Lung Cancer

About the journal

Publisher: Elsevier Scientific Publishers
Published: 1985 to the present, Ireland
Language: English
ISSN: 0169-5002 (print), 1872-8332 (electronic)
Its record in the NLM Catalog

2020s

Epidermal growth factor receptor-targeted near-infrared photoimmunotherapy for malignant pleural mesothelioma. M. Kano, A. Furusawa, S. Takao, et al. 2026;217:109427. PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer mostly associated with asbestos exposure. Effective treatments are limited, and the prognosis is extremely poor. Therefore, the development of novel therapeutic approaches is highly desirable. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that specifically kills target cells. It utilizes an antibody-IRDye700DX conjugate that binds target tumor cells. After near-infrared light irradiation of the tumor, rapid and highly selective cell damage results in immunogenic cell death. Anti-epidermal growth factor receptor (EGFR) antibody-IRDye700DX conjugate has already been approved in Japan for the treatment of head and neck cancer with near-infrared laser light activation. EGFR overexpression in MPM makes it a promising candidate for EGFR-targeted NIR-PIT, but its efficacy has not been reported previously. In this study, we investigated the therapeutic effects of NIR-PIT targeting EGFR using an MPM xenograft mouse model. In vitro, three MPM cell lines (NCI-H28, NCI-H226, and MSTO-211H) showed EGFR overexpression on the cell surface. EGFR-targeted NIR-PIT induced cell death in a dose-dependent manner in all MPM cell lines. In vivo, EGFR expression was verified, and anti-EGFR antibody binding was observed in both NCI-H226 and MSTO-211H tumors. After EGFR-targeted NIR-PIT, histological analysis demonstrated cancer cell death which significantly suppressed tumor growth in both tumor models and significantly extended survival in NCI-H226 tumor-bearing mice. Thus, these results suggest that EGFR-targeted NIR-PIT could be a promising treatment approach for MPM.

Published by Elsevier B.V.
A multidisciplinary review of several aspects of Asbestos-Related Lung Cancer (ARLC). N. van Zandwijk, A.L. Frank. 2024;189:107474. Editorial PubMed · Publisher
Asbestos history and use. A.L. Frank, N. van Zandwijk. 2024;193:107828. Historical article · Review PubMed · Publisher

Abstract

All six fiber types called asbestos can cause all the diseases related to exposure, including lung cancer. Known to the ancients, the modern history of asbestos hazards started in the 1890s with more and more data accumulating over time. Use increased exponentially in the middle of the 20th century with major use coming in construction and ship building. The recognition of asbestos as causing lung cancer dates to the early 1940s.

Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.
Asbestos Surveillance Program Aachen (ASPA): Cancer mortality among asbestos exposed power industry workers. N. Otte, E. Fraune, Y. Cetiner, et al. 2024;195:107899. PubMed · Publisher

Abstract

Background: The time between initial asbestos exposure and asbestos-related disease can span several decades. The Asbestos Surveillance Program aims to detect early asbestos-related diseases in a cohort of 8,565 power industry workers formerly exposed to asbestos.

Research Question: How does asbestos exposure patterns affect cancer mortality and the duration of latency until death?

Methods: A mortality follow-up was conducted with available vital status for 8,476 participants (99 %) and available death certificates for 89.9 % of deceased participants. Standardised mortality ratios (SMR) were calculated for asbestos-related cancers. The SMR of mesothelioma and lung cancer were stratified by exposure duration, cumulative asbestos exposure and smoking. The effect of age at first exposure, cumulative asbestos exposure and smoking on the duration of latency until death was examined using multiple linear regression analysis.

Results: The mortality risk of mesothelioma (n = 104) increased with cumulative asbestos exposure but not with exposure duration; the highest mortality (SMR: 23.20; 95 % CI: 17.62-29.99) was observed in participants who performed activities with short extremely high exposures (steam turbine revisions). Lung cancer mortality (n = 215) was not increased (SMR: 1.03; 95 % CI: 0.89-1.17). Median latency until death was 46 (15-63) years for mesothelioma and 44 (15-70) years for lung cancer and deaths occurred between age 64 and 82 years. Latency until death was not influenced by age at first exposure, cumulative exposure, or smoking.

Conclusion: Cumulative dose seems to be more appropriate than exposure duration for estimating the risk of mesothelioma death. Additionally, exposure with high cumulative doses in short time should be considered. Since only lung cancer mortality, not incidence, was recorded in this study, lung cancer risk associated with asbestos exposure could not be assessed and the lung cancer mortality was lower than expected probably due to screening effects and improved treatments. The critical time window of death from asbestos-related cancer is between the seventh and ninth decade of life. Future studies should further explore the concept of latency, especially since large ranges are reported throughout the literature.

Copyright © 2024. Published by Elsevier B.V.
Asbestos-Related lung Cancer: An underappreciated oncological issue. N. van Zandwijk, A.L. Frank, G. Reid, et al. 2024;194:107861. Review PubMed · Publisher

Abstract

Asbestos, a group of class I (WHO) carcinogenic fibers, is the main cause of mesothelioma. Asbestos inhalation also increases the risk to develop other solid tumours with lung cancer as the most prominent example [91]. The incidence of asbestos-related lung cancer (ARLC) is estimated to be to six times larger than the mesothelioma incidence thereby becoming an important health issue [86]. Although the pivotal role of asbestos in inducing lung cancer is well established, the precise causal relationships between exposures to asbestos, tobacco smoke, radon and 'particulate' (PM2.5) air pollution remain obscure and new knowledge is needed to establish appropriate preventive measures and to tailor existing screening practices[22,61,65]. We hypothesize that a part of the increasing numbers of lung cancer diagnoses in never-smokers can be explained by (historic and current) exposures to asbestos as well as combinations of different forms of air pollution (PM2.5, asbestos and silica).

Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.
Circulating tumor cell detection may offer earlier diagnosis in patients suspected of asbestos-related lung cancer. H. Ke, S. Kao, N. van Zandwijk, et al. 2024;192:107829. PubMed · Publisher

Abstract

Asbestos-Related Lung Cancer (ARLC) presents ongoing diagnostic challenges despite improved imaging technologies. The long latency period, coupled with limited access to occupational and environmental data along with the confounding effects of smoking and other carcinogens adds complexity to the diagnostic process. Compounding these challenges is the absence of a specific histopathologic or mutational signature of ARLC. A correlation between PD-L1 expression and response to immune checkpoint inhibition has not yet been proven. Thus, new biomarkers are needed to allow accurate diagnoses of ARLC, to enable prognostication and to offer personalized treatments. Liquid biopsies, encompassing circulating DNA and circulating tumor cells (CTCs), have gained attention as novel diagnostic methods in lung cancer to screen high-risk populations including those exposed to asbestos. CTCs can be enumerated and molecularly profiled to provide predictive and prognostic information. CTC studies have not been undertaken in populations at risk of ARLC to date. The potential of CTCs to provide real-time molecular insight into ARLC biology may significantly improve the diagnosis and management of ARLC patients.

Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.
Environmental asbestos exposure and lung cancer. M. Metintas, G. Ak, S. Metintas. 2024;194:107850. Review PubMed · Publisher

Abstract

Apart from living near an asbestos industry site, mine, or in an asbestos-contaminated house, environmental asbestos exposure is observed in certain regions where the (natural) soil is 'contaminated' with asbestos (fibers). In this essay, we review the association between environmental asbestos exposure and lung cancer in Turkey. Other studies have also suggested that environmental asbestos exposure is able to increase the risk of lung cancer. Lung cancer associated with environmental asbestos exposure seems to be diagnosed at a younger age, and the risk for women is in the same range as that for men. Our data indicate that the relationship between exposure dose and risk is linear and that a safe threshold cannot be established. Therefore, people living in areas with increased chances of environmental asbestos exposure should be mentored to take part in smoking cessation programs and considered candidates for inclusion in lung cancer screening programs. There is an obvious need for additional studies on this topic.

Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.
Lung cancer caused by asbestos: What a reporting pathologist needs to know. S. Klebe, V. Rathi, P.A. Russell. 2024;195:107849. Review PubMed · Publisher

Abstract

Asbestos is a carcinogen that can cause lung cancer. The suspicion that a lung cancer diagnosis may be associated with exposure to asbestos has no bearing on treatment. However, attributing an individual's lung cancer to asbestos exposure has important medicolegal implications and may impact public health measures and policy. Simultaneous exposure(s) to other carcinogens (such as tobacco smoke, silica and many others) adds complexity while trying to answer the causation question. The Helsinki criteria were formulated to assist attributing lung cancer to previous asbestos exposure. Surrogate markers can be used and include signs of asbestosis and pleural plaques. The most widely used criterion for the presence of asbestosis is interstitial fibrosis in conjunction with 2 or more asbestos bodies/1 cm2 tissue section by light microscopy. Identification of asbestos bodies ty light pr electron microscopy provides an important element for asbestos diagnosis. However, fibrosis may be subtle, and the distribution of asbestos bodies is not uniform throughout the lungs, some types of asbestos fibres have low biopersistence, and not all types of asbestos readily form asbestos bodies. Additional criteria require knowledge of exposure history, which is often unknown to pathologists, but reliance on morphology in isolation may lead to mis-classification of interstitial lung disease as idiopathic. While a smoking-related lung cancer signature has emerged, an asbestos-related lung cancer signature has not yet been identified. In this review we will discuss practice points for the surgical pathologist.

Copyright © 2024. Published by Elsevier B.V.
Lung cancer screening - Time for an update?. H.M. Marshall, K.M. Fong. 2024;196:107956. Review PubMed · Publisher

Abstract

Lung cancer screening can reduce the mortality of lung cancer, the leading cause of cancer death worldwide. Real world screening experience highlights areas for improvement in a complex and changing world, particularly ethnic disparity, and the potential for new and emerging risk factors, in addition to well known risk of smoking and asbestos exposure. Biomarkers offer the promise of objective risk assessment but are not yet ready for clinical practice. This review discusses some of the major issues faced by lung cancer screening and the potential role for biomarkers.

Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.
Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma. A.S. Mansfield, J. Vivien Yin, P. Bradbury, et al. 2024;195:107928. Randomized trial PubMed · Publisher · Free full text

Abstract

Purpose: The mesothelin-targeting antibody-drug conjugate anetumab ravtansine was evaluated in combination with the programmed cell death-1 (PD-1) inhibitor pembrolizumab based on the common expression of mesothelin and reports of activity in mesothelioma.

Patients And Methods: A phase 1 safety run-in of the combination of anetumab ravtansine (6.5 mg/kg iv q3weeks) and pembrolizumab (200 mg, IV q3weeks) was conducted, followed by a phase 2 randomization to the combination or pembrolizumab alone at medical centers across the United States and Canada in the National Cancer Institute's Experimental Therapeutics Clinical Trials Network. Patients with pleural mesothelioma that expressed mesothelin and had previously received platinum-based therapy were eligible.

Results: In phase 1 (n = 12) only one dose limiting toxicity was observed and the rules for dose reduction were not met. In phase 2, there was no difference in the confirmed response rates between the combination group (n = 18, 2 partial responses [PR], 11 %) and the pembrolizumab group (n = 17, 1 PR, 6 %; z = -0.5523, p = 0.29116). The median PFS was 12.2 months (95 % CI 5.1-not evaluable [NE]) for the combination, and 3.9 months for pembrolizumab (95 % CI 2.1-NE)(HR=0.55, p = 0.20). Patients with high baseline levels of soluble mesothelin who received anetumab ravtansine had a median PFS of 5 months.

Conclusions: The numeric difference in PFS between treatment groups was not statistically significant, likely related to a smaller than planned sample size. High levels of soluble mesothelin should potentially be considered to select against the use of mesothelin-targeting therapies in development that are neutralized by soluble mesothelin.

Copyright © 2024 Elsevier B.V. All rights reserved.
Resolving asbestos and ultrafine particulate definitions with carcinogenicity. S.M. Fitzgerald. 2024;189:107478. PubMed · Publisher

Abstract

As asbestos fibers and other fine particles have been studied extensively to correlate physical and chemical properties with their potential for negative human health impact on inhalation, there remains no concise definitions for the individual particle types nor collective considerations of combined variabilities. Extensive studies relating negative health to asbestos morphology, chemistry, surface effects, and biodurability form general qualitative bins of what is more likely causative or less, but do not provide enough information to quantitatively dismiss particles with parameters outside any given range. Further, natural mineral species and accessory mineralization makes standardization of universally applicable reference materials nearly unobtainable. With modern advent of engineered nanoparticles, we are adding even more unknowns to the universe of the microscopic size fraction and its potential for human disease, and our paradigm is challenged.

Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.
Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation. A. Tada, T. Minami, H. Kitai, et al. 2023;180:107219. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.

Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
New pathogenic germline variants identified in mesothelioma. L. Belcaid, B. Bertelsen, K. Wadt, et al. 2023;179:107172. Review PubMed · Publisher

Abstract

Background: Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling.

Methods: 44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Germline variants were selected according to association with inherited cancer using a 168-gene in silico panel, and variants classified according to ACMG/AMP classification as pathogenic (class 5) or likely pathogenic (class 4).

Results: In total, 16 patients (36%) were found to carry pathogenic or likely pathogenic variants in 13 cancer associated genes (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The germline PVs occurred in DNA repair pathways, including homologous recombination repair (HRR) (75%), nucleotide excision repair (6%), cell cycle regulatory (7%), base excision repair (6%), and hypoxic pathway (6%). Five (31%) patients with a germline PV had a first or second degree relative with mesothelioma compared to none for patients without a germline PV. Previously undiagnosed BRCA2 germline PVs were identified in two patients. Potential actionable targets based on the germline PVs were found in four patients (9%).

Conclusion: This study revealed a high frequency of germline PVs in patients with mesothelioma. Furthermore, we identified germline PVs in two genes (NBN & RAD51B) not previously associated with mesothelioma. The data support germline testing in mesothelioma and provide a rationale for additional investigation of the HRR pathway as a potential actionable target.

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
Occupational asbestos exposure and survival among lung cancer patients. H. Noelle, O. Pérol, M. Pérol, et al. 2023;179:107182. PubMed · Publisher

Abstract

Objective: This study investigated the association between occupational asbestos exposure (OAE) and survival in patients with histologically confirmed lung cancer (LC).

Methods: This monocentric study was conducted in the Comprehensive Cancer Centre Léon Bérard, Lyon, France. A systematic screening has been in place since 2014 for occupational exposure to carcinogens using a self-assessment questionnaire sent to all patients newly diagnosed with histologically confirmed LC identified through the multidisciplinary LC board from 2014 to 2019. When the physician suspected a work-related exposure from the questionnaire including job history, an occupational cancer consultation was carried out to detail carcinogen exposures and assess if the LC was work-related. Demographics, clinical characteristics and survival data were extracted from medical records. The association between asbestos exposure and overall survival (hazard ratio and 95% confidence intervals) was estimated by Cox proportional hazards regression.

Results: Overall, 702 patients were eligible to the present study, including 180 patients with OAE. In the crude analysis, LCs assessed as moderately or highly attributable to OAE were associated with decreased overall survival (HR = 1.32, 95 %CI 1.04-1.67) compared to LC without OAE or with a low degree of imputability to OAE (median follow-up 28.8 months). After adjustment for confounding (age at diagnosis, smoking status, stage, brain metastasis at diagnosis, and histology), the association of OAE with overall survival was no longer statistically significant (HR = 1.21, 95 %CI 0.94-1.56).

Conclusion: Overall survival in occupationally asbestos exposed LC patients may be decreased in comparison with non-exposed LC patients, warranting further investigations in larger studies.

Copyright © 2023 Elsevier B.V. All rights reserved.
BAP1 germline variants in Finnish patients with malignant mesothelioma. P. Repo, A. Staskiewicz, E. Sutinen, et al. 2022;165:102-107. PubMed · Publisher

Abstract

Objectives: Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1-inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM.

Materials And Methods: 56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing.

Results: Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p.(G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor.

Conclusion: The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has ≥ 2 BAP1-TPDS core tumors, including BINs.

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Geographic distribution of malignant mesothelioma incidence and survival in Australia. J.K. Cameron, J. Aitken, A. Reid, et al. 2022;167:17-24. PubMed · Publisher

Abstract

Objectives: To understand the geographic distribution of and area-level factors associated with malignant mesothelioma incidence and survival in Australia.

Materials And Methods: Generalised linear models and Bayesian spatial models were fitted using population registry data. Area-level covariates were socioeconomic quintile, remoteness category and state or territory. The maximised excess events test was used to test for spatial heterogeneity.

Results: There was strong evidence of spatial differences in standardised incidence rates for malignant mesothelioma but survival was uniformly poor. Incidence rates varied by state or territory and were lower in remote areas. Patterns in the geographic distribution of modelled incidence counts for malignant mesothelioma differed substantially from patterns of standardised incidence rates.

Conclusions: Geographic variation in the modelled incidence counts of malignant mesothelioma demonstrates varying demand for diagnostic and management services. The long latency period for this cancer coupled with migration complicates any associations with patterns of exposure, however some of the geographic distribution of diagnoses can be explained by the location of historical mines and asbestos-related industries.

Copyright © 2022 Elsevier B.V. All rights reserved.
Image-guided interventional radiological delivery of chimeric antigen receptor (CAR) T cells for pleural malignancies in a phase I/II clinical trial. M. Ghosn, W. Cheema, A. Zhu, et al. 2022;165:1-9. PubMed · Publisher · Free full text

Abstract

Objectives: We describe techniques and results of image-guided delivery of mesothelin-targeted chimeric antigen receptor (CAR) T cells in patients with pleural malignancies in a phase I/II trial (ClinicalTrials.gov: NCT02414269).

Materials And Methods: Patients without a pleural catheter or who lack effusion for insertion of a catheter (31 of 41) were administered intrapleural CAR T cells by interventional radiologists under image guidance by computed tomography or ultrasound. CAR T cells were administered through a needle in an accessible pleural loculation (intracavitary) or following an induced loculated artificial pneumothorax. In patients where intracavitary infusion was not feasible, CAR T cells were injected via percutaneous approach either surrounding and/or in the pleural nodule/thickening (intratumoral). Pre- and post-procedural clinical, laboratory, and imaging findings were assessed.

Results: CAR T cells were administered intrapleurally in 31 patients (33 procedures, 2 patients were administered a second dose) with successful delivery of planned dose (10-186 mL); 14/33 (42%) intracavitary and 19/33 (58%) intratumoral. All procedures were completed within 2 h of T-cell thawing. There were no procedure-related adverse events greater than grade 1 (1 in 3 patients had prior ipsilateral pleural fusion procedures). The most common imaging finding was ground glass opacities with interlobular septal thickening and/or consolidation, observed in 12/33 (36%) procedures. There was no difference in the incidence of fever, CRP, IL-6, and peak vector copy number in the peripheral blood between infusion methods.

Conclusion: Image-guided intrapleural delivery of CAR T cells using intracavitary or intratumoral routes is feasible, repeatable and safe across anatomically variable pleural cancers.

