bims-mesote 2022-07-17 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–07–17
six papers selected by
Laura Mannarino, Humanitas Research

Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations.
Nivolumab plus ipilimumab in malignant pleural mesothelioma.
Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow.
Clinical significance of 9P21 gene combined with BAP1 and MTAP protein expression in diagnosis and prognosis of mesothelioma serous effusion.
Understanding clinical decision-making in mesothelioma care: a mixed methods study.
Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma.

Cell Death Dis. 2022 Jul 15. 13(7): 612

Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations.

Laura Mannarino, Federica Mirimao, Nicolò Panini, Lara Paracchini, Sergio Marchini, Luca Beltrame, Rosy Amodeo, Federica Grosso, Roberta Libener, Irene De Simone, Giovanni L Ceresoli, Paolo A Zucali, Monica Lupi, Maurizio D'Incalci.

Although clinical antitumor activity of Tumor Treating Fields (TTFields) has been reported in malignant pleural mesothelioma (MPM) patients, the mechanisms behind the different selectivity displayed by the various MPM histotypes to this physical therapy has not been elucidated yet. Taking advantage of the development of well characterized human MPM cell lines derived from pleural effusion and/or lavages of patients' thoracic cavity, we investigated the biological effects of TTFields against these cells, representative of epithelioid, biphasic, and sarcomatoid histotypes. Growth inhibition and cell cycle perturbations caused by TTFields were investigated side by side with RNA-Seq analyses at different exposure times to identify pathways involved in cell response to treatment. We observed significant differences of response to TTFields among the cell lines. Cell cycle analysis revealed that the most sensitive cells (epithelioid CD473) were blocked in G2M phase followed by formation of polyploid cells. The least sensitive cells (sarcomatoid CD60) were only slightly affected by TTFields with a general delay in all cell cycle phases. Apoptosis was present in all samples, but while epithelioid cell death was already observed during the first 24 h of treatment, sarcomatoid cells needed longer times before they engaged apoptotic pathways. RNA-Seq experiments demonstrated that TTFields induced a transcriptional response already detectable at early time points (8 h). The number of differentially expressed genes was higher in CD473 than in CD60 cells, involving several pathways, such as those pertinent to cell cycle checkpoints, DNA repair, and histone modifications. Our data provide further support to the notion that the antitumor effects of TTFields are not simply related to a non-specific reaction to a physical stimulus, but are dependent on the biological background of the cells and the particular sensitivity to TTFields observed in epithelioid MPM cells is associated with a higher transcriptional activity than that observed in sarcomatoid models.

DOI: https://doi.org/10.1038/s41419-022-05073-4
Expert Rev Anticancer Ther. 2022 Jul 14.

Nivolumab plus ipilimumab in malignant pleural mesothelioma.

Camille Travert, Pascale Tomasini, Laurent Greillier.

   INTRODUCTION: Unresectable pleural mesothelioma is a poor prognosis disease. Improvement in overall survival (OS) has been shown with PEMETREXED combined to CISPLATIN. BEVACIZUMAB combined with chemotherapy is associated with an improvement in OS, compared to chemotherapy alone, but is not supported by health insurance everywhere.
AREAS COVERED: Immune Checkpoint Inhibition (ICI) monotherapy seemed to be promising, but is controversial. ICI combination showed significant results. NIVOLUMAB, an anti-Programmed-Death-receptor 1, associated to IPILIMUMAB, an anti-Cytotoxic-T-Lymphocyte-Associated-protein 4, was evaluated in two phase II trials and a phase III trial, recently published. This combination led to a significant benefit in survival in first line compared to chemotherapy (OS 18.1 months (95%CI(16.8-21.4)) vs 14.1 (95%CI(12.4-16.2) HR 0.74 (95%CI 0.6-0.91) p=0.002).
EXPERT OPINION: These results represent a big step in unresectable pleural mesothelioma. The benefit in non-epithelioid subtype is impressive (OS 18.1 months (95%CI 12.2-22.8) vs 8.8 months 95%CI (7.4-10.2) HR 0.46 (95%CI(0.31-0.68)). Benefit in epithelioid subtype (OS 18.7 months 95%CI(16.9-22) vs 16.5 95%CI(14.9-20.5) HR 0.86 95%CI(0.69-1.08)) is similar to the benefit of the combination of BEVACIZUMAB and chemotherapy. Identification of predictive biomarkers is needed to identify patients who are most likely to benefit from each therapeutic strategy.

Keywords:  Anti-Cytotoxic T-Lymphocyte Associated protein 4; Anti-programmed death ligand 1; Drug metabolism; Immune checkpoint inhibitors; Immunotherapy; Immunotherapy combination; Mesothelioma; Pharmacodynamics; Pharmacokinetics; Pleural malignancies

DOI:  https://doi.org/10.1080/14737140.2022.2102482
Transl Lung Cancer Res. 2022 Jun;11(6): 991-1008

Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow.

