteristics of Malignant Mesothelioma Cases in Korea: Findings of the Asbestos Injury Relief System from 2011-2015.

Soon-Chan Kwon, Sung-Soo Lee, Min-Sung Kang, Da-An Huh, Yong-Jin Lee.

  (1) Background: The purpose of this study was to investigate the epidemiological characteristics of malignant mesothelioma in Korea by investigating cases compensated under the asbestos injury relief system. (2) Methods: A total of 407 compensated cases between 2011 and 2015 were reviewed using medical records and resident registrations in order to investigate the dates of diagnosis and death. Asbestos exposure and patients' general characteristics were investigated through face-to-face interviews. The standardized incidence ratio was calculated as the number of observations from 2005 to 2014 per exposure region in Korea, using the mid-annual population of each region in 2009 as the standard population. (3) Results: Among the 407 cases, 65.1% were male. The pleura and peritoneum were affected in 76.9% and 23.1% of cases, respectively. For peritoneal mesothelioma, the median survival duration was longer (p = 0.005), and the proportion of affected women was higher than that in pleural mesothelioma. The standardized incidence ratio (95% CI) by province of primary exposure was Chungnam 3.33 (2.51-4.35), Ulsan 1.85 (0.97-3.21), and Seoul 1.32 (1.06-1.63). (4) Conclusions: Although the representativeness of the data is limited, it is sufficient to assume the epidemiologic characteristics of malignant mesothelioma, help improve the compensation system, and contribute to future policies.

Keywords:  asbestos; incidence; latent period; malignant mesothelioma; survival

DOI:  https://doi.org/10.3390/ijerph181910007
J Thorac Oncol. 2021 Oct 11. pii: S1556-0864(21)03215-9. [Epub ahead of print]

Brief Report: Molecular characterization of peritoneal mesotheliomas.

Michael Offin, Soo-Ryum Yang, Jacklynn Egger, Gowtham Jayakumaran, Rowanne S Spencer, Jessica Lopardo, Garrett M Nash, Andrea Cercek, William D Travis, Mark G Kris, Marc Ladanyi, Jennifer L Sauter, Marjorie G Zauderer.

BACKGROUND: Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort.
METHODS: Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and PD-L1 were examined by immunohistochemistry (IHC) when tissue was available. Overall survival (OS) was stratified by selected genomic and IHC features.
RESULTS: Fifty consented patients with MPeM (45 epithelioid, 5 non-epithelioid) demonstrated common alterations in BAP1 (60%; 30/50), NF2 (24%; 12/50) SETD2 (22%; 11/50), and TP53 (16%; 8/50). Seventy-six percent (38/50) of specimens were evaluable for allele-specific copy number analysis; 8% (3/38) had GNH. IHC positivity rates were 93% (37/40) for mesothelin, 96% (46/48) for WT1, 50% (19/38) for PD-L1 and 89% (34/38) for VISTA. BAP1 loss by IHC was observed in 76% (29/38), including five wildtype on NGS. Combining NGS and IHC for BAP1, OS was worse with alteration/loss compared to wildtype/retained in all patients (n=37 vs. 13, 43.8 vs. 117.3 months; p=0.04) Three of thirty patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, BAP1 E402*.
CONCLUSION: MPeM has a distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM while BAP1, NF2, TP53, SETD2, LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.

DOI: https://doi.org/10.1016/j.jtho.2021.09.012