Copyright © 2022 Elsevier B.V. All rights reserved.
Imaging in pleural mesothelioma: A review of the 15th International Conference of the International Mesothelioma Interest Group. S.G. Armato, A.K. Nowak, R.J. Francis, et al. 2022;164:76-83. Review PubMed · Publisher

Abstract

Imaging of mesothelioma plays a role in all aspects of patient management, including disease detection, staging, evaluation of treatment options, response assessment, pre-surgical evaluation, and surveillance. Imaging in this disease impacts a wide range of disciplines throughout the healthcare enterprise. Researchers and clinician-scientists are developing state-of-the-art techniques to extract more of the information contained within these medical images and to utilize it for more sophisticated tasks; moreover, image-acquisition technology is advancing the inherent capabilities of these images. This paper summarizes the imaging-based topics presented orally at the 2021 International Conference of the International Mesothelioma Interest Group (iMig), which was held virtually from May 7-9, 2021. These topics include an update on the mesothelioma staging system, novel molecular targets to guide therapy in mesothelioma, special considerations and potential pitfalls in imaging mesothelioma in the immunotherapy setting, tumor measurement strategies and their correlation with patient survival, tumor volume measurement in MRI and CT, CT-based texture analysis for differentiation of histologic subtype, diffusion-weighted MRI for the assessment of biphasic mesothelioma, and the prognostic significance of skeletal muscle loss with chemotherapy.

Copyright © 2021 Elsevier B.V. All rights reserved.
A reply to "managing oligoprogressive malignant pleural mesothelioma with stereotactic body radiation therapy". G.L. Ceresoli, P. Ghirardelli, D. Franceschini, et al. 2021;157:165-166. Letter · Comment PubMed · Publisher
CAR T-cell therapy for pleural mesothelioma: Rationale, preclinical development, and clinical trials. N.K. Chintala, D. Restle, H. Quach, et al. 2021;157:48-59. Review PubMed · Publisher · Free full text

Abstract

The aim of adoptive T-cell therapy is to promote tumor-infiltrating immune cells following the transfer of either tumor-harvested or genetically engineered T lymphocytes. A new chapter in adoptive T-cell therapy began with the success of chimeric antigen receptor (CAR) T-cell therapy. T cells harvested from peripheral blood are transduced with genetically engineered CARs that render the ability to recognize cancer cell-surface antigen and lyse cancer cells. The successes in CAR T-cell therapy for B-cell leukemia and lymphoma have led to efforts to expand this therapy to solid tumors. Herein, we discuss the rationale behind the preclinical development and clinical trials of T-cell therapies in patients with malignant pleural mesothelioma. Furthermore, we highlight the ongoing investigation of combination immunotherapy strategies to synergistically potentiate endogenous as well as adoptively transferred immunity.

Copyright © 2021 Elsevier B.V. All rights reserved.
Comparative effectiveness of second-line immune checkpoint inhibitor therapy versus chemotherapy for malignant pleural mesothelioma. R.Y. Kim, Y. Li, M.E. Marmarelis, et al. 2021;159:107-110. PubMed · Publisher · Free full text

Abstract

Objectives: Second-line immune checkpoint inhibition (ICI) was recently shown to have a survival advantage over placebo in malignant pleural mesothelioma (MPM), but the survival comparison to chemotherapy in patients with MPM receiving routine clinical care is unknown. Our objective was to examine the effectiveness of second-line ICI versus chemotherapy on overall survival (OS) outcomes in real-world patients with advanced MPM.

Materials And Methods: We performed a multicenter retrospective cohort study of real-world adult patients with advanced MPM who received first-line platinum-based chemotherapy and at least two total lines of systemic therapy. Patients received either second-line chemotherapy (gemcitabine and/or vinorelbine) or ICI therapy (pembrolizumab or nivolumab ± ipilimumab). The primary outcome was OS, defined as the time from second-line therapy initiation to death or end of the observation period. We used Kaplan-Meier methods and Cox proportional hazards modeling with adjustment for relevant patient demographic and clinical variables to compare OS between the two second-line treatment groups.

Results: Of the 176 patients with MPM, the median age was 75 years (IQR: 69-79.5 years), and most were white (77%), male (74%), and had epithelioid histology (67%). Thirty-five percent (61) received second-line chemotherapy and 65% (115) ICI therapy (80 pembrolizumab, 31 nivolumab, and 4 nivolumab + ipilimumab). Treatment with ICI was associated with significantly longer median OS compared to chemotherapy (8.7 vs 5.0 months, p=0.001; adjusted hazard ratio: 0.52, 95% CI: 0.34-0.81). The estimated 12-month OS probability was 36.7% (95% CI: 27.6%-45.8%) and 15.6% (95% CI: 7.7%-26.1%) in the ICI and chemotherapy groups, respectively.

Conclusion: In this "real-world" population of patients with MPM, treatment with ICI was associated with improved OS outcomes compared to chemotherapy in the second-line setting, in contrast with a recent clinical trial. Our findings suggest that ICI may benefit patients with advanced MPM and progression after initial platinum-based chemotherapy.

Copyright © 2021 Elsevier B.V. All rights reserved.
CT for detection of malignant posterior intercostal lymph nodes in patients undergoing pre-operative staging for malignant pleural mesothelioma. I. Berger, S. Simpson, J.S. Friedberg, et al. 2021;152:34-38. PubMed · Publisher · Free full text

Abstract

Introduction: Recent evidence suggests that patients with malignant pleural mesothelioma (MPM) undergoing extended pleurectomy/decortication (eP/D) with metastasis to the posterior intercostal lymph nodes (PILN) have a worse prognosis. In this study, we determine if MPM PILN metastasis can be reliably detected on computed tomography (CT).

Materials And Methods: Preoperative staging CT exams were reviewed for the presence of PILN in MPM patients undergoing eP/D between 2007-2013 with surgical sampling of their PILN. CT images were reviewed by two thoracic radiologists blinded to clinical records, including operative pathology reports. The number and short axis size of PILN were recorded and correlated with surgical pathology. Statistical analysis examined the value of preoperative CT to detect metastatic PILN.

Results: Of 36 patients that underwent eP/D with PILN sampling had preoperative CT images for review. At surgery, 22 of these patients had metastatic PILN and 14 had benign PILN. The positive and negative predictive values for one or more nodes seen on preoperative CT were 60 % and 38 % respectively. The number of PILN on preoperative CT did not predict metastasis (p = 0.40) with an average of 2 PILN seen, regardless of PILN pathology. The average nodal short axis size was 4.6 mm and 4.8 mm for benign and malignant PILN, respectively, and PILN short axis size did not predict metastasis (p = 0.39). There was little inter-observer variability between the size and number of nodes detected by each radiologist.

Conclusions: CT does not reliably identify metastatic PILN on preoperative CT for patients with MPM undergoing extended pleurectomy/decortication.

Copyright © 2020 Elsevier B.V. All rights reserved.
Development of unenhanced CT-based imaging signature for BAP1 mutation status prediction in malignant pleural mesothelioma: Consideration of 2D and 3D segmentation. X.J. Xie, S.Y. Liu, J.Y. Chen, et al. 2021;157:30-39. PubMed · Publisher

Abstract

Objectives: We aimed to explore the feasibility of 2D and 3D radiomics signature based on the unenhanced computed tomography (CT) images to predict BRCA1-associated protein 1 (BAP1) gene mutation status for malignant pleural mesothelioma (MPM) patients.

Materials And Methods: 74 patients with MPM were retrospectively enrolled (22 mutant BAP1, 52 wild-type BAP1 demonstrated by Sanger sequencing). The radiomic features were extracted respectively from the 2D and 3D segmentation of unenhanced pre-treatment CT images, and the dataset was randomly divided into training (n = 51) and test (n = 23) sets for radiomics model development and internal validation. The synthetic minority over-sampling technique (SMOTE) was used for data balancing in the training set. 2D or 3D features were sequentially selected by ICC > 0.8, correlation analysis (cut-value 0.7), univariate analysis or univariate logistic regression (LR), which were involved into multivariate LR for LR model construction. Following the comparison of the 2D and 3D models by the ROC analysis and Delong test for AUC, the calibration and clinical utility of 2D and 3D models were evaluated.

Results: 3D radiomic features showed better ICCs compared with 2D in both intra- (P < 0.001) and inter-observer (P < 0.001) analysis. 3D radiomic model based on selected features developed from a balanced training dataset presented a favorable predictive performance with AUC of 0.786 and 0.768 in the training and test sets, respectively. The predictive performance of 3D model was superior to 2D model (1 feature) both in the training (AUC 0.786 vs. 0.683, P = 0.036) and the test (AUC 0.768 vs.0.652, P = 0.441) set. The calibration curve and decision curves also indicate a better BAP1 prediction performance and clinical benefit for 3D model than that of 2D model.

Conclusion: The developed unenhanced CT-based 3D radiomics signature is potential as a noninvasive marker for predicting BAP1 mutation status.

Copyright © 2021. Published by Elsevier B.V.
Haematological toxicity of pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung with third-space fluid. W.C. Kwok, T.F. Cheong, K.Y. Chiang, et al. 2021;152:15-20. PubMed · Publisher

Abstract

Background: Pemetrexed was approved by United States Food and Drug Administration (US FDA) in combination with platinum for the treatment of advanced non-squamous non-small cell lung carcinoma (NSCLC) and malignant mesothelioma. Due to the structural similarity with methotrexate, there has been concern about the accumulation of pemetrexed in third space fluid that may result in increased toxicity. Previous small-scale studies have yet to conclusively prove this association.

Methods: This was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 329 patients with advanced stage non-squamous NSCLC that received first line pemetrexed and platinum. Patients who had non-evacuated third-space fluid, evacuated third-space fluid and without third-space fluid were compared. The primary endpoint was the occurrence of hematological toxicity.

Results: The presence of non-evacuated third-space fluid was shown to be associated with significantly more hematological toxicities, namely grade 3 or above hematological toxicities [Odd ratio (OR) = 2.450, p = 0.002], postponement of chemotherapy (OR = 3.837, p = 0.000) and need for dose adjustment (OR = 2.436, p = 0.022) when compared with those without third-space fluid. For patients with evacuated third-space fluid, these adverse effects were nullified.

Conclusions: Presence of non-evacuated third-space fluid in patients with advanced non-squamous NSCLC predispose patients to significant hematological toxicity when pemetrexed and platinum chemotherapy is used. Evacuation of third-space fluid should be considered before starting pemetrexed and platinum doublet.

Copyright © 2020 Elsevier B.V. All rights reserved.
Immune checkpoint inhibitor therapy for malignant pleural mesothelioma. A.K. Nowak, W.L. Chin, S. Keam, et al. 2021;162:162-168. Review PubMed · Publisher

Abstract

Mesothelioma is a rare and universally fatal cancer linked to exposure to asbestos. Until recently, standard of care treatment was chemotherapy; a treatment resulting in a minimal survival extension, and not improved upon for almost twenty years. However, the advent of cancer immunotherapy - and in particular the immune checkpoint inhibitor class of drugs - has resulted in recently approved new treatment options, with more currently under investigation. Here, we review clinical trials of both single agent and combination checkpoint inhibitors in mesothelioma, plus studies investigating their combination with chemotherapy. We also describe current advances in biomarker identification regarding prediction of patient response to checkpoint inhibitors. Finally, we assess the probable future direction of the field; including where current and developing technologies are likely to lead - in terms of both biomarker discovery and treatment options.

Copyright © 2021. Published by Elsevier B.V.
Letter to the Editor: Comment on 'Malignant pleural mesothelioma: Comparison of surgery-based trimodality therapy to medical therapy at two tertiary academic institutions'. 2021;159:127. Letter PubMed · Publisher
Malignant pleural mesothelioma: Comparison of surgery-based trimodality therapy to medical therapy at two tertiary academic institutions. F. Larose, N. Quigley, Y. Lacasse, et al. 2021;156:151-156. PubMed · Publisher

Abstract

Objectives: Medical management based on palliative chemotherapy is currently the standard of care in malignant pleural mesothelioma (MPM). Median survival of 12-16 months has been reported with modern chemotherapy regimens with or without anti-angiogenic agents. Multimodality therapy incorporating cytoreductive surgery, systemic chemotherapy and radiotherapy has been offered for years to fit patients with early-stage disease, but its role remains debated. Our objective was to compare overall survival in patients offered multimodality therapy in a specialized clinic setting in London, UK to that of patients offered exclusively medical treatment at another academic institution in Quebec, Canada.

Materials And Methods: We retrospectively compared the survival rates of 2 separate cohorts of patients treated consecutively: Cohort 1 (n = 106) received multimodality therapy including systemic chemotherapy, extended pleurectomy/decortication (P/D) and prophylactic radiotherapy in London (United Kingdom) between 2009 and 2016, while Cohort 2 (n = 98) received medical treatment at the Quebec Heart and Lung Institute (Canada) during the same period.

Results: In Cohort 1, all patients but two completed trimodality therapy. In cohort 2, 51 % received palliative care only and 40 % received systemic chemotherapy. Median survival was 32 months vs 10 months in Cohort 1 and Cohort 2, respectively (hazard ratio with age, gender, pathology and TNM staging as covariates: 3.81; 95 % CI: 2.67-5.45; p < 0.0001). Similar results were obtained in sensitivity analyses, after excluding those who received best supportive care only and in a propensity score-matched analysis.

Conclusion: Aggressive therapy of MPM using cancer-directed surgery, systemic chemotherapy and prophylactic radiotherapy may provide a significant survival benefit in selected patients.

Copyright © 2021 Elsevier B.V. All rights reserved.
Managing oligoprogressive malignant pleural mesothelioma with stereotactic body radiation therapy. A.R. Barsky, N. Yegya-Raman, S.I. Katz, et al. 2021;157:163-164. Letter · Comment PubMed · Publisher

Summary

In this letter, the authors responded to a multi-institutional study by Ghirardelli et al. of hypofractionated focal radiotherapy for oligoprogressive malignant pleural mesothelioma (MPM). That study reported 6- and 12-month local control (LC) rates of 84% and 76%, which the authors noted were lower than rates reported for stereotactic body radiation therapy (SBRT) in non-small cell lung cancer and lung metastases. They reviewed their own unpublished institutional series. Fifteen patients with histologically confirmed MPM were treated between 2012 and 2020 with pleural SBRT to 25 lesions for oligoprogressive disease after systemic therapy with or without surgery. Most were male (80%), all were Caucasian, and 87% had epithelioid histology. Median age was 68 years. The median prescribed dose was 40 Gy (range 30–50 Gy) in 5 fractions. At a median follow-up of 13.2 months there were two local failures, at 34.9 and 39.5 months. LC rates at 6, 12, 24, 36 and 48 months were 100%, 100%, 100%, 87.5% and 75%. Median time to further systemic therapy was 10.9 months, and there were no Grade 3 or higher SBRT-related toxicities. The authors suggested that the lower LC in other series was likely due to treatments with lower biologically effective dose (BED). Larger tumours or different later therapies may also have contributed. They concluded that pleural SBRT can achieve durable LC without appreciable toxicity, and they advocated high-BED SBRT within organ-at-risk tolerances.

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Salvage radiotherapy for oligo-progressive malignant pleural mesothelioma. P. Ghirardelli, D. Franceschini, A. D'Aveni, et al. 2021;152:1-6. PubMed · Publisher

Abstract

Objectives: No standard treatment option is available for patients with unresectable malignant pleural mesothelioma (MPM) progressing after upfront chemotherapy. We aimed to explore the role of focal radiotherapy (FRT) as a treatment modality for oligo-progressive MPM.

Materials And Methods: In this retrospective study, consecutive patients pretreated with ≥1 lines of chemotherapy were included. Oligo-progressive MPM was defined as an unresectable disease with radiological progression at ≤3 sites according to a chest-abdominal contrast-enhanced computed tomography. Patients were treated with either stereotactic body radiotherapy (SBRT, ≥5 Gy per fraction) or hypo-fractionated radiotherapy (hypoRT, <5 Gy per fraction). Time to further systemic therapy (TFST) and local control (LC) after FRT were the primary endpoints. Biologically effective dose (BED) was calculated using three different alpha/beta models (1.5 Gy, 3 Gy and 10 Gy).

Results: From April 2006 to March 2019, 37 patients were treated on 43 pleural lesions; 16/37 (43 %) had undergone upfront multimodality treatment (MMT) including surgery. FRT was given in 22/37 (59.5 %) after one line of chemotherapy. SBRT was delivered for 26/43 lesions (60.5 %), hypoRT for 17/43 (39.5 %). Median TFST was 6 months (95 % CI 4.9-7.1). LC at 6 months and 1 year was 84 % and 76 %, respectively. Median TFST was longer in patients treated after 1 vs >1 line of chemotherapy (9 vs 4 months, p = 0.001) and in patients pretreated with MMT (6 vs 3 months, p = 0.021). Six-month LC was better in patients treated with a BED > 100 using alpha/beta 1.5 and 3. No ≥ G3 acute or late toxicities were reported.

Conclusion: FRT was feasible in selected patients with oligo-progressive MPM, allowing delay of further systemic therapies, with no severe toxicity. FRT was more effective when performed at progression after one line of systemic therapy. Our results suggest a radio-resistant behavior of MPM.

Copyright © 2020 Elsevier B.V. All rights reserved.
Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial. S.I. Katz, L. Roshkovan, I. Berger, et al. 2021;154:5-12. PubMed · Publisher

Abstract

Objectives: Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy.

Materials And Methods: Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy.

Results: A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p < 0.001), and a moderate correlation between tumor volume and serum fibulin-3 levels (r = 0.36, p = 0.014). Twenty-eight patients in the immunotherapy trial had longitudinal serologic and radiographic data. Fold-changes in SMRP and fibulin-3 did not show significant correlations with modified RECIST measurements.

Conclusions: Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally.

Copyright © 2021. Published by Elsevier B.V.
Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models. H. Mumblat, A. Martinez-Conde, O. Braten, et al. 2021;160:99-110. PubMed · Publisher

Abstract

Objectives: Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields with antimitotic effects on cancerous cells. TTFields concomitant with pemetrexed and a platinum agent are approved in the US and EU as first line therapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma (MPM). The goal of the current study was to characterize the mechanism of action of TTFields in MPM cell lines and animal models.

Methods: Human MPM cell lines MSTO-211H and NCI-H2052 were treated with TTFields to determine the frequency that elicits maximal cytotoxicity. The effect of TTFields on DNA damage and repair, and the cytotoxic effect of TTFields in combination with cisplatin and/or pemetrexed were examined. Efficacy of TTFields concomitant with cisplatin and pemetrexed was evaluated in orthotopic IL-45 and subcutaneous RN5 murine models.

Results: TTFields at a frequency of 150 kHz demonstrated the highest cytotoxicity to MPM cells. Application of 150 kHz TTFields resulted in increased formation of DNA double strand breaks, elevated expression of DNA damage induced cell cycle arrest proteins, and reduced expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins. Co-treatment of TTFields with cisplatin or pemetrexed significantly increased treatment efficacy versus each modality alone, with additivity and synergy exhibited by the TTFields-pemetrexed and TTFields-cisplatin combinations, respectively. In animal models, tumor volume was significantly lower for the TTFields-cisplatin-pemetrexed combination compared to control, accompanied by increased DNA damage within the tumor.