Ildiko Kovacs, Edina Bugyik, Katalin Dezso, Julia Tarnoki-Zach, Elod Mehes, Marton Gulyas, Andras Czirok, Elisabeth Lang, Michael Grusch, Karin Schelch, Balazs Hegedus, Ildiko Horvath, Nandor Barany, Zsolt Megyesfalvi, Anna Tisza, Zoltan Lohinai, Mir Alireza Hoda, Konrad Hoetzenecker, Francesco Pezzella, Sandor Paku, Viktoria Laszlo, Balazs Dome.

   Background: The microanatomical steps of malignant pleural mesothelioma (MPM) vascularization and the resistance mechanisms to anti-angiogenic drugs in MPM are unclear.
Methods: We investigated the vascularization of intrapleurally implanted human P31 and SPC111 MPM cells. We also assessed MPM cell's motility, invasion and interaction with endothelial cells in vitro.
Results: P31 cells exhibited significantly higher two-dimensional (2D) motility and three-dimensional (3D) invasion than SPC111 cells in vitro. In co-cultures of MPM and endothelial cells, P31 spheroids permitted endothelial sprouting (ES) with minimal spatial distortion, whereas SPC111 spheroids repealed endothelial sprouts. Both MPM lines induced the early onset of submesothelial microvascular plexuses covering large pleural areas including regions distant from tumor colonies. The development of these microvascular networks occurred due to both intussusceptive angiogenesis (IA) and ES and was accelerated by vascular endothelial growth factor A (VEGF-A)-overexpression. Notably, SPC111 colonies showed different behavior to P31 cells. P31 nodules incorporated tumor-induced capillary plexuses from the earliest stages of tumor formation. P31 cells deposited a collagenous matrix of human origin which provided "space" for further intratumoral angiogenesis. In contrast, SPC111 colonies pushed the capillary plexuses away and thus remained avascular for weeks. The key event in SPC111 vascularization was the development of a desmoplastic matrix of mouse origin. Continuously invaded by SPC111 cells, this matrix transformed into intratumoral connective tissue trunks, providing a route for ES from the diaphragm.
Conclusions: Here, we report two distinct growth patterns of orthotopically implanted human MPM xenografts. In the invasive pattern, MPM cells invade and thus co-opt peritumoral capillary plexuses. In the pushing/desmoplastic pattern, MPM cells induce a desmoplastic response within the underlying tissue which allows the ingrowth of a nutritive vasculature from the pleura.

Keywords:  Mesothelioma; angiogenesis; orthotopic mouse model of mesothelioma; vascularization

DOI:  https://doi.org/10.21037/tlcr-21-828
Biomed Rep. 2022 Aug;17(2): 66

Clinical significance of 9P21 gene combined with BAP1 and MTAP protein expression in diagnosis and prognosis of mesothelioma serous effusion.

Guan-Ying Ma, Shuai Shi, Ping Wang, Xing-Guang Wang, Zhi-Gang Zhang.

  The diagnostic value of the 9P21 gene determined using fluorescence in situ hybridization (FISH) combined with BRCA1-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) expression detection by immunohistochemistry, was investigated in serous effusion samples of malignant mesothelioma. A total of 70 serous disease samples with serous effusion were collected from June 2017 to June 2020. Following biopsy specimen pathological diagnosis, samples were divided into malignant mesothelioma and benign mesothelioma. Differential expression of BAP1 and MTAP genes were identified in mesothelioma and mesenchymal hyperplasia. The 9P21 gene fragment was lost in mesothelioma. The positive rates of FISH, BAP1 and MTAP in biopsy specimens were 98.00, 94.00 and 90.00%. The specificity of the three were 96.00, 85.71 and 77.27%, the sensitivity were 90.00, 95.92 and 93.75%, and the positive rate of the combined detection of the three was 93.33%. The positive rate of serous fluid samples detected by the three methods (9P21 FISH probe combined with BAP1 and MTAP expression detected immunohistochemically) was 96.00, 92.00 and 88.00%, the specificity were 90.00, 77.27 and 71.43%, the sensitivity was 96.00, 93.75 and 89.80%, and the positive rate of the three combined detections was 91.33%. It was demonstrated that there was a high consistency between serous fluid samples and biopsy samples. According to clinicopathological analysis, sex, age, lesion site, Ki67 had little association with the occurrence and development of malignant mesothelioma, while asbestos exposure history was closely associated to the occurrence of mesothelioma. A high level of BAP1 gene was positively associated with the prognosis of mesothelioma, while a high level of MTAP gene was negatively associated with the prognosis of mesothelioma (P<0.05). Therefore, 9P21 FISH probe combined with BAP1 and MTAP can be used as a new method for the detection of malignant mesothelioma, and provide an important basis for the early diagnosis of mesothelioma.

