bims-mesote 2021-08-29 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2021–08–29
ten papers selected by
Laura Mannarino, Humanitas Research

Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma.
Epidemiology and Clinical Aspects of Malignant Pleural Mesothelioma.
Unsymmetric Cisplatin-Based Pt(IV) Conjugates Containing a PARP-1 Inhibitor Pharmacophore Tested on Malignant Pleural Mesothelioma Cell Lines.
Advances in Immunotherapy of Malignant Pleural Mesothelioma.
Neoadjuvant pemetrexed plus cisplatin followed by pleurectomy for malignant pleural mesothelioma.
Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study.
Use of Continuous Positive Airway Pressure (CPAP) to Limit Diaphragm Motion-A Novel Approach for Definitive Radiation Therapy for Inoperable Pleural Mesothelioma: A Pilot Study.
Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach.
Dosimetric Comparison Between Helical Tomotherapy and Volumetric Modulated Arc Therapy in Patients With Malignant Pleural Mesothelioma.
IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells.

Cancers (Basel). 2021 Aug 04. pii: 3932. [Epub ahead of print]13(16):

Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma.

Dannel Yeo, Laura Castelletti, Nico van Zandwijk, John E J Rasko.

  Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

Keywords:  CAR T cells; biomarker; cancer; immunotherapy; malignant mesothelioma; malignant pleural mesothelioma; mesothelin; therapeutic target

DOI:  https://doi.org/10.3390/cancers13163932
Cancers (Basel). 2021 Aug 20. pii: 4194. [Epub ahead of print]13(16):

Epidemiology and Clinical Aspects of Malignant Pleural Mesothelioma.

Fraser Brims.

  Mesothelioma is a cancer predominantly of the pleural cavity. There is a clear association of exposure to asbestos with a dose dependent risk of mesothelioma. The incidence of mesothelioma in different countries reflect the historical patterns of commercial asbestos utilisation in the last century and predominant occupational exposures mean that mesothelioma is mostly seen in males. Modern imaging techniques and advances in immunohistochemical staining have contributed to an improved diagnosis of mesothelioma. There have also been recent advances in immune checkpoint inhibition, however, mesothelioma remains very challenging to manage, especially considering its limited response to conventional systemic anticancer therapy and that no cure exists. Palliative interventions and support remain paramount with a median survival of 9-12 months after diagnosis. The epidemiology and diagnosis of mesothelioma has been debated over previous decades, due to a number of factors, such as the long latent period following asbestos exposure and disease occurrence, the different potencies of the various forms of asbestos used commercially, the occurrence of mesothelioma in the peritoneal cavity and its heterogeneous pathological and cytological appearances. This review will describe the contemporary knowledge on the epidemiology of mesothelioma and provide an overview of the best clinical practice including diagnostic approaches and management.

Keywords:  asbestos; epidemiology; mesothelioma; pleural disease

DOI:  https://doi.org/10.3390/cancers13164194
Molecules. 2021 Aug 05. pii: 4740. [Epub ahead of print]26(16):

Unsymmetric Cisplatin-Based Pt(IV) Conjugates Containing a PARP-1 Inhibitor Pharmacophore Tested on Malignant Pleural Mesothelioma Cell Lines.

Elisabetta Gabano, Giulia Pinton, Cecilia Balzano, Sara Boumya, Domenico Osella, Laura Moro, Mauro Ravera.

  Cisplatin is widely employed as a first-line chemotherapeutic agent for many solid tumors, including malignant pleural mesothelioma (MPM). However, its clinical use is limited by heavy side effects and acquired resistance, the latter being mainly related to enhanced DNA repair. Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPis) have been carried out, with the hope that such combinations might lead to improved therapeutic efficacy against tumors. Here, the synthesis and efficacy in reducing MPM cell viability of four cisplatin-based Pt(IV) prodrugs containing the PARPi 3-aminobenzamide (3-ABA) fragment are described. The most promising conjugate is more effective than cisplatin or cisplatin/3-ABA combination, administered in equimolar doses, in inhibiting PARP-1 activity and inducing apoptosis in BRCA1/2 wild type MPM cells, grown as monolayer or as multicellular spheroids.