Conclusion: This research demonstrated that the efficacy of TTFields for the treatment of MPM is associated with reduced expression of FA-BRCA pathway proteins and increased DNA damage. This mechanism of action is consistent with the observed synergism for TTFields-cisplatin vs additivity for TTFields-pemetrexed, as cisplatin-induced DNA damage is repaired via the FA-BRCA pathway.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
A comparison between MRI and CT in the assessment of primary tumour volume in mesothelioma. S. Tsim, G.W. Cowell, A. Kidd, et al. 2020;150:12-20. PubMed · Publisher

Abstract

Introduction: Primary tumour staging in Malignant Pleural Mesothelioma (MPM) using Computed Tomography (CT) imaging is confounded by perception errors reflecting low spatial resolution between tumour and adjacent structures. Augmentation using perfusion CT is constrained by radiation dosage. In this study, we evaluated an alternative tumour staging method using perfusion-tuned Magnetic Resonance Imaging (MRI).

Methods: Consecutive patients with suspected MPM were recruited to a prospective observational study. All had MRI (T1-weighted, isotropic, contrast-enhanced 3-Tesla perfusion imaging) and CT (contrast-enhanced) pre-biopsy. Patients diagnosed with MPM underwent MRI and CT volumetry, with readers blinded to clinical data. MRI volumetry was semi-automated, using signal intensity limits from perfusion studies to grow tumour regions within a pleural volume. A similar CT method was not possible, therefore all visible tumour was manually segmented. MRI and CT volumes were compared (agreement, correlation, analysis time, reproducibility) and associations with survival examined using Cox regression.

Results: 58 patients were recruited and had MRI before biopsy. 31/58 were diagnosed with MPM and these scans were used for volumetry. Mean (SD) MRI and CT volumes were 370 cm3 and 302 cm3, respectively. MRI volumes were larger (average bias 61.9 cm3 (SD 116), 95 % limits (-165.5 - 289 cm3), moderately correlated with CT (r = 0.56, p = 0.002) and independently associated with survival (HR 4.03 (95 % CI 1.5-11.55), p = 0.006). CT volumes were not associated with survival, took longer to compute than MRI volumes (mean (SD) 151 (19) v 14 (2) minutes, p=<0.0001) and were less reproducible (inter-observer ICC 0.72 for CT, 0.96 for MRI).

Conclusions: MRI and CT generate different tumour volumes in MPM. In this study, MRI volumes were larger and were independently associated with survival. MRI volumetry was quicker and more reproducible than CT.

Copyright © 2020 Elsevier B.V. All rights reserved.
A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma. P.A. Zucali, M. Perrino, F. De Vincenzo, et al. 2020;142:132-137. PubMed · Publisher

Abstract

Objectives: Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC).

Patients And Methods: GEM (1000 mg/m2) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS).

Results: In total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients.

Conclusions: The combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit.

Copyright © 2020 Elsevier B.V. All rights reserved.
A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma. W.S. Lam, J. Creaney, F.K. Chen, et al. 2020;140:87-92. PubMed · Publisher

Abstract

Objectives: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment.

Materials And Methods: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients.

Results: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes.

Conclusions: The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

Copyright © 2020 Elsevier B.V. All rights reserved.
Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) study. A.B. Thompson, T.J. Quinn, Z.A. Siddiqui, et al. 2020;146:120-126. PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a devastating disease with poor survival outcomes for most patients. Optimizing therapeutic approaches is thus vital, but has been hampered by a dearth of randomized trials to guide decision making. We used a population-level database to evaluate the impact of radiotherapy as a component of trimodality therapy on overall survival (OS) in MPM.

Methods: We retrospectively reviewed the SEER Radiation/Chemotherapy database for patients with MPM who received surgery and chemotherapy, with or without radiotherapy. A propensity score-matched analysis with inverse probability of treatment weighting (IPTW) was performed. Weight-adjusted univariate KM analysis was performed and doubly robust, IPTW-adjusted multivariable cox proportional hazards regression modeling was also performed to quantify the effect of radiotherapy on OS in trimodality therapy for MPM.

Results: 1015 patients were identified. 678 patients received surgery and chemotherapy, and 337 patients received trimodality therapy. For patients with localized disease, OS was significantly improved with trimodality therapy (HR 0.56, CI 0.4 - 0.8, p = 0.001), which persisted with IPTW adjustment (HR 0.65, CI 0.49 - 0.95, p = 0.0248). No significant benefit was seen for patients with regional or distant disease. On multivariate analysis, positive predictors of survival after IPTW adjustment were female sex, diagnosis after 2005, and left-sided disease.

Conclusions: These findings support a significant benefit to OS by incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM compared to only surgery and chemotherapy. It does not provide a significant overall survival benefit for patients with regional or metastatic disease.

Copyright © 2020 Elsevier B.V. All rights reserved.
Analysis of angiogenic and stromal biomarkers in a large malignant mesothelioma cohort. P.L. Chia, P. Russell, K. Asadi, et al. 2020;150:1-8. PubMed · Publisher

Abstract

Background: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other mesothelial membranes. Agents targeting vascular endothelial growth factor (VEGF) such as bevacizumab; and multi-kinase inhibitors such as nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM.

Methods: Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients with MM who were treated surgically. PDGF-CC, FGFR-1, VEGF and CD31 expression were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0-300 to each sample, based on the percentage of cells stained at different intensities. CD31 was evaluated via Chalkley's method to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM.

Results: CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology. PDGF-CC high (≥150) was seen in 203 /310 (65%) of all samples. VEGF high (≥80) was seen in 219/322 (68%) of all MM with 143/209 (68%) of epithelioid histology. FGFR-1 high (≥40) was seen in 127/310 (41%) of all MM. There was no association of VEGF and FGFR-1 IHC with survival nor differences between histological subtypes. There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGF-CC expression (OS 18.5 vs 13.2 months; HR 0.7928; 95% CI 0.5958 to 1.055, P = 0.1110). High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95% CI 0.2873 to 0.7941, P = 0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-CC and 20/31 (64%) with high VEGF scores. CD31 was found to be an independent prognostic factor in multivariate analysis (HR 1.540; 95% CI 1.018 to 2.330; p = 0.041).

Conclusions: High CD31 was an independent poor prognostic factor and high PDGF-CC expression was associated with poor survival in MM. Abrogating these pathways may have prognostic implications.

Copyright © 2020 Elsevier B.V. All rights reserved.
Characterization of the immune microenvironment in malignant pleural mesothelioma reveals prognostic subgroups of patients. N. Fusco, V. Vaira, I. Righi, et al. 2020;150:53-61. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare tumor with an extremely poor prognosis. Its pathogenesis is related to an immune response against asbestos fibers. The T-lymphocytes, including CD8POS and CD4POS cells, are an important part of the MPM immune microenvironment, and likely contribute to the therapy resistance observed in these tumors. Here, we sought to characterize the MPM-specific lymphocytes subpopulations within the tumor immune microenvironment to identify novel clinically relevant immunologic subtypes of tumors. Representative formalin-fixed, paraffin-embedded (FFPE) tissue blocks of 88 MPMs were included in tissue microarrays and subjected to tumor-infiltrating lymphocytes (TILs) quantification and subtyping by immunohistochemistry (IHC) with antibodies specific for CD4, CD8, and CD19. Further, PD-L1 (clone 22C3) expression was assessed by IHC as a combined positive score (CPS). Our data show that PD-L1 expression by tumor cells or the presence of a sarcomatoid component is related to increased stromal TILs presence in MPM. Survival analyses showed that low CD4POS and high CD8POS stromal TILs are associated with poor patients' survival. In MPMs with PD-L1 CPS > 1, stromal CD8HIGH was a poor prognostic factor, akin stromal CD4POS peritumoral TILs correlated with a worse prognosis. Furthermore, we demonstrated that a high CD4POS/CD8POS ratio in the tumor immune microenvironment is an independent prognostic factor for survival. Finally, we provided evidence that the characterization of the stromal immune landscape of MPM predicts responses to chemotherapy in subgroups of MPM. The results of this study provide novel insights into the clinical scenario of immune-related biomarkers in MPM.

Copyright © 2020 Elsevier B.V. All rights reserved.
Detection of TGF-β in pleural effusions for diagnosis and prognostic stratification of malignant pleural mesothelioma. P. Stockhammer, T. Ploenes, D. Theegarten, et al. 2020;139:124-132. PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with dismal prognosis but variable course of disease. To support diagnosis and to risk stratify patients, more reliable biomarkers are warranted. Emerging evidence underlines a functional role of transforming growth factor-beta (TGF-β) in MPM tumorigenesis though its utility as a clinical biomarker remains unexplored.

Materials And Methods: Corresponding pleural effusions and serum samples taken at primary diagnosis were analyzed for TGF-β by ELISA, and for mesothelin (SMRP) by chemiluminescence enzyme immunoassay. Tumor load was quantified in MPM patients by volumetric analysis of chest CT scans. All findings were correlated with clinicopathological characteristics.

Results: In total 48 MPM patients, 24 patients with non-malignant pleural disease (NMPD) and 30 patients with stage IV lung cancer were enrolled in this study. Pleural effusions from MPM patients had significantly higher TGF-β levels than from NMPD or lung cancer patients (p < 0.0001; AUC for MPM vs NMPD: 0.78, p = 0.0001). Both epithelioid and non-epithelioid MPM were associated with higher TGF-β levels (epithelioid: p < 0.05; non-epithelioid: p < 0.0001) and levels of TGF-β correlated with disease stage (p = 0.003) and with tumor volume (p = 0.002). Interestingly, high TGF-β levels in pleural effusion, but not in serum, was significantly associated with inferior overall survival (TGF-beta ≥14.36 ng/mL: HR 3.45, p = 0.0001). This correlation was confirmed by multivariate analysis. In contrast, effusion SMRP levels were exclusively high in epithelioid MPM, negatively correlated with effusion TGF-β levels and did not provide prognostic information.

Conclusion: TGF-β levels determined in pleural effusion may be a promising biomarker for diagnosis and prognostic stratification of MPM.

Copyright © 2019 Elsevier B.V. All rights reserved.
Frequent expression of conventional endothelial markers in pleural mesothelioma: usefulness of claudin-5 as well as combined traditional markers to distinguish mesothelioma from angiosarcoma. Y. Nakashima, K. Inamura, H. Ninomiya, et al. 2020;148:20-27. PubMed · Publisher

Abstract

Objectives: Distinguishing pleural sarcomatoid mesotheliomas from true sarcomas is challenging because the former does not always express the mesothelial markers, and diagnosis is often made on the basis of keratin expression. Consequently, sarcomas such as angiosarcomas that express keratin complicate the differential diagnosis. Furthermore, some mesotheliomas have been reported to express endothelial markers. The aim of this study is to identify useful markers for distinguishing pleural sarcomatoid mesothelioma from angiosarcoma.

Materials And Methods: This study enrolled 147 patients with pleural mesothelioma-93 with epithelioid, 25 with biphasic, and 29 with sarcomatoid subtypes-and 41 patients with angiosarcomas in various organs. The expression levels of cytokeratin, mesothelial, and endothelial markers were assayed in both groups to identify the markers that could assist in distinguishing mesothelioma from angiosarcoma. Cytokeratin (AE1/AE3, CAM 5.2), endothelial (CD31, CD34, ERG, factor VIII, and claudin-5), and mesothelial (calretinin, WT-1, podoplanin (D2-40), EMA, and CK5/6) markers were immunohistochemically assayed using tissue blocks.

Results: More than 90% of the mesotheliomas and less than 20% of the angiosarcomas expressed cytokeratin. Calretinin was expressed in 82% of all types of mesotheliomas but in only 48% of sarcomatoid mesotheliomas. Endothelial markers were expressed in mesothelioma tissues-CD31 in 10.3%, CD34 in 3.5%, ERG in 29%, and factor VIII in 3.4%-and the positivity was higher in sarcomatoid than in epithelioid and biphasic mesotheliomas. Claudin-5 was expressed in all the angiosarcomas, but not in any of the mesotheliomas.

Conclusion: We found overlapping immunophenotypes in pleural mesotheliomas and angiosarcomas, but the sensitivity and specificity of claudin-5 expression were sufficient to distinguish between them. The differential diagnosis of mesothelioma should therefore include claudin-5 in a panel of immunohistochemical markers to distinguish mesothelioma from angiosarcoma.

Copyright © 2020 Elsevier B.V. All rights reserved.
Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre. K. Marshall, S. Jackson, J. Jones, et al. 2020;150:195-200. PubMed · Publisher

Abstract

Background: Detection of homozygous deletion of the p16 gene (CDKN2A) by fluorescence in situ hybridization (FISH) has been investigated as an ancillary technique in the diagnosis of malignant mesothelioma.

Method: This retrospective study reviewed the results of all p16 FISH tests performed at a regional mesothelioma centre from February 2012 to November 2019 in cases of possible mesothelioma to examine the diagnostic utility of this test as well as patients characteristics and survival in p16 FISH positive mesothelioma versus p16 FISH negative mesothelioma.

Results: P16 FISH testing was requested in 216 pathological samples in the study period. The test failure rate was 4% (10/216). Median time from request to result was 10 days (IQR 7-13, range 1-30). The sensitivity, specificity, NPV and PPV were 60 %, 100 %, 39 % and 100 % respectively. There were no false positive results and this genetic aberration was only detected in cases of mesothelioma. The prevalence of p16 FISH positive mesothelioma was higher in cytological specimens compared to histological specimens (75 % vs 58 %, p = 0.03) and lower in women compared to men (33 % vs 66 %, p = 0.003). P16 FISH positive mesothelioma was associated with significantly worse survival (median overall survival 285 vs 339 days, p = 0.0018). This remained significant after adjusting for confounding variables (OR 4.4, 95 %CI 1.84-11.14, p = 0.001).

Conclusions: In this study, 60 % of mesotheliomas harbour a homozygous deletion of CDKN2A and can be accurately, reliably and efficiently identified by p16 FISH testing. This test can be embedded within routine practice in mesothelioma pathways to enhance diagnostic accuracy.

Copyright © 2020. Published by Elsevier B.V.
Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement. G. Bronte, A. Delmonte, M.A. Burgio, et al. 2020;142:47-50. Case report PubMed · Publisher

Abstract

Objectives: Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors.

Materials And Methods: Here we report the case of a 45-year-old woman presenting with dyspnea and evidence of pleural effusion. She was diagnosed with malignant epithelioid pleural mesothelioma with brain metastasis and peritoneal carcinosis, refractory to initial standard chemotherapy treatment. Because of high PDL1 expression (100 %), she was treated with the anti-PD1 agent, pembrolizumab.

Results: Chemotherapy with cisplatin and pemetrexed was started, imaging studies showing stable disease after 3 treatment cycles. The patient underwent pleural decortication but rapidly progressed and thus started chemotherapy with carboplatin and gemcitabine. After 2 cycles she experienced seizures caused by a brain metastasis. This secondary lesion was surgically removed and confirmed as a metastasis from mesothelioma. Samples from both the primary tumor and the metastasis were molecularly characterized, the pleural sample proving ALK-positive and the brain sample, ALK-negative. PD-L1 was positive in 10 % of tumor cells in the pleural biopsy and 100 % in the brain lesion. Next generation sequencing analysis was negative for both samples. It was decided to start alectinib. Disease progression (peritoneal carcinosis and liver metastases) was documented after one month followed by complete bowel obstruction and recurrence in the site of the brain surgery. Alectinib was stopped and supportive care begun with parenteral nutrition via nasogastric tube. Pembrolizumab was started and after 15 days the patient's condition had significantly improved, enabling recanalization and restoration of enteral nutrition. Imaging displayed complete response of the brain metastasis, peritoneal carcinosis, bone lesions and mediastinal nodal metastases. A partial response was documented in the pleural and pulmonary nodules, with stable liver metastases. The patient is still undergoing immunotherapy and has no cancer-related symptoms.

Conclusions: Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments.

Copyright © 2020 Elsevier B.V. All rights reserved.
Malignant pleural mesothelioma: Treatment patterns and outcomes from the Spanish Lung Cancer Group. J. Remon, E. Nadal, M. Dómine, et al. 2020;147:83-90. PubMed · Publisher

Abstract

Background: Malignant mesothelioma is a rare but aggressive tumor arising from the pleura, typically associated with exposure to asbestos. The purpose of this investigation was to describe mesothelioma patient characteristics, treatment patterns, and outcomes in Spain.

Material And Methods: Patients diagnosed with malignant mesothelioma of the pleura were recorded in an anonymous online database (BEMME, Epidemiologic Spanish Malignant Mesothelioma Database) from June 2008 through May 2013. Patient and tumor characteristics at time of diagnosis, as well as subsequent treatments (surgery, radiation, and chemotherapy), were collected. Among patients treated with chemotherapy, we explored type of chemotherapy regimen and outcomes by treatments.

Results: A total of 560 malignant pleural mesothelioma (MPM) patients were recorded. The median age at diagnosis was 68 years, mainly with epithelioid histology (62 %), and any asbestos exposure was noted in 45 % of patients. Nearly two-thirds of patients (71 %) received chemotherapy, mainly platinum-pemetrexed combination, as part of their treatment. Surgery and radiotherapy were given in 36 % and 17 % of patients, respectively. The median overall survival (OS) in the whole cohort was 13.0 months (95 % confidence interval (CI), 11.1-14.8 months) with 1-year OS of 53.2 % (95 % CI, 48.7-57.7 %). In patients receiving first-line chemotherapy (N = 315), the median OS was 13.4 months (95 % CI, 10.8-16.0 months), reaching 20.2 months (95 % CI, 17.2-23.2 months) for those 68 patients receiving maintenance chemotherapy. Results of multivariate analyses showed significant association of ECOG-performance status, histology and treatment response with improved OS in MPM patients treated with palliative chemotherapy.

Conclusions: Despite multimodal therapeutic intervention, survival of patients with mesothelioma in Spain remains poor. Although it did not reach significance in the multivariate analysis, a meaningful additional survival benefit was observed among those patients receiving maintenance chemotherapy.

Copyright © 2020 Elsevier B.V. All rights reserved.
Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas. J.M. Sands, T. Nguyen, P. Shivdasani, et al. 2020;140:35-41. PubMed · Publisher

Abstract

Objectives: Potentially targetable genomic alterations have been identified in lung squamous cell carcinoma (LUSC), but none have yet translated into effective therapy. We examined potential benefits of next generation sequencing (NGS) in a cohort of consecutive LUSC patients with emphasis on distinctions between smokers and light/never smokers and implications for clinical trial enrollment.

Methods: We retrospectively evaluated results from an internally developed NGS assay (OncoPanel) targeting ∼300 genes with a mean overall target coverage of >200x for consecutive LUSC seen at our institution over 30 months.