Keywords:  expression; fluorescence in situ hybridization; malignant mesothelioma; prognosis; serous cavity effusion

DOI:  https://doi.org/10.3892/br.2022.1549
BMJ Open Respir Res. 2022 Jul;pii: e001312. [Epub ahead of print]9(1):

Understanding clinical decision-making in mesothelioma care: a mixed methods study.

Catherine Henshall, Paul Dawson, Najib Rahman, Hannah Ball, Anand Sundralingam, Mitra Shahidi, Edward McKeown, John Park, Helen Walthall, Zoe Davey.

   INTRODUCTION: Malignant pleural mesothelioma is a rare, incurable cancer arising from previous asbestos exposure; patients have a poor prognosis, with a median survival rate of 8-14 months. Variation in mesothelioma clinical decision-making remains common with a lack of multidisciplinary knowledge sharing, leading to inconsistencies in treatment decisions. The study aimed to explore which factors impacted on clinicians' decision-making in mesothelioma care, with a view to optimising the mesothelioma care pathway.
METHODS: This mixed methods study consisted of documentary analysis of local and national guidelines, policies or documents pertaining to mesothelioma care pathways, secondary analysis of mesothelioma patient data, and interviews with clinicians attending lung cancer and/or mesothelioma-specific multidisciplinary team meetings. The study took place at three National Health Service trusts in England. Documentations relating to patients' treatment pathways were collated and reviewed qualitatively. Records of patients with mesothelioma were extracted from hospital patient records and data collected on diagnosis date, treatment, mortality rates, survival postdiagnosis, age and clinical care team. Data were statistically analysed. Interviews with clinicians explored influences on clinical decision-making, including challenges or barriers involved. Data were thematically analysed. The Strengthening the Reporting of Observational Studies in Epidemiology reporting checklist was used.
RESULTS: There were differences in the structure and delivery of mesothelioma treatment and care between trusts. Four main themes were identified: 'collaboration and communication', 'evidence base and knowledge', 'role of the clinician' and 'role of the patient'. Two cross-cutting themes relating to the role of the mesothelioma nurse specialist and the impact of COVID-19 were identified.
DISCUSSION: There is a need to review the structure of mesothelioma multidisciplinary team meetings to ensure patients are reviewed by clinicians with appropriate knowledge, expertise and understanding of how, why and when decisions should be made. There is a need for expert clinicians in mesothelioma care to promote an up-to-date evidence and knowledge base within the wider multidisciplinary team.

Keywords:  Asbestos Induced Lung Disease; Mesothelioma; Palliative Care; Pleural Disease; Rare lung diseases

DOI:  https://doi.org/10.1136/bmjresp-2022-001312
Eur J Cancer. 2022 Jul 11. pii: S0959-8049(22)00371-9. [Epub ahead of print]172 357-366

Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma.

Daphne W Dumoulin, Luca Cantini, Robin Cornelissen, Madelief Vink, Larissa Klaase, Kick Sloof, Nura Tebayna, Joanne M Mankor, Sara J Baart, Rudi Hendriks, Anne-Marie C Dingemans, Marcella Willemsen, Joachim G J V Aerts.

   PURPOSE: Lurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet.
PATIENTS AND METHODS: Clinical data of patients with SCLC and MPM who were treated with lurbinectedin were prospectively collected. Comprehensive immune cell profiling by flow cytometry was performed on screening and treating peripheral blood samples.
RESULTS: A total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as ≥3-line of therapy. In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95% CI: 1.4-3.0), and median overall survival was 7.0 months (95% CI: 4.7-not reached). Objective radiological response and disease control rate after 12 weeks were 16% and 28%, respectively. In the MPM cohort, median progression-free survival was 2.8 months (95% CI: 1.4-4.2), and median overall survival was 7.2 months (95% CI: 5.9-not reached). Disease control rate after 12 weeks was 29%, whereas no partial responses were registered. No new safety signals were observed. Lurbinectedin treatment was significantly associated with the depletion of circulating classical monocytes, which correlated with a better PFS in patients with SCLC. Lurbinectedin increased the proliferation of CD4+ and CD8+ T cells (SCLC) and natural killer and natural killer T cells (SCLC and MPM) and altered co-stimulatory and co-inhibitory receptor expression on circulating lymphocytes.
CONCLUSION: Lurbinectedin has a manageable safety profile and shows clinical activity in pre-treated patients with SCLC and MPM. Its immune-modulatory functions make lurbinectedin a potential platform for immunotherapy combinations.

Keywords:  Lurbinectedin; immune monitoring; immunotherapy; malignant pleural mesothelioma/MPM; small cell lung cancer/SCLC

DOI:  https://doi.org/10.1016/j.ejca.2022.06.020