Keywords:  PARP-1 inhibitors; Pt(IV) complexes; cisplatin; malignant pleural mesothelioma; prodrugs

DOI:  https://doi.org/10.3390/molecules26164740
Onco Targets Ther. 2021 ;14 4477-4484

Advances in Immunotherapy of Malignant Pleural Mesothelioma.

Dongying Liao, Yongchao Yu, Qingyun Mei, Ziwei Wang, Xiaojiang Li, Yingjie Jia, Fanming Kong.

  Malignant pleural mesothelioma (MPM) represents the uncommon cancer originating from pleural mesothelial cells, which is associated with dismal prognostic outcome. According to CheckMate-743 results, nivolumab plus ipilimumab has been approved to treat the unresectable MPM in treatment-naive patients as a first-line therapy by the FDA in October 2020. Immunotherapy is expected to be the best choice for MPM treatment. In the following article, the past treatment plan and the progress of immunotherapy for MPM will be reviewed.

Keywords:  immunotherapy; ipilimumab; malignant pleural mesothelioma; nivolumab; progression

DOI:  https://doi.org/10.2147/OTT.S317434
J Thorac Cardiovasc Surg. 2021 Jul 17. pii: S0022-5223(21)01048-5. [Epub ahead of print]

Neoadjuvant pemetrexed plus cisplatin followed by pleurectomy for malignant pleural mesothelioma.

Seiki Hasegawa, Kohei Yokoi, Morihito Okada, Fumihiro Tanaka, Mototsugu Shimokawa, Takashi Daimon, Takashi Nakano.

   PURPOSE: Despite becoming the preferred surgical technique for malignant pleural mesothelioma, pleurectomy/decortication has received few prospective clinical trials. Therefore, the Japan Mesothelioma Interest Group conducted a prospective multi-institutional study to evaluate the feasibility of neoadjuvant chemotherapy followed by pleurectomy/decortication.
METHODS: Patients with histologically confirmed, resectable malignant pleural mesothelioma underwent neoadjuvant chemotherapy comprising pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for 3 cycles, followed by pleurectomy/decortication. The primary end point was macroscopic complete resection rate regardless of the surgical technique used.
RESULTS: Among the 24 patients enrolled, 20 received neoadjuvant chemotherapy and 18 proceeded to surgery, all of whom achieved macroscopic complete resection. Pleurectomy/decortication was performed in 15 patients. The trial satisfied the primary end point, with a macroscopic complete resection rate of 90% (18/20, 95% confidence interval, 68.3-98.8). No treatment-related 30- and 90-day mortality occurred. The overall survival after 1 and 2 years and median overall survival after registration were 95.0% (95% confidence interval, 69.5-99.3), 70.0% (95% confidence interval, 45.1-85.3), and 3.45 years (95% confidence interval, 1.64 to not available), respectively. The cumulative incidence of progression after 1 and 2 years and median time to progression were 33.3% (95% confidence interval, 17.3-64.1), 61.1% (95% confidence interval, 42.3-88.3), and 1.71 years (95% confidence interval, 1.00-2.99), respectively. The best postoperative value for forced expiratory volume was 78.0% of preoperative values.
CONCLUSIONS: Neoadjuvant chemotherapy followed by pleurectomy/decortication was feasible with acceptable survival and mortality/morbidity. Postoperative pulmonary function was approximately 80% of the preoperative pulmonary function.

Keywords:  malignant pleural mesothelioma; neoadjuvant chemotherapy; pleurectomy/decortication; surgery

DOI:  https://doi.org/10.1016/j.jtcvs.2021.07.017
Transl Lung Cancer Res. 2021 Jul;10(7): 3030-3042

Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study.

Alexander Mathilakathu, Sabrina Borchert, Michael Wessolly, Elena Mairinger, Hendrik Beckert, Julia Steinborn, Thomas Hager, Daniel C Christoph, Jens Kollmeier, Jeremias Wohlschlaeger, Thomas Mairinger, Kurt Werner Schmid, Robert F H Walter, Luka Brcic, Fabian D Mairinger.