Results: Tissue was obtained from 172 patients for targeted NGS. 42 (24 %) samples were insufficient for testing. Median age of tested patients was 66, including 87 % moderate/heavy versus 13 % light/never smokers; 66 % were stage IIIB or IV. Of 130 patients with evaluable NGS results, 49 (38 %) had at least 1 alteration qualifying for enrollment to a LungMAP treatment arm (PIK3CA, MET, FGFR family, cell cycle, or homologous recombination pathways) or for an approved therapy or other clinical trial (e.g. EGFR sensitizing mutations, MET exon 14 splice mutations, TSC1/2 mutation, or microsatellite instability). Therapeutic targets were enriched in light/never smokers (47 % vs 35 % moderate/heavy smokers). Unexpectedly, genomic features suggested an alternative diagnosis (metastatic cutaneous squamous carcinoma; mesothelioma) in 7 patients, including 35 % of never/light smokers.

Conclusion: NGS in a real-world LUSC cohort yields potentially targetable genomic alterations informing clinical trial enrollment and approved therapies and critical diagnostic insights. Our findings strongly support current guidelines recommending mutational profiling of LUSC arising in light/never smoking patients; the utility of sequencing in smokers with LUSC appears to be limited to identification of research targets.

Copyright © 2019 Elsevier B.V. All rights reserved.
NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer. J.L. Leal, G. Peters, M. Szaumkessel, et al. 2020;146:154-159. PubMed · Publisher

Abstract

Objectives: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC.

Methods: Archival tumor tissue from patients with MPM, lung NETs, SCLC and NSCLC were used to create tissue microarrays. Immunohistochemistry (IHC) was performed using a cocktail of antibodies against TRK, ROS1 and ALK. IHC positive samples underwent RNA sequencing using the ArcherDX FusionPlex CTL diagnostic assay. Clinical data were obtained through retrospective chart review.

Results: We performed IHC on 1116 samples: 335 MPMs, 522 NSCLCs, 105 SCLCs and 154 lung NETs. There were 23 IHC positive cases (2.1%) including eight MPMs (2.4%), eight NETs (5.2%), five SCLC (4.8%) and two NSCLC (0.4%). The following fusions were detected: one MPM with an NTRK ex10-TPM3 ex8, another MPM with an ALK ex20-EML4ex13, one lung intermediate-grade NET (atypical carcinoid) with an ALK ex20-EML4 ex6/intron6, and two NSCLCs with an ALK ex20-EML4 ex6/intron6 rearrangement. None of the patients received targeted treatment.

Conclusions: To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized.

Copyright © 2020 Elsevier B.V. All rights reserved.
Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716. S.J. Danson, J. Conner, J.G. Edwards, et al. 2020;150:145-151. PubMed · Publisher

Abstract

Objectives: Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM.

Materials And Methods: Patients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response.

Results: Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks.

Conclusions: Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

Copyright © 2020 Elsevier B.V. All rights reserved.
Questioning the prognostic role of BAP-1 immunohistochemistry in malignant pleural mesothelioma: A single center experience with systematic review and meta-analysis. L. Cantini, F. Pecci, A. Murrone, et al. 2020;146:318-326. Meta-analysis · Systematic review PubMed · Publisher

Abstract

Introduction: The prognostic role of BRCA1 associated protein-1 (BAP1) expression in malignant pleural mesothelioma (MPM) is a matter of debate. We aimed to clarify whether MPM patients with loss of BAP1 expression have better overall survival (OS) compared to BAP1 positive patients.

Methods: BAP1 immunohistochemical staining of tumor samples from 60 MPM patients treated at our institution with first-line chemotherapy was evaluated. A systematic literature search was also performed. Only cohort studies that investigated BAP1 by immunohistochemistry (IHC) and reported hazard ratio (HR) values for OS obtained through multivariate analysis (or adjusted for histotype) were considered. A dataset comprising 638 MPM patients was added to our cohort and included in the meta-analysis.

Results: In our cohort, 23 samples (38 %) were BAP1 positive/retained (≥1 %) and 37 samples (62 %) were BAP1 negative/loss. BAP1 loss was associated with epithelioid histotype (p 0.01). Median OS times were 14.8 months (95 % CI: 10.7-29.3) and 18.1 months (95 % CI: 11.2-25.8) for negative and positive BAP1 expression, respectively (p 0.2). At multivariate analysis, again no differences were observed among the two groups (p 0.81). Similarly, the meta-analysis consisting of 698 patients showed no difference in terms of OS according to BAP1 status (HR 1.11; 95 % CI, 0·76-1·61; p 0.60).

Conclusions: BAP1 expression is not an independent prognostic factor for MPM patients and it should not be considered without taking into account tumor histotype. Future studies should investigate its predictive role in patients treated with new emerging therapies such as immunotherapy.

Copyright © 2020 Elsevier B.V. All rights reserved.
Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma. S.K. Lam, S. Yan, S. Xu, et al. 2020;148:138-148. PubMed · Publisher

Abstract

Introduction: Inhalation of asbestos fibers is the key culprit in malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM continues to increase globally due to the prolonged lag time in malignant transformation. The development of a novel adjuvant therapy for the minority of individuals with resectable early-stage disease and effective treatment for those with unresectable MPM are urgently needed. Our preliminary data revealed that ornithine decarboxylase (ODC) is highly expressed in MPM xenografts. This study aimed to determine the treatment effects of α-difluoromethylornithine (DFMO), a specific ODC inhibitor, in MPM xenografts.

Results: In an "extended adjuvant DFMO treatment" setting, nude mice were fed with DFMO for 7 days prior to inoculation of 200,000 cells. DFMO suppressed tumor growth and increased median survival in both xenografts. In H226 xenograft, 43 % of treated mice had not reached the humane endpoint by day 132, mimicking long-term survival. DFMO decreased spermidine, increased nitrotyrosine and activated apoptosis in both xenografts. Furthermore, increase in nitrosocysteine, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesion and inhibition of the Akt/mTOR pathway were induced by DFMO in H226 xenograft. In "DFMO treatment" setting, 107 cells were inoculated into nude mice and DFMO treatment commenced when tumor size reached ∼50-100 mm3. DFMO also suppressed tumor growth by similar mechanisms. Supplementation with spermidine reversed the therapeutic effect of DFMO. DFMO increased actin nitration at tyrosine 53 and inhibited actin polymerization.

Conclusion: DFMO is preclinically effective in treating MPM.

Copyright © 2020 Elsevier B.V. All rights reserved.
Targeting ROR1 in combination with pemetrexed in malignant mesothelioma cells. N. Miyake, N. Ochi, H. Yamane, et al. 2020;139:170-178. PubMed · Publisher

Abstract

Objective: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in a subset of malignant cells. However, it remains unknown whether ROR1 is targetable in malignant mesothelioma (MM). Therefore, in this study, we investigated the effects of ROR1 inhibition in mesothelioma cells.

Materials And Methods: Growth inhibition, colony formation, apoptosis, and mRNA/protein levels using siRNA-transfected MM cells were evaluated. Cluster analysis using Gene Expression Omnibus repository of transcriptomic information was also performed.

Results: Our results indicated that in three (H2052, H2452, and MESO-1) among four MM cell lines, ROR1 inhibition had anti-proliferative and apoptotic effects and suppressed the activation of AKT and STAT3. Although growth inhibition by siROR1 was minimal in another mesothelioma cell line (H28), colony formation was significantly suppressed. Microarray, quantitative polymerase chain reaction, and Western blot analyses showed that there were differences in the suppression of mRNA and proteins between H2452 and H28 cells transfected with siROR1 compared with those transfected with control siRNA. Cluster analysis further showed that MM tumors had relatively high ROR1 expression, although the cluster in them was different from that in MM cell lines. Thymidylate synthase, a target of pemetrexed, was downregulated in H2452 cells transfected with siROR1. Accordingly, a combination of pemetrexed with siROR1 was found to be effective in the three MM cell lines we studied.

Conclusion: Our findings may provide novel therapeutic insight into the treatment of advanced MM.

Copyright © 2019 Elsevier B.V. All rights reserved.

2010s

A case of primary lung squamous cell carcinoma mimicking malignant mesothelioma producing granulocyte colony stimulating factor with chemotherapy (cisplatin and gemcitabine)-associated thrombotic thrombocytopenic purpura (TTP); An autopsy case report. Y. Suzuki, K. Kanazawa, R. Kanai, et al. 2019;136:105-108. Case report PubMed · Publisher

Abstract

Objectives: Thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy. In recent years, an extensive variety of drugs, including certain cytotoxic agents, have been reported to be associated with TTP. Additionally, several studies have reported that granulocyte colony-stimulating factor (G-CSF) was produced by lung carcinoma. G-CSF-producing carcinoma also produces various other cytokines, which may cause vascular endothelial damage and trigger TTP development. However, there has been no report describing G-CSF-producing carcinoma combined with TTP. We report a rare case of pseudomesothliomatous squamous cell lung carcinoma producing G-CSF along with chemotherapy associated TTP.

Materials And Methods: A 66-year-old man with pseudomesotheliomatous primary squamous cell lung carcinoma was treated with chemotherapy consisting of cisplatin and gemcitabine as the first line treatment. However, thrombocytopenia, acute renal dysfunction and acute respiratory failure occurred after starting the first chemotherapy cycle. As a result, the patient died, and an autopsy was performed.

Results: According to the autopsy findings, a diagnosis of primary lung squamous cell carcinoma producing G-CSF associated with TTP was made.

Conclusion: Chemotherapy-related TTP should be considered when anemia and thrombocytopenia progress rapidly in patients who are under chemotherapy treatment. Furthermore, the current case may provide a possible link between TTP and G-CSF-producing tumor.

Copyright © 2019 Elsevier B.V. All rights reserved.
Baseline predictors of negative and incomplete pleural cytology in patients with suspected pleural malignancy - Data supporting 'Direct to LAT' in selected groups. S. Tsim, S. Paterson, D. Cartwright, et al. 2019;133:123-129. PubMed · Publisher

Abstract

Objectives: Negative effusion cytology is more common in certain forms of Malignant Pleural Effusion (MPE) and results in pathway delay. Local Anaesthetic Thoracoscopy (LAT) is extremely sensitive and safe but cannot be offered to all. A stratified pathway, including 'Direct to LAT' in selected cases could enhance patient experience but requires reliable baseline predictors of unhelpful cytology, including both negative (no malignant cells) and incomplete results (malignant cells identified but predictive markers failed), since pleural biopsies will be required in the latter for optimal management. This retrospective analysis of a prospective multi-centre study, sought to identify baseline features for pathway rationalization.

Materials And Methods: 363/638 (57%) of patients recruited to the DIAPHRAGM study (ISRCTN10079972) were included. Prospective data, including final diagnoses, asbestos exposure and fluid cytology results were supplemented by retrospective Computed Tomography (CT) and predictive marker reports. Independent predictors of negative and incomplete cytology were determined by multivariable logistic regression. Contingency tables were used to assess diagnostic value of cytology in associated phenotypes.

Results: 238/363 (66%) patients were diagnosed with MPE (18 tumour types). Fluid cytology was negative in 151/238 (63%) and independently associated with asbestos-exposure (Odds Ratio (OR) 5.34) and a malignant CT (OR 2.25). When both features were recorded the sensitivity and negative predictive value of fluid cytology were 19% (95% CI 11-30%) and 9% (95% CI 4-20%)), respectively. Cytology was incomplete in 34/238 (14%), i.e. 47% of positive cytology cases) but was not associated with any baseline feature. ORs for incomplete cytology in Ovarian, Breast, Renal and Lung Cancer were 83, 22, 21 and 9, respectively.

Conclusion: Negative cytology is extremely likely in patients with asbestos exposure and a malignant CT report. A 'Direct-to-LAT' approach may be appropriate in this setting. No baseline predictors of incomplete cytology were identified.

Copyright © 2019 Elsevier B.V. All rights reserved.
Comment on: "Low-dose computed tomography screening for lung cancer in people with workplace exposure to asbestos". E.J.A. Harris, A.W. Musk, N. DeKlerk, et al. 2019;136:148-149. Letter PubMed · Publisher
Comment on: "Low-dose computed tomography screening for lung cancer in people with workplace exposure to asbestos". F. Barbone, F. Barbiero, G. Fasola. 2019;136:150. Letter PubMed · Publisher
Corrigendum to "Low-dose computed tomography screening for lung cancer in people with workplace exposure to asbestos" [Lung Cancer, 131 (May) (2019) 23-30]. P. Maisonneuve, C. Rampinelli, R. Bertolotti, et al. 2019;134:279. PubMed · Publisher

Summary

This corrigendum, published in Lung Cancer in 2019 (volume 134, page 279), corrected an error in the authors' article "Low-dose computed tomography screening for lung cancer in people with workplace exposure to asbestos," which appeared in Lung Cancer, volume 131 (May 2019), pages 23–30. The authors stated that one of the affiliations in the original article had been mistakenly translated. They gave the correct wording of affiliation e as the Department of Thoracic Surgery, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy, and stated that it had been corrected in the corrigendum. The authors apologised for any inconvenience caused. The notice reprinted the full author list and affiliations. These included institutions in Milan, Rozzano, Reggio Emilia and Rome, Italy, among them the European Institute of Oncology, the Humanitas Clinical and Research Center, and the Italian National Insurance Institute for Workplace Injuries (INAIL). The corrigendum did not report any changes to the methods, data, results or conclusions of the original article, and it presented no study findings of its own.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
High BIN1 expression has a favorable prognosis in malignant pleural mesothelioma and is associated with tumor infiltrating lymphocytes. T. Ahmadzada, K. Lee, C. Clarke, et al. 2019;130:35-41. PubMed · Publisher

Abstract

Objectives: A number of key immune regulators show prognostic value in malignant pleural mesothelioma (MPM), but the association between Bridging integrator 1 (BIN1), indoleamine 2,3 dioxygenase 1 (IDO1) and patient outcome has not been investigated. We aimed to determine the expression of BIN1 and IDO1, their association with other markers and impact on overall survival (OS) in MPM.

Materials And Methods: The expression of BIN1, IDO1, CD3, CD20 and CD68 were evaluated by immunohistochemistry in 67 patients who underwent pleurectomy/decortication. Survival analyses were performed using the Kaplan Meier method and significant biomarkers were entered into a Cox Regression multivariate model, accounting for known prognostic factors such as age, gender, histological subtype, PD-L1 expression and neutrophil-to-lymphocyte ratio.

Results: Immune markers were variably expressed in tumor cells, ranging from 0% to 100% for BIN1 (median: 89%), and 0% to 77.5% for IDO1 (median: 0%). Expression of markers of tumor-infiltrating lymphocytes (TILs) and macrophages ranged from 0% to more than 50%. BIN1 expression was high in 35 patients (51%) and was associated with increased OS (median: 12 vs 6 months for high and low BIN1 respectively,p = 0.03). Multivariate analysis showed BIN1 remained an independent prognostic indicator (HR 0.39; 95% CI: 0.18-0.82, p = 0.01). The majority of patients had immune inflamed tumors (77%) and there was a significant association between TILs and BIN1 (p = 0 < 0.01), PD-L1 (p=0.04) and CD68+ macrophages in the tumor (p < 0.01). There were no significant associations between PD-L1 and BIN1 or IDO1.

Conclusion: High BIN1 expression is a favorable prognostic biomarker and is associated with TILs in MPM.

Copyright © 2019 Elsevier B.V. All rights reserved.
Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. M. Yoshimura, Y. Kinoshita, M. Hamasaki, et al. 2019;130:187-193. PubMed · Publisher

Abstract

Objective: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with poor prognosis. Loss of BRCA-associated protein 1 (BAP1) protein expression as detected by immunohistochemistry (IHC) and homozygous deletion (HD) of the 9p21 locus as detected by fluorescence in situ hybridization (FISH) permits differentiation of MPM from reactive mesothelial hyperplasia (RMH). We have previously reported that detecting the loss of methylthioadenosine phosphorylase (MTAP) using IHC is a surrogate assay for 9p21 FISH. Furthermore, enhancer of zeste homolog 2 (EZH2), which encodes a component of polycomb repressor complex 2 (PRC-2), has been overexpressed in various tumors as well as MPM. In the current study, we investigated whether EZH2 IHC assay, alone or in combination with BAP1 and MTAP IHC, is useful for distinguishing MPM from RMH.

Materials And Methods: We examined IHC expression of EZH2, BAP1, and MTAP, and 9p21 FISH in MPM (n = 38) and RMH (n = 29) and analyzed the sensitivity and specificity of each detection assay for distinguishing MPM from RMH.

Results And Conclusion: EZH2, BAP1, and MTAP IHC, and 9p21 FISH were characterized by a 100% specificity each and 44.7%, 52.6%, 47.4%, and 65.8% sensitivities, respectively. A combination of EZH2 and BAP1 IHC, and 9p21 FISH showed the greatest sensitivity (89.5%). Using IHC alone (EZH2, BAP1, and MTAP IHC) also yielded a good sensitivity of 86.9%; this level is high enough for routine diagnostics. There were no statistically significant associations between expression of EZH2 and that of other markers (BAP1 and MTAP IHC) or 9p21 HD. However, a high expression level of EZH2 was significantly associated with short survival (P = 0.025). In conclusion, adding a high expression level of EZH2 to a combination of BAP1 and MTAP loss, all detected by IHC, demonstrated useful for discriminating MPM from RMH.

Copyright © 2019 Elsevier B.V. All rights reserved.
Imaging in pleural mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group. S.G. Armato, R.J. Francis, S.I. Katz, et al. 2019;130:108-114. Review PubMed · Publisher · Free full text

Abstract

Mesothelioma patients rely on the information their clinical team obtains from medical imaging. Whether x-ray-based computed tomography (CT) or magnetic resonance imaging (MRI) based on local magnetic fields within a patient's tissues, different modalities generate images with uniquely different appearances and information content due to the physical differences of the image-acquisition process. Researchers are developing sophisticated ways to extract a greater amount of the information contained within these images. This paper summarizes the imaging-based research presented orally at the 2018 International Conference of the International Mesothelioma Interest Group (iMig) in Ottawa, Ontario, Canada, held May 2-5, 2018. Presented topics included advances in the imaging of preclinical mesothelioma models to inform clinical therapeutic strategies, optimization of the time delay between contrast administration and image acquisition for maximized enhancement of mesothelioma tumor on CT, an investigation of image-based criteria for clinical tumor and nodal staging of mesothelioma by contrast-enhanced CT, an investigation of methods for the extraction of mesothelioma tumor volume from MRI and the association of volume with patient survival, the use of deep learning for mesothelioma tumor segmentation in CT, and an evaluation of CT-based radiomics for the prognosis of mesothelioma patient survival.

Copyright © 2018 Elsevier B.V. All rights reserved.
Low-dose computed tomography screening for lung cancer in people with workplace exposure to asbestos. P. Maisonneuve, C. Rampinelli, R. Bertolotti, et al. 2019;131:23-30. Meta-analysis · Review PubMed · Publisher

Abstract

Objectives: Smoking is the main risk factor for lung cancer, but environmental and occupational exposure to carcinogens also increase lung cancer risk. We assessed whether extending low-dose computed tomography (LDCT) screening to persons with occupational exposure to asbestos may be an effective way reducing lung cancer mortality.

Materials And Methods: We conducted a nested case-control study within the COSMOS screening program, assessing past asbestos exposure with a questionnaire. LDCT scans of asbestos-exposed participants were reviewed to assess the presence of pulmonary, interstitial and pleural alterations in comparison to matched unexposed controls. We also performed an exhaustive review, with meta-analysis, of the literature on LDCT screening in asbestos-exposed persons.

