Mesothelioma is an aggressive tumor originating from the mesothelial cells of the pleural or peritoneal cavity. This thesis focuses on the treatment of pleural mesothelioma. For long, chemotherapy... Show moreMesothelioma is an aggressive tumor originating from the mesothelial cells of the pleural or peritoneal cavity. This thesis focuses on the treatment of pleural mesothelioma. For long, chemotherapy has been the standard of care, leading to an overall survival of about 15 months. In this thesis, a phase 2 trial is performed using two checkpoint inhibitors, nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4), to treat recurrent mesothelioma after at least one line of chemotherapy. Of the 34 patients evaluable for response 29% had a partial response and 38% patients had stable disease, so 68% of patients achieved disease control, the primary endpoint. These results exceeded expectations and rejected the alternative hypothesis. In part III translational research was performed on blood samples, pleural biopsies and breath analyses at baseline and after 6 weeks of treatment. In order to find markers of response and try to explain how immunotherapy affects the tumor microenvironment and immune cell subsets of the peripheral blood. Show less
Carbone, M.; Pass, H.I.; Ak, G.; Alexander, H.R.; Baas, P.; Baumann, F.; ... ; Hassan, R. 2022
The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently,... Show moreThe most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact. (C) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. Show less
Introduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other... Show moreIntroduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.Methods: Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.Results: Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.Conclusions: Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. Show less
Malignant mesothelioma is a cancer, often originating from the pleura of the chest. There are no curative treatment options and systemic palliative treatments are scarce. It is suspected that the... Show moreMalignant mesothelioma is a cancer, often originating from the pleura of the chest. There are no curative treatment options and systemic palliative treatments are scarce. It is suspected that the growth process in mesothelioma is highly dependent on the creation of new vessels stimulated by the tumour itself, also called angiogenesis. In this thesis, 2 drugs that inhibit angiogenesis were tested aiming at improving progression-free survival (PFS). Thalidomide was given as a maintenance treatment after first-line chemotherapy in a large randomised study. Axitinib was given in combination with first-line chemotherapy in a smaller randomised trial, in which we included pre- and post-treatment biopsies. The vascularisation of the tumour and the possible influence of vascular growth factors were examined. In the translational part of this study, we showed that axitinib treatment efficiently prevented tumour neovascularisation. However, this did not improve PFS. The thalidomide study also showed no benefit in PFS or survival. Meanwhile the literature has shown that many angiogenesis inhibitors do not achieve a positive result either. We will have to look for other treatment options to improve the prognosis of mesothelioma patients. Show less
Malignant pleural mesothelioma (MPM) is a cancer of the pleura with few treatment options and an infaust prognosis. We developed a short-term primary tumor culture model from tumor cells derived... Show moreMalignant pleural mesothelioma (MPM) is a cancer of the pleura with few treatment options and an infaust prognosis. We developed a short-term primary tumor culture model from tumor cells derived from pleural fluid of MPM patients and performed drug screening on these cultures to guide treatment decisions of corresponding patients. We observed a high concordance between in vitro results and clinical outcomes and defined three subgroups responding differently to the anti-cancer drugs tested. Gene expression profiling yielded distinct signatures that segregated these subgroups and demonstrated that the fibroblast growth factor pathway was most prominently involved. Pharmacogenomic profiling revealed a subgroup of immortalized and primary MPM lines that appeared highly sensitive to FGFR inhibition. BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples. Furthermore, 34 patients were treated in a clinical trial with nivolumab which demonstrated meaningful clinical efficacy and a manageable safety profile in pretreated patients with mesothelioma. PD-L1 expression did not predict for response in this population. Show less
Nicholson, A.G.; Sauter, J.L.; Nowak, A.K.; Kindler, H.L.; Gill, R.R.; Remy-Jardin, M.; ... ; Galateau-Salle, F. 2020
Introduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where... Show moreIntroduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes.Methods: A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification.Results: Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.Conclusions: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Show less
Buikhuisen, W.A.; Scharpfenecker, M.; Griffioen, A.W.; Korse, C.M.; Tinteren, H. van; Baas, P. 2016
After the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or... Show moreAfter the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or progression. We conducted a systematic review of the literature for the activity, effectiveness and toxicity of second line treatment. The results are presented according to the class of drugs: chemotherapy and targeted or biological agent. (C) 2015 Elsevier Ireland Ltd. All rights reserved. Show less