   Background: Malignant pleural mesothelioma (MPM) is a rare malignant tumor associated with asbestos exposure, with infaust prognosis and overall survival below 20 months in treated patients. Platinum is still the backbone of the chemotherapy protocols, and the reasons for the rather poor efficacy of platinum compounds in MPM remain largely unknown. Therefore, we aimed to analyze differences in key signaling pathways and biological mechanisms in therapy-naïve samples and samples after chemotherapy in order to evaluate the effect of platinum-based chemotherapy.
Methods: The study cohort comprised 24 MPM tumor specimens, 12 from therapy-naïve and 12 from patients after platinum-based therapy. Tumor samples were screened using the NanoString nCounter platform for digital gene expression analysis with an appurtenant custom-designed panel comprising a total of 366 mRNAs covering the most important tumor signaling pathways. Significant pathway associations were identified by gene set enrichment analysis using the WEB-based GEne SeT AnaLysis Toolkit (WebGestalt).
Results: We have found reduced activity of TNF (normalized enrichment score: 2.03), IL-17 (normalized enrichment score: 1.93), MAPK (normalized enrichment score: 1.51), and relaxin signaling pathways (normalized enrichment score: 1.42) in the samples obtained after platinum-based therapy. In contrast, AMPK (normalized enrichment score: -1.58), mTOR (normalized enrichment score: -1.50), Wnt (normalized enrichment score: -1.38), and longevity regulating pathway (normalized enrichment score: -1.31) showed significantly elevated expression in the same samples.
Conclusions: We could identify deregulated signaling pathways due to a directed cellular response to platinum-induced cell stress. Our results are paving the ground for a better understanding of cellular responses and escape mechanisms, carrying a high potential for improved clinical management of patients with MPM.

Keywords:  Gene Set Enrichment Analysis; Malignant pleural mesothelioma (MPM); platinum resistance, gene expression

DOI:  https://doi.org/10.21037/tlcr-21-201
Biology (Basel). 2021 Jul 24. pii: 711. [Epub ahead of print]10(8):

Use of Continuous Positive Airway Pressure (CPAP) to Limit Diaphragm Motion-A Novel Approach for Definitive Radiation Therapy for Inoperable Pleural Mesothelioma: A Pilot Study.

Assaf Moore, Marc J Kindler, Aaron Max Allen.

  Malignant pleural mesothelioma (MPM) is a deadly disease and radiotherapy (RT) plays an important role in its management. Recent developments in technique have made it is possible to deliver RT to MPM in the intact lung. However, it is imperative to reduce normal lung doses. We present a pilot study examining the use of CPAP and VMAT radiotherapy to reduce toxicity when treating MPM, involving three consecutive patients with MPM, not amenable to surgery, who were treated according to Helsinki committee approval. Patients were simulated using four-dimentional CT simulation with the assistance of CPAP lung inflation, then were treated using both IMRT and VMAT techniques. Radiation lung dose was optimized based on accepted lung dose constraints. Patients were followed for toxicity as well as local control and survival. Results: Three patients were treated with CPAP-based IMRT treatment. These patients tolerated the treatment and DVH constraints were able to be met. The comparison plans among the four VMAT arcs and the IMRT static field treatment were able to accomplish the treatment planning objectives without significant advantages with either technique. The treatment combined with CPAP reduced the normal lung dose in MPM patients with intact lungs. This technique is worthy of further investigation.

Keywords:  VMAT; mesothelioma; radiotherapy

DOI:  https://doi.org/10.3390/biology10080711
Int J Mol Sci. 2021 Aug 20. pii: 9014. [Epub ahead of print]22(16):

Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach.

Daniela Lisini, Sara Lettieri, Sara Nava, Giulia Accordino, Simona Frigerio, Chandra Bortolotto, Andrea Lancia, Andrea Riccardo Filippi, Francesco Agustoni, Laura Pandolfi, Davide Piloni, Patrizia Comoli, Angelo Guido Corsico, Giulia Maria Stella.

  Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.

Keywords:  advanced cell therapies; local therapy; mesothelioma; micro-environment

DOI:  https://doi.org/10.3390/ijms22169014
Clin Oncol (R Coll Radiol). 2021 Aug 21. pii: S0936-6555(21)00291-0. [Epub ahead of print]

Dosimetric Comparison Between Helical Tomotherapy and Volumetric Modulated Arc Therapy in Patients With Malignant Pleural Mesothelioma.