Results: Exposure to asbestos, initially self-reported by 9.8% of COSMOS participants, was confirmed in 216 of 544 assessable cases, corresponding to 2.6% of the screened population. LDCT of asbestos-exposed persons had significantly more pleural plaques, diaphragmatic pleural thickening and pleural calcifications, but similar frequency of parenchymal and interstitial alterations to unexposed persons. From 16 papers, including this study, overall lung cancer detection rates at baseline were 0.81% (95% CI 0.50-1.19) in asbestos-exposed persons, 0.94% (95% CI 0.47-1.53) in asbestos-exposed smokers (12 studies), and 0.11% (95% CI 0.00-0.43) in asbestos-exposed non-smokers (9 studies).

Conclusion: Persons occupationally exposed to asbestos should be monitored to gather more information about risks. Although LDCT screening is effective in the early detection lung cancer in asbestos-exposed smokers, our data suggest that screening of asbestos-exposed persons with no additional risk factors for cancer does is not viable due to the low detection rate.

Copyright © 2019 Elsevier B.V. All rights reserved.
Lymphangitic carcinomatosis: A common radiographic manifestation of local failure following extended pleurectomy/decortication in patients with malignant pleural mesothelioma. I. Berger, K.A. Cengel, C.B. Simone, et al. 2019;132:94-98. PubMed · Publisher

Abstract

Introduction: The lymphangitic carcinomatosis (LC) pattern of metastatic malignancy is associated with a poor prognosis but is currently not well defined in malignant pleural mesothelioma (MPM). Here, we report the incidence and prognostic significance of the radiographic development of LC in MPM following extended pleurectomy/decortication (EPD).

Methods: Consecutive patients with biopsy-proven MPM undergoing EPD with intraoperative photodynamic therapy (PDT) at our institution from 2008 to 2014 were included in this retrospective study. Patients without available post-surgical clinical or imaging data for direct review were excluded. CT images were reviewed by an experienced, board-certified thoracic radiologist and confirmed by consensus review. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan Meier methodology. Hazard ratios were compared with a cox proportional hazard model.

Results: 44 patients underwent EPD with PDT during the study period and had available clinical and imaging data. During the follow-up period (median 34 months), 17 patients (39%) developed LC at a median of 10 months after surgery (IQR 5-21 months). 16 of the 17 patients who developed LC (94%) died during the follow-up period, compared to 17 of the 27 who did not develop LC (63%). OS for the LC versus non-LC group was 53% versus 93% at 1 year and 18% versus 67% at 3 years. LC was significantly associated with a lower OS (HR 4.07; 95% confidence interval 1.44-11.48; p = 0.008). PFS for the LC group versus non-LC group was 8 months (IQR 5-9 months) compared to 17 months (IQR 11-24 months) (p < 0.001).

Conclusion: LC is a common form of failure in MPM following EPD and is associated with a poor prognosis. Thus, further studies are warranted to determine if any evidence of preoperative LC should be an absolute contraindication to EPD and may warrant an EPP or no surgery at all.

Copyright © 2019. Published by Elsevier B.V.
Molecular pathways and diagnosis in malignant mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group. D.B. Chapel, A. Churg, E. Santoni-Rugiu, et al. 2019;127:69-75. Review PubMed · Publisher

Abstract

The pathologist plays a central role in the diagnosis and management of malignant mesothelioma, including definitive tissue-based diagnosis in conjunction with clinical and radiographic data; diverse ancillary studies of diagnostic, prognostic, and predictive importance; and research efforts to better define the pathobiology of mesothelioma and develop novel clinical applications. The pivotal role of pathology in care of mesothelioma patients was on display at the recent meeting of the International Mesothelioma Interest Group (iMig) in Ottawa, Canada. This review summarizes the key findings of the "Molecular Pathways and Diagnosis in Malignant Mesothelioma" plenary session, including a large multi-institutional validation of a composite nuclear grading system for pleural mesothelioma, including incorporation of tumor necrosis as an additional independent prognostic factor; the correlation between nuclear grading in small biopsies and paired resection specimens in pleural mesothelioma; a multi-institutional study of important clinical and pathologic prognostic factors in peritoneal mesothelioma; the diagnostic role of HEG1 immunohistochemistry as a highly sensitive and specific marker of mesothelial lineage; the prevalence and diagnostic significance of MET protein overexpression in mesothelioma, as well as the correlation between MET protein overexpression and MET gene amplification; and the prognostic role of EZH2 protein overexpression in mesothelioma, together with data indicating an important pathogenic role for EZH2 in mesothelioma tumorigenesis. Special consideration is given to the convergence of diagnostic, prognostic, and predictive tools and their role in guiding highly personalized patient-centered management, and to the translation of novel research findings to practical techniques for routine pathologic practice.

Copyright © 2018 Elsevier B.V. All rights reserved.
Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis. N. de Rouw, S. Croes, R. Posthuma, et al. 2019;130:156-158. Case report PubMed · Publisher

Abstract

Objectives: Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment.

Methods: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg·h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated.

Results: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg·h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed.

Conclusion: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.

Copyright © 2019. Published by Elsevier B.V.
Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma. M. Takeda, Y. Ohe, H. Horinouchi, et al. 2019;137:64-70. PubMed · Publisher

Abstract

Objectives: CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies.

Material And Methods: The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs).

Results: Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response.

Conclusions: YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018). L. Wu, I. Dell'Anno, M. Lapidot, et al. 2019;127:138-145. Review PubMed · Publisher

Abstract

Here we summarize the most recent update of mesothelioma research in basic science presented at the 14th iMig2018 international conference. The symposium of basic science track mainly focused on the drivers of mesothelioma initiation and progression, molecular pathogenesis, and perspectives on potential therapeutic approaches. This review covers several promising fields including strategies efficiently inhibiting YAP/TAZ functions or their critical downstream targets, heparanase inhibitors, RAN depletion, and MIF/CD74 inhibitors that may be developed as novel therapeutic approaches. In addition, targeting mesothelioma stem cells by depleting M2-polarized macrophages in tumor microenvironment or blocking Tnfsf18 (GITRL)-GITR signalling might be translated into therapeutic modalities in mesothelioma treatment.

Copyright © 2018 Elsevier B.V. All rights reserved.
Response to comment on: "Low-dose computed tomography screening for lung cancer in people with workplace exposure to asbestos". P. Maisonneuve, S. Iavicoli, G. Veronesi. 2019;136:151-152. Letter PubMed · Publisher
Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma. N. Kumar, D. Alrifai, K.K. Kolluri, et al. 2019;127:164-166. PubMed · Publisher

Abstract

Introduction BRCA1 associated protein-1 (BAP1) is a key tumor driver in mesothelioma and a potential biomarker predicting response to several targeted therapies in clinical testing. Whether it also modulates response to cytotoxic chemotherapy is undetermined. This study used retrospective response analysis of BAP1 expression in archival tumor biopsies taken from patients in the MS01 trial (NCT00075699). We aimed to determine if BAP1 expression correlated with overall survival within the three treatment arms in this trial, namely active symptom control (ASC); ASC plus mitomycin, vinblastine and cisplatin (MVP); and ASC plus vinorelbine. Materials and methods We used immunohistochemical analysis of tumor samples from the MS01 trial to identify subgroups with and without nuclear BAP1 expression. We performed correlative analysis of clinical characteristics (age at diagnosis, sex and histological subtype) and overall survival within treatment arms with nuclear BAP1 expression. Results 89 tumor samples from the 409 patients originally in the trial were available for analysis. Of these, 60 samples harbored a positive internal control, in the form of positive staining of inflammatory cells for BAP1, and were carried forward for analysis. Correlative analysis suggested no significant association between loss of nuclear BAP1 expression and age at diagnosis, sex and histological subtype. Kaplan Meier survival analysis revealed a small, though non-significant, overall survival disadvantage associated with BAP1 expression in tumors from patients treated with vinorelbine. Discussion This exploratory analysis suggests BAP1 expression may modify response to vinorelbine in MPM, possibly due to prevention of mitotic microtubule formation. We suggest ongoing and planned clinical studies of vinorelbine in MPM assess BAP1 expression as a predictive biomarker of response.

Copyright © 2018. Published by Elsevier B.V.
Survival in patients with malignant pleural effusion undergoing talc pleurodesis. M. Hassan, R.M. Mercer, N.A. Maskell, et al. 2019;137:14-18. PubMed · Publisher

Abstract

Objectives: Recent observations indicate a potential survival benefit in patients with malignant pleural effusion (MPE) who achieve successful pleurodesis in comparison to patients who experience effusion recurrence post pleurodesis. This study aimed to explore this observation using two datasets of patients with MPE undergoing talc pleurodesis.

Materials And Methods: Dataset 1 comprised patients who underwent talc pleurodesis at Oxford Pleural Unit for MPE. Dataset 2 comprised patients enrolled in the TIME1 clinical trial. Pleurodesis success was defined as absence of need for further therapeutic procedures for MPE in the three months following pleurodesis. Data on various clinical, laboratory and radiological parameters were collected and survival was compared according to pleurodesis outcome (success vs. failure) after adjusting for the aforementioned parameters.

Results: Dataset 1 comprised 60 patients with mean age 74.1±10.3 years. The most common primary malignancies were mesothelioma, breast and lung cancer. 29 patients (48.3%) achieved pleurodesis. The adjusted odds ratio (aOR) for poor survival with pleurodesis failure was 2.85 (95% CI 1.08-7.50, =p 0.034). Dataset 2 comprised 259 patients from the TIME1 trial. The mean age was 70.8±10.3 and the most common primary malignancies were mesothelioma, lung and breast cancer. Pleurodesis was successful in 205 patients (79%). aOR for poor survival was 1.62 (95% CI 1.09-2.39, p = 0.015).

Conclusion: Achieving pleurodesis seems to impart a survival benefit in patients with MPE. Further studies are required to explore factors that may contribute to this phenomenon and to address the difference in survival between pleurodesis and indwelling pleural catheter interventions.

Copyright © 2019 Elsevier B.V. All rights reserved.
The role of radiation treatment in pleural mesothelioma: Highlights of the 14th International Conference of the International mesothelioma interest group. R.M. MacRae, M. Ashton, O. Lauk, et al. 2019;132:24-27. Review PubMed · Publisher

Abstract

Radiation remains an important component of mesothelioma treatment in 2018. Its use as a treatment modality continues to evolve as the technology for planning and delivery continues to improve. Use of radiation to improve local control in the involved hemithorax has been a common adjuvant treatment post extrapleural pneumonectomy for many years. Modern treatment options with advanced planning techniques including protons and intensity modulated radiation therapy lead to new potential options for treatment post lung-sparing surgery or in the unresectable setting. Presentations and discussions on the implementation of these strategies for palliation, treatment of oligometastatic recurrence or unresectable disease were the focus of a session dedicated to the role of radiation therapy at the 14th International Conference of the International Mesothelioma Interest Group and are reviewed in this article. Preclinical data to better understand how to integrate radiation and the delivery of novel systemic therapy approached like check point inhibitors are also presented.

Copyright © 2019 Elsevier B.V. All rights reserved.
A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis. Y. Kinoshita, M. Hamasaki, M. Yoshimura, et al. 2018;125:198-204. PubMed · Publisher

Abstract

Objectives: Histologic diagnosis of malignant pleural mesothelioma (MPM) is not always straightforward. Loss of BRCA1-associated protein 1 (BAP1) expression as detected by immunohistochemistry (IHC) (BAP1 IHC) and homozygous deletion (HD) of 9p21 as detected by fluorescencein situ hybridization (FISH) (9p21 FISH) are effective for distinguishing malignant mesothelial proliferation from benign proliferation. We have previously reported that immunohistochemical expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, is correlated with the deletion status of 9p21 FISH in MPM tissues. In this study, we investigated whether a combination of MTAP and BAP1 IHC could distinguish sarcomatoid MPM from fibrous pleuritis.

Materials And Methods: We examined IHC expressions of MTAP and BAP1 and 9p21 FISH in sarcomatoid/desmoplastic (n = 18) and biphasic MPM (n = 12) and in fibrous pleuritis (n = 17). In biphasic MPM, only sarcomatoid components were evaluated for IHC and FISH. The sensitivity and specificity of each detection assay for discriminating MPM cases from fibrous pleuritis was determined. In addition, we compared the IHC expression of MTAP with the deletion status of 9p21 FISH.

Results: MTAP IHC and BAP1 IHC showed 80% and 36.7% sensitivity, respectively, and both showed 100% specificity in differentiating MPM from fibrous pleuritis. A combination of MTAP and BAP1 IHC yielded greater sensitivity (90%) than that detected for MTAP IHC alone or BAP1 IHC alone. Moreover, a high degree of concordance was observed between the results of MTAP IHC and HD of 9p21 FISH (κ = 0.63).

Conclusions: With an accurate interpretation of results, combined MTAP and BAP1 IHC is a reliable and effective method for distinguishing sarcomatoid MPM from fibrous pleuritis.

Copyright © 2018 Elsevier B.V. All rights reserved.
A patient with malignant pleural mesothelioma carrying BRAF V600E mutation responding to vemurafenib. Y. Chen, B. Chen, X. Zhu, et al. 2018;116:96-98. Case report · Letter PubMed · Publisher

Summary

The authors reported a 65-year-old Chinese man with advanced malignant pleural mesothelioma carrying a BRAF V600E mutation who was treated with vemurafenib, an inhibitor of mutated BRAF. He presented at Zhuji People's Hospital, Zhejiang Province, China, with three months of fatigue and weight loss, and denied occupational asbestos exposure. CT showed a left pleural effusion, nodules in the opposite lung and bone destruction. Thoracoscopic biopsy confirmed epithelioid mesothelioma, positive for WT-1 and calretinin. He received three cycles of pemetrexed-based chemotherapy, then stopped because of intolerable toxicity; response could not be evaluated. Three months later the disease had progressed, with new liver lesions. He declined a liver re-biopsy, so gene sequencing was performed on circulating tumour cells from blood. It showed a BRAF V600E mutation (52.06% abundance), which Sanger sequencing confirmed. He then took vemurafenib off-label at 960 mg twice daily. Within one week he no longer needed painkillers and his breathlessness eased. At six weeks CT showed a partial response in the pleura, lung and liver. Side effects were grade 2 fatigue, nausea and vomiting. Six weeks later the disease progressed and vemurafenib was stopped, giving 12 weeks of progression-free survival. The authors described this as the first reported case of its kind and concluded that vemurafenib showed modest activity, which needs confirmation in larger series of patients.

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Antibody drug conjugates in thoracic malignancies. J.M. Pacheco, D.R. Camidge. 2018;124:260-269. Review PubMed · Publisher

Abstract

Antibody drug conjugates (ADCs) have the potential to alter the efficacy: toxicity ratio of cytotoxic therapy utilizing surface markers on cancer cells as antibody targets to preferentially deliver toxic payloads to tumor cells while limiting systemic toxicity. Multiple ADCs, differing in their antibody targets, cytotoxic payloads and linker molecules are currently being evaluated in non-small-cell lung cancer, small-cell lung cancer and malignant pleural mesothelioma. Here we review the available data in thoracic malignancies and the potential issues influencing the efficacy and toxicity of these approaches.

Copyright © 2018 Elsevier B.V. All rights reserved.
Assessing the completeness and correctness of the registration of malignant mesothelioma in Belgium. M. Rosskamp, H. De Schutter, K. Henau, et al. 2018;122:38-43. PubMed · Publisher

Abstract

Objectives: Malignant mesothelioma (MM) is a rare and aggressive cancer mostly caused by asbestos exposure, and for which the diagnosis is difficult. This study aimed to assess the completeness and correctness of MM registration using 3 independent national databases: the Belgian Cancer Registry (BCR), the population-based mortality statistics (certificates of death, COD), and the Belgian Mesothelioma Registry (BMR).

Methods: The study cohort included all MM reported to the BCR and diagnosed between 2004 and 2012 (n = 2292), all patients reviewed by the pathology commission of the BMR (2004-2012; n = 2019), and COD data for all Belgian citizens (2004-2013). Available data were compared in terms of registered cases, histological diagnosis, performed immunohistochemical (IHC) tests, and IHC test results.

Results: Comparison of BCR with BMR registrations showed 94.8% concordant cases. The proportion of MM diagnoses originally reported to BCR with unspecified MM morphology was reduced from 25.8% to less than 1%.

Results: from IHC tests were available for 95.3% of concordant MM cases. Different IHC patterns could be distinguished by MM histology. MM cases registered at BCR for which COD mentioned an MM as underlying cause of death represented 76.4% of deceased cases. MM long-term survivors (survival >3 years; 10.9%) were characterised by distinct clinical and biological characteristics.

Conclusions: A comparison of independent Belgian MM registration databases elucidated under-registration and misclassification and revealed possible reasons for observed discordances. Combining all the available information resulted in enhanced completeness and correctness of MM registration in Belgium and allowed for the identification and characterisation of MM long-term survivors.

Copyright © 2018 Elsevier B.V. All rights reserved.
Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma. R. Tranchant, L. Quetel, F. Montagne, et al. 2018;126:15-24. PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited therapeutic options, requiring the development of efficient targeted therapies based on molecular phenotype of the tumor and to identify predictive biomarkers of the response.

Materials And Methods: The effect of inhibitors was investigated by cell viability assessment on primary MPM cell lines established in our laboratory from patient tumors, well characterized at the molecular level. Effects on apoptosis, cell proliferation and viability on MPM growing in multicellular spheroid were also assessed for verteporfin. Gene and protein expression, and gene knockdown by RNA interference were used to define mechanism of inhibition and specific predictive biomarkers.

Results: Anti-tumor effect of eight major signaling pathways inhibitors involved in mesothelial carcinogenesis was investigated. Three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor. Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors.

Conclusion: Our study shows that drug screening on well-characterized MPM cells allows for the identification of novel potential therapeutic strategies and defining specific biomarkers predictive of the drug response.

Copyright © 2018 Elsevier B.V. All rights reserved.
Computed tomography in the evaluation of malignant pleural mesothelioma-Association of tumor size to a sarcomatoid histology, a more advanced TNM stage and poor survival. J. Paajanen, S. Laaksonen, I. Ilonen, et al. 2018;116:73-79. PubMed · Publisher

Abstract

Objectives: Appropriate clinical staging of malignant pleural mesothelioma (MPM) is critical for correct treatment decisions. Newly revised TNM staging protocol has been released for MPM. We investigated baseline computed tomography (CT) characteristics of MPM patients, the new staging system and a simple tumor size (TS) assessment in terms of survival.

Materials And Methods: As part of our study that included all MPM patients diagnosed in Finland 2000-2012, we retrospectively reviewed 161 CT scans of MPM patients diagnosed between 2007 and 2012 in the Hospital District of Helsinki and Uusimaa. TS was estimated by using the maximal tumor thickness and grading tumor extension along the chest wall. Cox Regression models were used to identify relationships between survival, clinicopathological factors and CT-findings.

Results: The median length of follow-up was 9.7 months and the median survival 9.1 months. The right sided tumors tended to be more advanced at baseline and had worse prognosis in the univariate analyses. In the multivariate survival model, TS, pleural effusion along with non-epithelioid histology were predictors of poor survival. Tumor size correlated significantly with a sarcomatoid histopathological finding and several parameters linked to a more advanced TNM stage. Most patients were diagnosed with locally advanced stage, while 12 (7%) had no sign of the tumor in CT.

Conclusion: In this study, we demonstrate a novel approach for MPM tumor size evaluation that has a strong relationship with mortality, sarcomatoid histology and TNM stage groups. TS could be used for prognostic purposes and it may be a useful method for assessing therapy responses.

Copyright © 2018 Elsevier B.V. All rights reserved.
Current efforts in research of pleural mesothelioma-An analysis of the ClinicalTrials.gov registry. K. Süveg, P.M. Putora, T. Berghmans, et al. 2018;124:12-18. Review PubMed · Publisher

Abstract

Objectives: Currently there are many uncertainties in the optimal treatment of malignant pleural mesothelioma (MPM), this is reflected in discrepancies between current guidelines. Our aim was to evaluate the current status of prospective interventional clinical trials within the ClinicalTrials.gov registry in MPM in order to predict a potential impact on MPM management in the next years.

Material And Methods: The records of 263.832 clinical trials registered were searched in December 2017. Trials starting between 2005 and 2017 (n = 262) were selected for further manual review. Trials including other tumour entities or mesothelioma originating outside the pleura (n = 94) were excluded, as well as trials where the primary endpoint has already been published (n = 22).

Results: In total, 91 clinical trials were identified and selected for further analysis. Most trials had a single arm design, were in phase I, and were non-randomized. Academic centres were recorded as primary sponsors in the majority of trials (56%), followed by industry in 21%. Most studies investigated targeted (n = 42) or cytotoxic therapies (n = 39). Ten studies investigated different genetic therapies. In 67% of the trials (n = 61) targeted and/or cytotoxic therapies were involved. Treatments involving surgery were investigated in 12 trials (13%), radiotherapy in 10 trials (11%). Only five studies (6%) were phase 3 studies and one was a phase 2/3 study. Four of these five phase 3 trials investigated targeted therapies, while one trial investigated prophylactic radiotherapy of operative tracts.

Conclusions: Currently running trials in MPM are mostly in early phases and dominated by systemic therapies. Very few trials evaluate loco-regional therapeutic approaches. The current controversy surrounding the use of surgery and radiotherapy within multimodal therapy strategies will not be answered by these trials in the coming years.

Copyright © 2018 Elsevier B.V. All rights reserved.
Early Contrast Enhancement: A novel magnetic resonance imaging biomarker of pleural malignancy. S. Tsim, C.A. Humphreys, G.W. Cowell, et al. 2018;118:48-56. PubMed · Publisher · Free full text

Abstract

Introduction: Pleural Malignancy (PM) is often occult on subjective radiological assessment. We sought to define a novel, semi-objective Magnetic Resonance Imaging (MRI) biomarker of PM, targeted to increased tumour microvessel density (MVD) and applicable to minimal pleural thickening.

Materials And Methods: 60 consecutive patients with suspected PM underwent contrast-enhanced 3-T MRI then pleural biopsy. In 58/60, parietal pleura signal intensity (SI) was measured in multiple regions of interest (ROI) at multiple time-points, generating ROI SI/time curves and Mean SI gradient (MSIG: SI increment/time). The diagnostic performance of Early Contrast Enhancement (ECE; which was defined as a SI peak in at least one ROI at or before 4.5 min) was compared with subjective MRI and Computed Tomography (CT) morphology results. MSIG was correlated against tumour MVD (based on Factor VIII immunostain) in 31 patients with Mesothelioma.

Results: 71% (41/58) patients had PM. Pleural thickening was <10 mm in 49/58 (84%). ECE sensitivity was 83% (95% CI 61-94%), specificity 83% (95% CI 68-91%), positive predictive value 68% (95% CI 47-84%), negative predictive value 92% (78-97%). ECE performance was similar or superior to subjective CT and MRI. MSIG correlated with MVD (r = 0.4258, p = .02).

Discussion: ECE is a semi-objective, perfusion-based biomarker of PM, measurable in minimal pleural thickening. Further studies are warranted.

Copyright © 2018 Elsevier B.V. All rights reserved.
Facility volume and postoperative outcomes for malignant pleural mesothelioma: A National Cancer Data Base analysis. V. Verma, C.A. Ahern, C.G. Berlind, et al. 2018;120:7-13. PubMed · Publisher

Abstract

Purpose: This study of a large, contemporary national database evaluated postoperative outcomes and overall survival (OS) for malignant pleural mesothelioma (MPM) by facility volume.

Methods: The National Cancer Database was queried for newly-diagnosed non-metastatic MPM undergoing definitive surgery (extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)). Patients were dichotomized into those receiving therapy at a high-volume facility (HVF), defined a priori at the 90th percentile of case volume, with all others categorized as lower-volume facilities (LVFs). Statistics included multivariable logistic regression, Kaplan-Meier analysis, propensity-matching, and multivariable Cox proportional hazards modeling. Sensitivity analysis varied the dichotomized HVF-LVF cutoff and evaluated effects on postoperative outcomes and OS.

Results: Of 1307 patients, 621 (48%) were treated at LVFs and 686 (52%) at HVFs. HVFs were more often in the Middle/South Atlantic regions, and less likely in New England, South, and Midwest. Notably, 75% of procedures at HVFs were P/Ds, versus 84% at LVFs (p < 0.001). Patients treated at HVFs experienced shorter length of postoperative hospitalization (p = 0.035), lower 30-day readmission rates (4.6% vs. 6.1%, p = 0.021), and lower 90-day mortality rates (10.0% vs. 14.6%, p = 0.029). Median OS for respective groups were 18 versus 15 months (p = 0.010), which were not significant following propensity-matching (p = 0.540). On multivariable analysis, facility volume did not independently predict for OS. Sensitivity analyses confirmed the postoperative outcomes and OS findings.

Conclusions: This is the largest investigation to date assessing facility volume and outcomes following surgery for MPM. Although no independent effects on OS were observed, postoperative outcomes were more favorable at HVFs. These findings have implications for postoperative management, patient counseling, referring providers, and cost-effectiveness.

Copyright © 2018 Elsevier B.V. All rights reserved.
Genomic changes of chromosomes 8p23.1 and 1q21: Novel mutations in malignant mesothelioma. G. Serio, L. Vimercati, A. Pennella, et al. 2018;126:106-111. PubMed · Publisher

Abstract

Introduction: Malignant mesothelioma is an aggressive malignancy of the thoracic cavity caused by prior asbestos exposure. In the peritoneum the mesothelioma is an extremely rare condition. In the present preliminary study, high-resolution array-comparative genomic hybridization (a-CGH) was performed to identify genetic imbalances in a series of malignant peritoneal mesothelioma cases.

Materials And Methods: Between 1990 and 2008, among the cases recorded in the Apulia Mesothelioma Register, we found 22 peritoneal mesothelioma cases. CGH-array was performed on samples from all patients.

Results: The CGH-array analysis revealed multiple chromosomal imbalances. Interestingly, deletion at 8p23.1 was observed in 12 cases. Furthermore, another novel deletion at 1q21 was present in 11. Often, 1q21 and 8p23.1 losses were present in the same patient (7 cases). Losses of BAP1 and CDKN2A loci were not detected.

Discussion: The region at 8p23.1 contains the beta-defensin gene cluster (DEF) and 1q21 contains ubiquitin conjugating enzyme E2 (UBE2Q1). We hypotesized that the loss of function of ubiquitination, as well as of the defensins, could play an important role in the initial development and subsequent progression of mesothelioma.

Copyright © 2018 Elsevier B.V. All rights reserved.
Highlights of the 14th international mesothelioma interest group meeting: Pathologic separation of benign from malignant mesothelial proliferations and histologic/molecular analysis of malignant mesothelioma subtypes. A. Churg, K. Nabeshima, G. Ali, et al. 2018;124:95-101. PubMed · Publisher

Abstract

Objectives: The separation of benign from malignant mesothelial proliferations and exact subclassification of mesothelioma subtypes is crucial to determining patient care and prognosis but morphologically can be very difficult.

Methods: This session of the 2018 IMIG meeting addressed these problems.

Results: A new immunohistochemical marker, methylthioadenosine phosphorylase, was shown to correlate well with CDKN2A FISH and is cheaper and faster to run. A 117 gene expression panel also provided good separation on both tissue biopsy and cytology samples. Review of a series of mesotheliomas thought to be biphasic produced only a moderate level of agreement among expert pathologists with some cases being classified as purely epithelioid or sarcomatoid; these classifications had prognostic significance. The entity called transitional mesothelioma was found to behave exactly like sarcomatoid mesothelioma. RNA-seq analysis of a large series of mesotheliomas from a public database showed that, genetically, the morphologic breakdown into epithelioid, sarcomatoid, or biphasic mesotheliomas is artificial because there is a continuous spectrum of genomic changes. There are now criteria for the diagnosis of mesothelioma in situ and this is potentially important, since such cases might be curable.

Conclusions: This session documented new morphological and molecular approaches to separating benign from malignant mesothelial proliferations and to subclassifying malignant mesoteheliomas in clinical relevant ways.

Copyright © 2018 Elsevier B.V. All rights reserved.
Loss of C/EBP-β LIP drives cisplatin resistance in malignant pleural mesothelioma. J. Kopecka, I.C. Salaroglio, L. Righi, et al. 2018;120:34-45. PubMed · Publisher

Abstract

Objectives: Cisplatin-based chemotherapy is moderately active in malignant pleural mesothelioma (MPM) due to intrinsic drug resistance and to low immunogenicity of MPM cells. CAAT/enhancer binding protein (C/EBP)-β LIP is a pro-apoptotic and chemosensitizing transcription factor activated in response to endoplasmic reticulum (ER) stress.

Materials And Methods: We investigated if LIP levels can predict the clinical response to cisplatin and survival of MPM patients receiving cisplatin-based chemotherapy. We studied the LIP-dependent mechanisms determining cisplatin-resistance and we identified pharmacological approaches targeting LIP, able to restore cisplatin sensitiveness, in patient-derived MPM cells and animal models. Results were analyzed by a one-way analysis of variance test.

Results: We found that LIP was degraded by constitutive ubiquitination in primary MPM cells derived from patients poorly responsive to cisplatin. LIP ubiquitination was directly correlated with cisplatin chemosensitivity and was associated with patients' survival after chemotherapy. Overexpression of LIP restored cisplatin's pro-apoptotic effect by activating CHOP/TRB3/caspase 3 axis and up-regulating calreticulin, that triggered MPM cell phagocytosis by dendritic cells and expanded autologous anti-tumor CD8+CD107+T-cytotoxic lymphocytes. Proteasome inhibitor carfilzomib and lysosome inhibitor chloroquine prevented LIP degradation. The triple combination of carfilzomib, chloroquine and cisplatin increased ER stress-triggered apoptosis and immunogenic cell death in patients' samples, and reduced tumor growth in cisplatin-resistant MPM preclinical models.

Conclusion: The loss of LIP mediates cisplatin resistance, rendering LIP a possible predictor of cisplatin response in MPM patients. The association of proteasome and lysosome inhibitors reverses cisplatin resistance by restoring LIP levels and may represent a new adjuvant strategy in MPM treatment.

Copyright © 2018 Elsevier B.V. All rights reserved.
Malignant cells from pleural fluids in malignant mesothelioma patients reveal novel mutations. S. Sneddon, I. Dick, Y.C.G. Lee, et al. 2018;119:64-70. PubMed · Publisher

Abstract

Objectives: Malignant mesothelioma (MM) is an asbestos related tumour affecting cells of serosal cavities. More than 70% of MM patients develop pleural effusions which contain tumour cells, representing a readily accessible source of malignant cells for genetic analysis. Although common somatic mutations and losses have been identified in solid MM tumours, the characterization of tumour cells within pleural effusions could provide novel insights but is little studied.

Materials And Methods: DNA and RNA were extracted from cells from short term cultures of 27 human MM pleural effusion samples. Whole exome and transcriptome sequencing was performed using the Ion Torrent platform. Somatic mutations were identified using VarScan2 and SomaticSniper. Copy number alterations were identified using ExomeCNV in R. Significant copy number alterations were identified across all samples using GISTIC2.0. The association between tumour intrinsic properties and survival was analyzed using the Cox proportional hazards regression model.

Results: We identified BAP1, CDKN2A and NF2 alterations in the cells from MM pleural effusions at a higher frequency than what is typically seen in MM tumours from surgical series. The median mutation rate was 1.09 mutations/Mb. TRAF7 and LATS2 alterations were also identified at a high frequency (66% and 59% respectively). Novel regions of interest were identified, including alterations in FGFR3, and the regions 19p13.3, 8p23.1 and 1p36.32.

Conclusion: Short term cultures of tumour cells from MM pleural effusions offer an accessible alternative to surgical tumour biopsies in the study of MM genomics and reveal novel mutations of interest. Pleural effusion tumour cells provide an opportunity for the monitoring of tumour dynamics, treatment response and the clonal evolution of MM tumours.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
Real-life treatment practice for malignant pleural mesothelioma in Belgium. M. Rosskamp, G. Macq, K. Nackaerts, et al. 2018;125:258-264. PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, for which treatment is often limited to palliative combination chemotherapy. Multimodality-therapy, including radical surgery, is largely restricted to clinical trials, leaving its benefit currently unclear. This study aimed to get a comprehensive view on real-world MPM treatment at the Belgian population level, to assess survival and to identify prognostic factors.

Materials And Methods: The study period covered the incidence years 2004-2012 (N = 1453). Starting from the Belgian Cancer Registry, additional information regarding patient characteristics, diagnosis and treatment was retrieved from multiple data sources. Adjusted cox proportional-hazard regression models using time-dependent covariates were performed to assess survival in relation to treatment patterns and centre volume.

Results: Sixty-nine percent of patients underwent tumour-directed treatment, mostly cisplatin-pemetrexed chemotherapy. Radical surgery was mainly performed in younger patients with epithelioid subtype. Centre volume, surgery and chemotherapy showed a positive relation with survival in univariable analyses, but only chemotherapy remained significantly relevant in multivariable analyses. Younger patients, females, and epithelioid subtypes also independently had a better survival.

Conclusion: This large population-based study provides insights in MPM treatment practice in Belgium. Centre volume and surgery being related to survival in univariable analyses, only chemotherapy remained prognostic after adjustment.

Copyright © 2018 Elsevier B.V. All rights reserved.
Tumor-specific genetic variants can be detected in circulating cell-free DNA of malignant pleural mesothelioma patients. M. Hylebos, K. Op de Beeck, P. Pauwels, et al. 2018;124:19-22. PubMed · Publisher

Abstract

Objectives: Patients diagnosed with malignant pleural mesothelioma (MPM) face a poor prognosis, with an overall survival plateauing at a median of one year. This can be explained by difficulties in early diagnosis, effective treatment and treatment monitoring. Circulating cell-free tumor DNA (ctDNA) is emerging as an interesting biomarker addressing some of these issues. So far, the development of ctDNA in MPM lags behind that in other tumors. In this study, the possibility of tracing tumor-specific genetic variants, identified in MPM tissue, in circulating DNA of the corresponding patients is investigated.

Materials And Methods: Whole exome sequencing was performed on paired tumor and germline DNA of ten MPM patients, of which five were treatment naïve. For each patient, a tumor-specific variant was selected and traced in tumor, germline and circulating DNA using droplet digital PCR in two independent runs.

Results: All but one tumor-specific variants, selected after whole exome sequencing, were validated on primary tumor tissue using droplet digital PCR analysis. Patient-specific, selected variants could be detected in circulating DNA of three MPM patients, either in one or both independent droplet digital PCR runs. Mutated fractions in circulating DNA ranged from 0.28 to 0.9%. Interestingly, all patients whose circulating DNA samples contained tumor-specific variants, were treatment naïve.

Conclusion: We demonstrated for the first time the presence of ctDNA within circulating DNA of treatment naïve MPM patients. This finding opens perspectives towards the use of ctDNA as a biomarker for (early and differential) diagnosis, treatment and treatment monitoring of MPM, which all remain challenging.

Copyright © 2018 Elsevier B.V. All rights reserved.
A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group. S.A. Laurie, D. Hao, N.B. Leighl, et al. 2017;104:65-69. PubMed · Publisher

Abstract

Objectives: Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM.

Methods: This open-label multicentre phase II trial [NCT01769547] enrolled fit, consenting adult patients with advanced MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Dovitinib was administered orally at 500mg/day for 5days on, 2days off, in 28-day cycles. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. The primary end-point was the proportion of patients progression-free at 3 months (PF3) using a two-stage design.

Results: 12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1-8). One unconfirmed partial response was observed. PF3 was 50% (95% confidence interval 28.4% to 88.0%); although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population. One of 12 tumour specimens had low amplification of FGFR-1.

Conclusions: Dovitinib has minimal activity in previously-treated MPM. The role of the FGFR pathway in MPM remains unclear.

Copyright Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Challenging a dogma; AJCC 8th staging system is not sufficient to predict outcomes of patients with malignant pleural mesothelioma. O. Abdel-Rahman. 2017;113:128-133. PubMed · Publisher

Abstract

Background: The 8th edition of malignant pleural mesothelioma (MPM) American Joint Committee on Cancer (AJCC) staging system has been published. The current analysis aims to evaluate its performance in a population-based setting among patients recorded within the surveillance, epidemiology and end results (SEER) database.

Methods: SEER database (2004-2013) has been accessed through SEER*Stat program and AJCC 8th edition stage groups were reconstructed. Survival analyses (overall and cancer-specific) were conducted according to 6th and 8th editions through Kaplan-Meier analysis. Cox-regression multivariate model was also utilized for pair wise comparisons between different prognostic groups for overall and cancer-specific survival.

Results: A total of 5382 patients with MPM were identified in the period from 2004 to 2013. According to the 6th edition, significant pair wise P values for overall survival included: IA vs. III (P=0.027); IA vs. IV: P<0.0001; IB vs. IV: P<0.0001; II vs. III: P<0.0001; II vs. IV: P<0.0001; III vs. IV: P<0.0001). According to the 8th edition, significant pair wise P values for overall survival included: all stages vs. IV: P<0.0001; IA vs. II: P=0.046; IA vs. IIIA: P=0.022; IA vs. IIIB: P <0.0001; IB vs. II: P<0.0001; IB vs. IIIB: P<0.0001; II vs. IIIA: P<0.0001; IIIA vs. IIIB: P<0.0001). C-index for 6th edition was 0.539 (SE: 0.008; 95% CI: 0.524-0.555); while C-index for 8th edition was 0.540 (SE: 0.008; 95% CI: 0.525-0.556). Based on the above findings, a simplified staging system was proposed and overall and cancer-specific survivals were evaluated according to the simplified system. For overall and cancer-specific survival assessment, P values for all pair wise comparisons among different stages were significant (<0.01).