T Müdder, G R Sarria, C Henkenberens, J Holz, S Garbe, F Röhner, S Stumpf, T Buchstab, F A Giordano, C Leitzen.

   AIMS: To carry out a dosimetric comparison and constraints feasibility proof of adjuvant radiotherapy through helical tomotherapy or volumetric modulated arc therapy (VMAT) for malignant pleural mesothelioma patients after pleurectomy/decortication.
MATERIALS AND METHODS: Retrospective calculations were carried out on previously acquired simulations. A whole-pleura volume with 50.4 Gy in 28 fractions was prescribed, simulating a no residual tumour situation. Calculations were carried out using an anisotropic analytical algorithm with a 2.0 mm grid. Beam-on time, planning target volume (PTV) coverage, homogeneity index and organ at risk exposure were compared.
RESULTS: Sixteen patient plans were calculated per device. Constraints were met overall by both modalities. For helical tomotherapy and VMAT plans, median beam-on times were 13.8 (11.6-16.1) min and 6.4 (6.1-7.0) min; P = 0.006. The median left-sided radiotherapy PTV D98 were 48.1 (48.0-48.8) Gy and 47.6 (46.5-48.3) Gy; P = 0.023. No significant difference for right-sided radiotherapy was found. PTV D2 for left-sided radiotherapy was higher with VMAT (P = 0.014). For right-sided radiotherapy, helical tomotherapy showed higher doses (P = 0.039). No homogeneity index differences for left-sided radiotherapy (P = 1.00) and right-sided radiotherapy (P = 0.598) were seen. Significant organ at risk exposure differences were found on left-sided radiotherapy whole-lung V20, as well as D50 (both P = 0.008). Higher contralateral lung and ipsilateral kidney exposures were found with VMAT plans for both treatment sides.
CONCLUSION: Adjuvant radiotherapy after pleurectomy/decortication in malignant pleural mesothelioma patients, with a VMAT- or helical tomotherapy-based platform, is dosimetrically feasible. Lung sparing was mostly improved with helical tomotherapy. Technique selection must be carried out according to availability and clinical criteria.

Keywords:  Dosimetry; VMAT; mesothelioma; tomotherapy; whole-pleura radiotherapy

DOI:  https://doi.org/10.1016/j.clon.2021.08.005
Cancers (Basel). 2021 Aug 09. pii: 4011. [Epub ahead of print]13(16):

IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells.

Grazia Carbotti, Beatrice Dozin, Stefania Martini, Chiara Giordano, Francesca Scordamaglia, Michela Croce, Gilberto Filaci, Silvano Ferrini, Marina Fabbi.

  Malignant mesothelioma (MM) is a rare tumor with an unfavorable prognosis. MM genesis involves asbestos-mediated local inflammation, supported by several cytokines, including IL-6. Recent data showed that targeting PD-1/PD-L1 is an effective therapy in MM. Here, we investigated the effects of IL-6 trans-signaling and the IL-6-related cytokine IL-27 on human MM cells in vitro by Western blot analysis of STAT1/3 phosphorylation. The effects on PD-L1 expression were tested by qRT-PCR and flow-cytometry and the release of soluble (s)PD-L1 by ELISA. We also measured the concentrations of sPD-L1 and, by multiplexed immunoassay, IL-6 and IL-27 in pleural fluids obtained from 77 patients in relation to survival. IL-27 predominantly mediates STAT1 phosphorylation and increases PD-L1 gene and surface protein expression and sPD-L1 release by human MM cells in vitro. IL-6 has limited activity, whereas a sIL-6R/IL-6 chimeric protein mediates trans-signaling predominantly via STAT3 phosphorylation but has no effect on PD-L1 expression and release. IL-6, IL-27, and sPD-L1 are present in pleural fluids and show a negative correlation with overall survival, but only IL-27 shows a moderate albeit significant correlation with sPD-L1 levels. Altogether these data suggest a potential role of IL-27 in PD-L1-driven immune resistance in MM.

Keywords:  IL-27; IL-6; PD-L1; STAT1/3; mesothelioma; microenvironment; overall survival; pleural effusion

DOI:  https://doi.org/10.3390/cancers13164011