Conclusion: The prognostic performance of both the 6th and 8th AJCC editions is unsatisfactory; there is a need for a more practical and prognostically relevant staging system for MPM.

Copyright © 2017 Elsevier B.V. All rights reserved.
Chest ultrasonography in health surveillance of asbestos related pleural disease. S. Scarlata, P. Finamore, G. Giannunzio, et al. 2017;111:139-142. PubMed · Publisher

Abstract

High resolution computed tomography, (HRCT), is currently considered the diagnostic gold standard to diagnose early stage malignant pleural mesothelioma and other non-malignant pleural conditions, but it is expensive and exposes the patient to radiation dose. In a screening and population medicine perspective, Thoracic Ultrasounds may become a valuable alternative because it can detect minimal changes in pleural surface, is widely available and safe. On these bases, we therefore validated thoracic US in subjects with history of exposure to asbestos, having HRCT as the reference standard. One hundred-fifty subjects were screened and 117 were recruited. Pleural abnormalities at US and/or HRCT were detected in 66 out of 117 subjects (prevalence=57%), and their prevalence was unrelated to both mansion and smoking habit, while mean age and mean length of exposure were higher in those having pleural abnormalities (age=47±5 vs 44±6years, p<0.05;years of exposure=20±7 vs 17±5, p<0.05). Thirteen out of 19 subjects with pleural abnormalities at HRCT were also identified by thoracic US, whereas 47 participants had lesions seen at US, but not at the HRCT scan. Positive and negative percent agreement were 66.6% and 51.8%, respectively; the McNemar's test for equality showed a p-value <0.001. In conclusion, chest US might complement HRCT in the health surveillance of asbestos exposed population to detect earlier lesions or to follow up US approachable lesions. Further research is needed to clarify whether this approach may enhance early recognition of pleural mesothelioma and ameliorate prognosis.

Copyright © 2017 Elsevier B.V. All rights reserved.
Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy. M. Tomasetti, M. Amati, J. Neuzil, et al. 2017;107:65-72. Review PubMed · Publisher

Abstract

Lung cancer (LC) and malignant mesothelioma (MM) are malignancies linked to environmental/occupational exposure, which are increasing in incidence. Despite advances in chemotherapy, radiation therapy and surgical management of LC and MM, the median survival remains less than 12 months. Early detection represents one of the most promising approaches to reducing the growing cancer burden by increasing chemotherapy treatment efficiency. At present, early diagnosis is rather difficult and depends on invasive sampling of pleural fluid or tissue. Currently the most widely used screening method for the surveillance of exposed subjects is computed tomography (CT), which is costly, exposes patients to repeated high doses of radiation, and typically detects the malignancy at its advanced stage. Recently, a virtually non-invasive 'liquid biopsy' has emerged as source to characterize tumour heterogeneity. The genetic/epigenetic changes during tumour evolution can be detected in fluids and used as cancer biomarkers. Therefore, increasingly interest has been paid to circulating (cell-free) nucleic acids (cfDNA/cfmiRNAs) epigenetically modulated during cell transformation. Hypermethylation of tumour suppressor genes is frequently observed in cancers, and such epigenetic changes are potential markers for detecting and monitoring tumours. The same predictive biomarkers can be used as therapy targets.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Cost-effectiveness analysis of additional bevacizumab to pemetrexed plus cisplatin for malignant pleural mesothelioma based on the MAPS trial. M. Zhan, H. Zheng, T. Xu, et al. 2017;110:1-6. Randomized trial PubMed · Publisher

Abstract

Purpose: Malignant pleural mesothelioma (MPM) is a rare malignancy, and pemetrexed/cisplatin (PC) is the gold standard first-line regime. This study evaluated the cost-effectiveness of the addition of bevacizumab to PC (with maintenance bevacizumab) for unresectable MPM based on a phase III trial that showed a survival benefit compared with chemotherapy alone.

Methods: To estimate the incremental cost-effectiveness ratio (ICER) of the incorporation of bevacizumab, a Markov model based on the MAPS trial, including the disease states of progression-free survival, progressive disease and death, was used. Total costs were calculated from a Chinese payer perspective, and health outcomes were converted into quality-adjusted life year (QALY). Model robustness was explored in sensitivity analyses.

Results: The addition of bevacizumab to PC was estimated to increase the cost by $81446.69, with a gain of 0.112 QALYs, resulting in an ICER of $727202.589 per QALY. In both one-way sensitivity and probabilistic sensitivity analyses, the ICER exceeded the commonly accepted willingness-to-pay threshold of 3 times the gross domestic product per capita of China ($23970.00 per QALY). The cost of bevacizumab had the most important impact on the ICER.

Conclusions: The combination of bevacizumab with PC chemotherapy is not a cost-effective treatment option for MPM in China. Given its positive clinical value and extremely low incidence of MPM, an appropriate price discount, assistance programs and medical insurance should be considered to make bevacizumab more affordable for this rare patient population.

Copyright © 2017 Elsevier B.V. All rights reserved.
External validation of prognostic indices for overall survival of malignant pleural mesothelioma. Y. Kataoka, Y. Yamamoto, T. Otsuki, et al. 2017;113:88-92. PubMed · Publisher

Abstract

Objective: There are several prognostic indices (PIs) to predict overall survival (OS) in malignant pleural mesothelioma (MPM) patients. Before using a clinical prediction model in the actual clinical setting, empiric evaluation of its performance based on datasets that were not used to develop the model (i.e., external validation) is essential. The purpose of this study was to conduct an external validation of the PIs for MPM.

Materials And Methods: A retrospective cohort study was performed on MPM patients treated at 2 tertiary hospitals in Japan between 2007 and 2015. The primary outcome was OS. Harrell's c-index, and was calculated to examine the discrimination of three models. The bootstrapping technique was used to evaluate optimism.

Results: The participants comprised 183 patients who underwent surgical treatment (n=61), chemotherapy (n=101), and best supportive care (BSC, n=21). The median OS rates were 1014days for surgery, 690days for chemotherapy, and 545days for best supportive care (BSC). The respective discriminations (95% confidence interval) of the Eastern Cooperative Oncology Group Performance Status, the European Organisation for Research and Treatment of Cancer index, regimen, PS, histology or stage (rPHS) index, and Tagawa index for the OS of MPM patients were 0.532 (0.444-0.620), 0.560 (0.472-0.648), 0.584 (0.452-0.716), and 0.525 (0.453-0.596) for surgery; 0.632 (0.539-0.724), 0.622 (0.548-0.696), 0.677 (0.587-0.766), and 0.545 (0.436-0.653) for chemotherapy; and 0.504 (0.365-0.644), 0.583 (0.456--0.710), 0.704 (0.508-0.899), and 0.583 (0.436-0.730) for BSC.

Conclusions: Each PI showed poor discrimination for MPM patients who underwent surgical treatment. The rPHS index showed moderate discrimination for patients given chemotherapy and BSC.

Copyright © 2017 Elsevier B.V. All rights reserved.
Immune checkpoint inhibition in malignant mesothelioma: Does it have a future?. A.S. Mansfield. 2017;105:49-51. Editorial PubMed · Publisher

Summary

In this editorial, the author reviewed recent results of immune checkpoint inhibitors targeting PD-1 or its ligand PD-L1 in malignant pleural mesothelioma (MPM), for which no second-line therapy is specifically approved. He noted that PD-L1 is expressed in about 40% of MPM cases, that its expression is a negative prognostic marker, and that emerging data suggest it varies between paired lesions, potentially limiting its use as a predictive biomarker. In a phase 1 pembrolizumab cohort of PD-L1-positive patients, 25 were treated. Of these, 24% responded and 52% had stable disease. An update reported a 40% clinical benefit rate and median overall survival of 18 months. In a phase 2 pembrolizumab trial with 35 enrolled patients, 21% had partial responses and 56% had stable disease, and median progression-free survival was 6.2 months. Two patients died on study, and responses occurred regardless of PD-L1 expression. A phase 2 nivolumab trial of 34 patients reported a 50% disease control rate. An avelumab cohort of 53 patients reported a 9.4% response rate and 56.6% disease control. The author attributed differences between trials partly to differing response assessment methods, PD-L1 tests and lack of stratification for BAP-1 mutations, and concluded that no strategy could be called superior. He posited that immunotherapy will likely replace second-line approaches and challenge front-line therapy, and urged continued clinical trial participation.

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Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry. T. Hida, M. Hamasaki, S. Matsumoto, et al. 2017;104:98-105. PubMed · Publisher

Abstract

Objectives: Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is still challenging. Detection of homozygous deletion (HD) of 9p21 region including p16INK4A (p16) by fluorescence in situ hybridization (FISH) and immunohistochemical detection of loss of BRCA1 associated protein 1 (BAP1), are reliable markers for MPM diagnosis. However, not all laboratories are equipped to perform 9p21 FISH; immunohistochemistry (IHC) is a more common and feasible technique. Thus, we sought to develop a IHC-based method that could predict the deletion of p16 in MPM in concordance with 9p21 FISH.

Materials And Methods: We examined the expression of the 9p21.3-related proteins (p14, p15, p16, and methylthioadenosine phosphorylase (MTAP)) and BAP1 using IHC in 51 MPM and 25 RMH cases, and assessed their correlation with HD of p16 detected by FISH. The diagnostic usefulness of IHC of the 9p21.3-related proteins and BAP1 and their combinations was assessed using the cut-off values set by receiver operating characteristic (ROC) analysis.

Results: Among the 9p21.3-related proteins, MTAP IHC findings showed best concordance with 9p21 FISH results (kappa coefficient of 0.69) and a specificity of 100%. We also examined the combinations of MTAP IHC with the other products. The loss of p16 and MTAP had better concordance (kappa coefficient of 0.71), although lower specificity (85%). For differentiating MPM from RMH, only MTAP showed 100% specificity among the 9p21.3-related proteins, as did BAP1 IHC and 9p21 FISH. Among BAP1 combinations, only that of BAP1 with MTAP showed 100% specificity. Its sensitivity was 76.5%, which was lower than BAP1 IHC and 9p21 FISH combination (84.3%), but higher than BAP1 IHC alone (60.8%) or 9p21 FISH alone (60.8%).

Conclusions: A combination of MTAP or BAP1 loss detected by IHC can likely detect MPM with good sensitivity and 100% specificity, and serve as useful ancillary IHC for discriminating MPM from RMH.

Copyright Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Mesothelioma continues to increase even 40 years after exposure - Evidence from long-term epidemiological observation. B. Świątkowska, N. Szeszenia-Dąbrowska. 2017;108:121-125. PubMed · Publisher

Abstract

Background: Because asbestos dust is considered one of the most dangerous types of dust for people's health, issues related to the effects of asbestos exposure still remain questions about the role of cessation of exposure.

Objectives: The aim of the present study was to determine the importance of temporal patterns, especially the time since the end of exposure in the risk of pleural mesothelioma.

Methods: A total of 131 patients with pleural mesothelioma and 655 frequency matched by gender and year of birth controls enrolled in the health surveillance programme for asbestos-related diseases over the years 2000-2014, were included in the analysis. Conditional logistic regression models were applied to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: The results show that the risk of pleural mesothelioma continued to increase even after 40 years since the last exposure. The estimated odds ratio for the subjects who had their last exposure 40 years ago, compared with the odds ratio of those who had their last exposure 5 years ago, was 2.68 (95%CI: 1.16-.621). We also observed that crocidolite exposure was associated with a very high significant mesothelioma risk, 5-fold higher for those working with mixed exposure compared to the subjects who worked only with chrysotile.

Conclusions: Dose-response relationships in populations occupationally exposed are critical to the study related to environment asbestos contamination. Our findings confirm the strong evidence that mesothelioma risk increases along with the increasing time since exposure termination.

Copyright © 2017 Elsevier B.V. All rights reserved.
Need for randomized clinical trials testing targeted therapies in malignant pleural mesothelioma. N. Sobhani, G. Roviello, S.P. Corona, et al. 2017;114:103-105. Letter · Comment PubMed · Publisher
Pathological complete response in malignant pleural mesothelioma patients following induction chemotherapy: Predictive factors and outcomes. B. Lau, S. Kumar, T. Yan, et al. 2017;111:75-78. PubMed · Publisher

Abstract

A small proportion of patients with malignant pleural mesothelioma (MPM) achieve pathological complete response (CR) following treatment with current practice induction chemotherapy. Our analysis of 58 patients with MPM treated with platinum-based chemotherapy showed 4 patients (7%) attained pathological CR at subsequent extrapleural pneumonectomy (EPP). Patient and tumour factors such as age, gender, smoking habit, histological subtype, and clinical stage were not found to be associated with pathological CR. Patients with pathological CR had longer disease-free survival (29.2 vs. 13.8 months; p=0.08) and overall survival (76.4 vs. 23.4 months; p=0.06) but this did not reach statistical significance. Our study suggests that patients who achieve pathological CR after chemotherapy may have improved survival in MPM.

Copyright © 2017 Elsevier B.V. All rights reserved.
Patterns of care and survival among patients with malignant mesothelioma in the United States. L. Enewold, E. Sharon, A. Thomas. 2017;112:102-108. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is a rare malignancy that is associated with poor survival. This study aimed to describe the patterns of care and subsequent survival among malignant mesothelioma patients in the United States, while adjusting for patient demographics and comorbidities.

Methods: A random sample of patients diagnosed with histologically confirmed mesothelioma in 2011, as reported to the National Cancer Institute's Surveillance Epidemiology and End Results program, were included. Logistic regression and Cox proportional hazard regression were utilized to identify factors associated with receipt of therapy and all-cause mortality, respectively, among patients with pleural mesothelioma.

Results: This study included 389 patients with pleural mesothelioma and 53 patients with non-pleural mesothelioma. Almost a third (29.3%) of the pleural patients and 21.5% of the non-pleural patients received no therapy. Additionally, approximately 60% of both patient groups received systemic therapy. Among pleural mesothelioma patients, receipt of therapy was less likely among older patients. Median survival was 9 months among the pleural patients and 18 months among the non-pleural patients. Receipt of either surgery or systemic therapy and particularly the combination of these two modalities was associated with better all-cause survival. Additionally, among pleural mesothelioma patients, younger age and lower socioeconomic status were found to be associated with better all-cause survival. Comorbidity score was not found to be associated with receipt of treatment nor was it independently associated with survival among pleural mesothelioma patients.

Conclusion: These findings indicate the need for efforts to ensure equitable application of currently available therapies to all patients.

Published by Elsevier B.V.
Pharmacokinetic evaluation of intrapleural perfusion with hyperthermic chemotherapy using cisplatin in patients with malignant pleural effusion. H. Sakaguchi, H. Ishida, H. Nitanda, et al. 2017;104:70-74. PubMed · Publisher

Abstract

Objectives: Malignant pleural effusion (MPE) has a poor prognosis. Most patients are treated with tube thoracostomy and sclerotherapy, although its success rate is around 64%. We have investigated intrapleural perfusion with hyperthermic chemotherapy (IPHC) using cisplatin in a study with a pharmacokinetic evaluation.

Methods: Patients with MPE, performance status of 0-1, possibility of good lung expansion and Cr<1.2mg/dL were treated with IPHC. The circuit was filled with 2000mL of normal saline containing cisplatin at a dose of 80mg/m2. Under video-assisted thoracoscopic surgery, the thoracic cavity was filled and perfused at a speed of approximately 1L/min at a temperature of 43°C for 1h. Perfusion solution and plasma samples were periodically collected, and concentrations of protein-unbound (free) platinum, which was the active derivative of cisplatin, and total platinum were determined by flameless atomic absorption spectrometry.

Results: Twenty patients with MPE (8 lung cancers, 7 mesotheliomas, and 5 others) were enrolled in this study. Rate of free platinum concentration relative to total platinum concentration in perfusion solution after 1hr IPHC at 43°C was 61.1±12.9%. Area under curve (AUC) of free platinum in the pleural space was calculated to be 26.3μg/mLxh, resulting in complete control of pleural effusion for 3 months after IHPC in all cases (95% confidence interval: 83-100%). While, absorption rate of total platinum from the pleural space was 33.8±17.0% (27.4±13.6mg/m2), and the maximum concentration of total platinum in serum was low, 0.66±0.31μg/mL, resulting in controllable side effects; grade 1 renal toxicity: 6 patients, grade 1 emesis: 7 patients.

Conclusions: IPHC with cisplatin showed favorable pharmacokinetic profiles for an optional treatment to control malignant pleural effusion.

Copyright Â© 2016 The Author(s). Published by Elsevier B.V. All rights reserved.
Phenotypes of lung cancer and statistical interactions between tobacco smoking and occupational exposure to asbestos and crystalline silica from a large case-only study: The CaProMat study. M. El Zoghbi, P. Salameh, I. Stücker, et al. 2017;112:140-155. PubMed · Publisher

Abstract

Objectives: The aim of this study was to assess the effect modification of the association between tobacco smoking and phenotypes of lung cancer (histological type, tumor location, and age at diagnosis) by occupational exposure to asbestos or to crystalline silica.

Materials And Methods: The CaProMat study is a pooled case-only study including 7256 male lung cancer cases recruited between 1996 and 2011 in France and Canada. Two job-exposure matrices (JEMs) were used to assess occupational exposure to asbestos and crystalline silica. Statistical interactions between tobacco smoking and occupational exposure to asbestos or crystalline silica were assessed using unconditional logistic regression models for histological type and tumor location and linear regression models for age at diagnosis.

Results: Tobacco smoking was associated with squamous cell carcinoma and small cell carcinomas as well as an earlier age at diagnosis. Additional exposure to either asbestos or crystalline silica did not modify the effect of tobacco smoking for either histological type or age at diagnosis. Neither tobacco smoking nor occupational exposure to asbestos or crystalline silica influenced tumor location.

Conclusions: Tobacco smoking was the main factor related to histological type and age at diagnosis. Those associations were not modified by occupational exposure to asbestos or crystalline silica.

Copyright © 2017 Elsevier B.V. All rights reserved.
Precision immunotherapy; dynamics in the cellular profile of pleural effusions in malignant mesothelioma patients. L.A. Lievense, K. Bezemer, R. Cornelissen, et al. 2017;107:36-40. PubMed · Publisher

Abstract

Objectives: Clinical studies have proven the potential of immunotherapy in malignancies. To increase efficacy, a prerequisite is that treatment is tailored, so precision immune-oncology is the logical next step. In order to tailor treatment, characterization of the patient's tumor environment is key. Pleural effusion (PE) often accompanies malignant pleural mesothelioma (MPM) and is an important part of the MPM environment. Furthermore, the composition of PE is used as surrogate for the tumor. In this study, we provide an insight in the dynamics of the MPM environment through characterization of PE composition over time and show that the immunological characteristics of PE do not necessarily mirror those of the tumor.

Materials And Methods: From 5 MPM patients, PE and tumor biopsies were acquired at the same time point. From one of these patients multiple PEs were obtained. PEs were acquired performing thoracocenteses and total cell amounts were determined. Immunohistochemistry was performed to quantify immune cell composition (T cells, macrophages) and tumor cells in PE derived cytospins and tumor biopsies.

Results: The PE amount and (immune) cellular composition varied considerably over time between multiple (n=10) thoracocenteses. These dynamics could in part be attributed to the treatment regimen consisting of standard chemotherapy and dendritic cell (DC)-based immunotherapy. In addition, the presence of T cells and macrophages in PE did not necessarily mirror the infiltration of these immune cells within tumor biopsies in 4 out of 5 patients.

Conclusions: In this proof-of-concept study with limited sample size, we demonstrate that the composition of PE is dynamic and influenced by treatment. Furthermore, the immune cell composition of PE does not automatically reflect the properties of tumor tissue. This has major consequences when applying precision immunotherapy based on PE findings in patients. Furthermore, it implies a regulated trafficking of immune regulating cells within the tumor environment.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Targeting BAP1: a new paradigm for mesothelioma. L.M. Schunselaar, W. Zwart, P. Baas. 2017;109:145-146. Editorial PubMed · Publisher

Abstract

New treatment strategies for malignant pleural mesothelioma (MPM) are important. BAP1 mutations are present in 47-67% of the MPM tumors, making this a good target for treatment. Multiple functions of BAP1 are investigated in the preclinical situation. Due to many functions of BAP1, the phenotypic effect of BAP1 is diverse. Preclinical data on inhibitors reversing these phenotypic effects are promising. However, the mechanism of BAP1 is not fully elucidated yet and further research about the mechanism and possible inhibitors is necessary.

Copyright © 2017 Elsevier B.V. All rights reserved.
The diagnostic performance of routinely acquired and reported computed tomography imaging in patients presenting with suspected pleural malignancy. S. Tsim, D.B. Stobo, L. Alexander, et al. 2017;103:38-43. PubMed · Publisher · Free full text

Abstract

Objectives: Contrast-enhanced computed tomography (CT) provides essential cross-sectional imaging data in patients with suspected pleural malignancy (PM). The performance of CT in routine practice may be lower than in previously reported research. We assessed this relative to 'real-life' factors including use of early arterial-phase contrast enhancement (by CT pulmonary angiography (CTPA)) and non-specialist radiology reporting.

Materials And Methods: Routinely acquired and reported CT scans in patients recruited to the DIAPHRAGM study (a prospective, multi-centre observational study of mesothelioma biomarkers) between January 2014 and April 2016 were retrospectively reviewed. CT reports were classified as malignant if they included specific terms e.g. "suspicious of malignancy", "stage M1a" and benign if others were used e.g. "indeterminate", "no cause identified". All patients followed a standard diagnostic algorithm. The diagnostic performance of CT (overall and based on the above factors) was assessed using 2×2 Contingency Tables.

Results: 30/345 (9%) eligible patients were excluded (non-contrast (n=13) or non-contiguous CT (n=4), incomplete follow-up (n=13)). 195/315 (62%) patients studied had PM; 90% were cyto-histologically confirmed. 172/315 (55%) presented as an acute admission, of whom 31/172 (18%) had CTPA. Overall, CT sensitivity was 58% (95% CI 51-65%); specificity was 80% (95% CI 72-87%). Sensitivity of CTPA (performed in 31/315 (10%)) was lower (27% (95% CI 9-53%)) than venous-phase CT (61% (95% CI 53-68%) p=0.0056). Sensitivity of specialist thoracic radiologist reporting was higher (68% (95% CI 55-79%)) than non-specialist reporting (53% (95% CI 44-62%) p=0.0488). Specificity was not significantly different.

Conclusion: The diagnostic performance of CT in routine clinical practice is insufficient to exclude or confirm PM. A benign CT report should not dissuade pleural sampling where the presence of primary or secondary pleural malignancy would alter management. Sensitivity is lower with non-thoracic radiology reporting and particularly low using CTPA.

Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Analysis of expression of PTEN/PI3K pathway and programmed cell death ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM). S. Cedrés, S. Ponce-Aix, N. Pardo-Aranda, et al. 2016;96:1-6. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3K pathway and PD-L1 in MPM and its relationship with the patient́s prognosis

Material And Methods: Twenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3K pathway and PD-L1 RESULTS: Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p <0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3K pathway

Conclusions: This study shows PTEN/PI3K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3K pathway in MPM.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Chemokines involved in the early inflammatory response and in pro-tumoral activity in asbestos-exposed workers from an Italian coastal area with territorial clusters of pleural malignant mesothelioma. M. Comar, N. Zanotta, F. Zanconati, et al. 2016;94:61-7. PubMed · Publisher

Abstract

Objectives: Immune mediators are likely to be relevant for the biological response to asbestos exposure. The aim of this study was to investigate the association between immune mediators involved in inflammation, cell survival and angiogenesis, and asbestos-related diseases in workers from a coastal area of North-East Italy with a high incidence of pleural malignant mesothelioma (PMM).

Materials And Methods: A selected custom set of 12 soluble mediators was evaluated with a Luminex platform in sera, pleural fluid and mesothelioma biopsies from 123 asbestos-exposed workers (38 free from pleural-pulmonary disorders, 46 with non-malignant asbestos diseases, 39 with PMM) and in sera from 33 healthy controls from the same territorial area.

Results: Increased immune mediator concentrations were observed in the sera of the asbestos-exposed workers compared to controls for human fibroblast growth factor (FGF-b), vascular endothelial growth factor (VEGF), CCL5 (RANTES), CXCL10 (IP-10), CLEC11A (SCGF-b), CCL27 (CTACK), CCL11 (EOTAXIN), IL-5 and IL-6 (p<0.001). The chemokines IP-10 and RANTES were associated with the severity of asbestos-related diseases. In the workers with PMM, the immune proteins secreted by mesothelioma biopsies showed detectable levels of RANTES, VEGF, and IP-10. In the same workers with PMM, a significant relationship between serum and pleural fluid concentrations was found for RANTES alone.

Conclusions: Occupational exposure to asbestos seems to drive the production of specific growth factors dually involved in the early inflammatory response and in pro-tumoral activity before clinical evidence of related disorders, suggesting that their over-expression may precede the onset of asbestos-related diseases. These findings suggest that some chemokines may have a prognostic role in the progression of asbestos-related diseases and could be used for the health surveillance of either workers with an occupational history of asbestos exposure or patients affected by non-malignant asbestos-related diseases.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Combination of cisplatin and lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma: Report of two cases. Y. Metaxas, R. Cathomas, M. Mark, et al. 2016;102:136-138. Case report · Letter PubMed · Publisher

Abstract

Malignant mesothelioma is an aggressive disease with dismal prognosis despite multimodal treatment including chemotherapy, surgery and radiotherapy. At progression it is possible to provide systemic second-line treatment but its effects are limited. Herein we report two patient cases with mesothelioma who received second-line chemotherapy with the combination of cisplatin and the novel compound lurbinectedin. The combination showed promising activity in both cases with manageable toxicity. We discuss the results of this regime in the light of historical as well as emerging data in mesothelioma.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Diagnostic accuracy of sequential co-registered PET+MR in comparison to PET/CT in local thoracic staging of malignant pleural mesothelioma. K. Martini, A. Meier, I. Opitz, et al. 2016;94:40-5. PubMed · Publisher

Abstract

Purpose: To investigate the diagnostic accuracy of sequential co-registered PET+MR (PET+MR) for local staging of malignant pleural mesothelioma (MPM) compared to PET/CT.

Material And Methods: In a prospective clinical trial 34 consecutive patients (median age 66 years; range 40-79 years; 1 female, 33 male) with known MPM, who underwent PET/CT and PET+MR exams for either staging or re-staging/follow-up were evaluated. Imaging was conducted using a tri-modality PET/CT-MR set-up (Discovery PET/CT 690, 3T Discovery MR 750w, both GE Healthcare, Waukesha, WI, USA). In 26 cases histopathology served as standard of reference. Two independent readers evaluated images for T and N stage, confidence level (sure to unsure; 1-3) and subjective overall image quality (very good to non-diagnostic; 1-4). Inter-observer agreement of T and N stages (Cohen's kappa) and interclass correlation coefficient (ICC) between PET/CT vs. PET+MR was calculated.

Results: Inter observer agreement for evaluation of T and N Stage in PET/CT images was excellent (k=0.844 and k=0.824, respectively), whereas PET+MR imaging showed substantial agreement in T and N stage (k=0.729 and k=0.691, respectively). The ICC of PET/CT vs. PET+MR for evaluation of both, T and N Stage, was excellent (ICC=0.951 and ICC=0.93, respectively). Diagnostic confidence was scored significantly higher in PET+MR compared to PET/CT (mean score=1.66 and 1.93, respectively; p=0.004). Image quality was diagnostic for all image series. Comparing pT and pN stage vs cT and cN stage (n=26 cases), both imaging modalities showed excellent agreement for T stage (ICCPET+MR=0.888 vs. ICCPET/CT=0.853, respectively) and substantial to moderate agreement for N stage (ICCPET+MR=0.683 vs. ICC=0.595PET/CT, respectively).

Conclusion: Our findings suggest that diagnostic accuracy of PET+MR is comparable to PET/CT for local staging of MPM, whereas radiologists felt significantly more confident staging PET+MR compared to PET/CT images (p=0003), using dedicated sequences.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Diffuse malignant mesothelioma and synchronous lung cancer: A clinicopathological study of 18 cases. K.J. Butnor, N.A. Brownlee, A. Mahar, et al. 2016;95:1-7. PubMed · Publisher

Abstract

Objectives: To examine the clinicopathologic characteristics of individuals with diffuse malignant mesothelioma (DMM) occurring concurrently with lung cancer (LC).

Materials And Methods: A database of approximately 3800 patients with DMM was reviewed, from which 18 patients (0.5%) who had synchronous LC were identified. The clinicopathologic features, as well as the occupational exposure history and fiber burden analysis data were examined.

Results: The patient median age was 68 years (range 58-84 years). Of the 18 patients (14 male, 4 female), 11 (61%) had epithelial, 5 (28%) had biphasic, and 2 (11%) had sarcomatoid DMM, with the majority (16 cases; 89%) originating in the pleura and only 2 were peritoneal. Among the histologic types of LC, adenocarcinoma was most frequent (12 cases; 67%), while 5 cases of squamous cell carcinoma, and 1 case of small cell carcinoma were observed. Three patients also had a history of prior malignancy (1 with testicular seminoma and bladder carcinoma and 2 with prostate carcinoma). Fifteen patients had a positive smoking history. All but 3 had documented asbestos exposure. Three had histologic features of asbestosis. Mineral analysis performed in 8 showed an elevated asbestos fiber burden in 4 (22%). Amosite was detected in 4 patients, crocidolite in 3, and non-commercial amphiboles in 5.

Conclusion: The finding of simultaneous carcinoma of the lung and DMM is distinctly unusual. The majority of patients are male smokers with pleural epithelial DMM and lung adenocarcinoma. This study represents the largest cohort of patients reported to date with synchronous malignant mesothelioma and lung cancer, and we propose guidelines for making a diagnosis of synchronous malignant mesothelioma and primary lung cancer.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Hot spot mutations in Finnish non-small cell lung cancers. S. Mäki-Nevala, V.K. Sarhadi, M. Rönty, et al. 2016;99:102-10. PubMed · Publisher

Abstract

Objectives: Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features.

Materials And Methods: Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM).

Results: Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PIK3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure.

Conclusion: Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
How does the timing of chemotherapy affect outcome following radical surgery for malignant pleural mesothelioma?. A.J. Sharkey, K.J. O'Byrne, A. Nakas, et al. 2016;100:5-13. PubMed · Publisher

Abstract

Objectives: There is little evidence regarding the use of chemotherapy as part of multimodality treatment of malignant pleural mesothelioma (MPM). We aimed to determine whether, in those patients fit for chemotherapy, a delay in this treatment affected survival.

Materials And Methods: We analysed postoperative variables of 229 patients undergoing either extrapleural pneumonectomy (EPP) (81 patients) or extended pleurectomy-decortication (EPD) (197 patients) for MPM at a single centre. There was no standard protocol for additional chemotherapy and varied with referral centre. Outcome was compared between 4 chemotherapy strategies: true adjuvant therapy, neo-adjuvant therapy, therapy reserved until evidence of disease progression in those otherwise fit in the post-operative setting, and those unfit for chemotherapy.

Results: There was no effect of the timing of chemotherapy on overall or progression free survival in patients fit enough for treatment (p=0.39 and p=0.33 respectively). However delaying chemotherapy until evidence of disease progression in patients with non-epithelioid disease had a detrimental effect on overall survival (OS), and on progression free survival (PFS) in lymph node positive patients (15.6 vs. 8.2 months p=0.001, and 14.9 vs. 6.0 months p=0.016). Further analysis of 169 patients receiving platinum/pemetrexed as first line treatment, showed similar results; there was no effect of the timing of chemotherapy on OS or PFS (p=0.80 and p=0.53 respectively) and an improved OS in patients with non-epithelioid disease, and improved PFS in those with lymph node metastases, if chemotherapy was given in the immediate adjuvant setting (p=0.001 and 0.038) when therapy was not delayed until disease progression.

Conclusion: Our results suggest that the timing of additional chemotherapy may be important in those with a poorer prognosis on the basis of cell type and nodal stage. In these patients additional postoperative chemotherapy should not be delayed.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Imaging in pleural mesothelioma: A review of the 13th International Conference of the International Mesothelioma Interest Group. S.G. Armato, K.G. Blyth, J.J. Keating, et al. 2016;101:48-58. Review PubMed · Publisher · Free full text

Abstract

Imaging plays an important role in the detection, diagnosis, staging, response assessment, and surveillance of malignant pleural mesothelioma. The etiology, biology, and growth pattern of mesothelioma present unique challenges for each modality used to capture various aspects of this disease. Clinical implementation of imaging techniques and information derived from images continue to evolve based on active research in this field worldwide. This paper summarizes the imaging-based research presented orally at the 2016 International Conference of the International Mesothelioma Interest Group (iMig) in Birmingham, United Kingdom, held May 1-4, 2016. Presented topics included intraoperative near-infrared imaging of mesothelioma to aid the assessment of resection completeness, an evaluation of tumor enhancement improvement with increased time delay between contrast injection and image acquisition in standard clinical magnetic resonance imaging (MRI) scans, the potential of early contrast enhancement analysis to provide MRI with a role in mesothelioma detection, the differentiation of short- and long-term survivors based on MRI tumor volume and histogram analysis, the response-assessment potential of hemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans, the correlation of CT-based tumor volume with post-surgical tumor specimen weight, and consideration of the need to update the mesothelioma tumor response assessment paradigm.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma. M. Hamasaki, S. Matsumoto, S. Abe, et al. 2016;99:155-61. PubMed · Publisher

Abstract

Objectives: Homozygous deletion (homo-d) of the p16 (CDKN2A) gene, as determined by fluorescence in situ hybridization (FISH), helps differentiate malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH). Heterozygous deletion (hetero-d) has also been identified variably in p16 FISH. This study aimed to investigate the significance of homo-d and hetero-d of p16 in the diagnosis and prognosis of MPM.

Materials And Methods: p16 FISH was performed in 93 MPMs and 47 RMHs. Real-time polymerase chain reaction (PCR) and methylation specific PCR (MSP) were also performed for cases in which DNA was available. Overall survival (OS) was assessed via the Kaplan-Meier method and logrank test.

Results: Cutoff values for homo-d and hetero-d were set at 10% and 47%, respectively, based on p16 FISH results in RMH. In MPM, 80/93 (86.0%) were homo-d positive, and 15/93 (16.1%) were hetero-d positive. No RMH was homo/hetero-d positive. In nine cases of MPM with the low homo-d (<30%)/high hetero-d (>47%) pattern, FISH with a shorter probe caused a slight increase (from 20.1% to 26.5%) in the mean percentage of homo-d and a decrease in that of hetero-d (from 59.6% to 55.6%). Four cases in which the low homo-d/high hetero-d pattern was maintained with the shorter probe were further analyzed by real-time PCR, which separated them into a two (n=2) or one allele deletion group (n=2). MSP revealed no promoter methylation in the two cases with one allele deletion. The OS was significantly shorter in homo-d positive cases (n=24) than homo-d negative cases (n=5, p=0.0002) in the 29 MPM cases with follow-up data. Also, low homo-d/high hetero-d cases (n=5) had a significantly better prognosis than high homo-d (≥30%) cases (n=17, p=0.011).

Conclusions: Within p16 homo-d positive MPMs with poorer prognosis, the low homo-d/high hetero-d pattern may belong to a better prognostic subgroup in homo-d positive MPMs.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Metformin and survival of people with type 2 diabetes and pleural mesothelioma: A population-based retrospective cohort study. H. Wu, J. Walker, R.A. Damhuis, et al. 2016;99:194-9. PubMed · Publisher

Abstract

Objectives: This study aimed to investigate the effect of metformin on survival of people with type 2 diabetes and pleural mesothelioma.

Materials And Methods: We conducted a retrospective cohort study of people with type 2 diabetes diagnosed with pleural or unspecified mesothelioma between 1993 and 2014 using linked Scottish population-based diabetes and cancer datasets. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models were used to describe the association between use of metformin and all-cause mortality following diagnosis of pleural mesothelioma.

Results: There were 300 people with type 2 diabetes and pleural or unspecified mesothelioma of whom 148 had ever used metformin and 290 died during follow up. The median survival time was 8.8 months and 6.5 months for metformin users and non-users respectively (p=0.37, log-rank test). After adjusting for age, sex, diabetes duration, socio-economic status, and other anti-diabetic medications the hazard ratio for mortality associated with metformin was 0.99 (95% confidence intervals: 0.76-1.28; p=0.92). Similar non-statistically significant associations were obtained in sensitivity analyses based on metformin use in year prior to diagnosis of mesothelioma, use of metformin for more than one year, in people below the mean age at diagnosis of mesothelioma (74 years) and 74 years of age or older, limitation to pleural mesothelioma and following further adjustment for body mass index and smoking.

Conclusion: There was no evidence that metformin improved survival among people with type 2 diabetes and pleural mesothelioma or to support trials of metformin in people with mesothelioma.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Characterization of hypoxia in malignant pleural mesothelioma with FMISO PET-CT. R.J. Francis, T. Segard, L. Morandeau, et al. 2015;90(1):55-60. PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is a chemotherapy resistant tumor with a poor prognosis. Hypoxia is increasingly recognized as an important factor in tumor aggressiveness and cellular resistance to chemotherapy and radiation treatment. This prospective pilot study was performed with [F-18] fluoromisonidazole (FMISO) PET-CT to characterize hypoxia in patients with MPM.

Materials And Methods: Twenty prospectively recruited patients with histologically or cytologically confirmed MPM not currently receiving systemic or local treatment underwent both FMISO and fluorodeoxyglucose (FDG) PET-CT scans within 2 weeks. FMISO and FDG PET-CT scans were independently analyzed visually and semi-quantitatively using SUVmax and tumor to background ratio (TBR) in order to assess tumor hypoxia and metabolic activity. Lesion by lesion analysis was performed in sites of measurable pleural masses.

Results: Visual analysis demonstrated tumor FMISO activity in 17 of 20 patients, and tumor FDG activity in 19 of 20 patients. Focal areas of bulky tumor were most likely to demonstrate hypoxia. In 19 patients suitable for semi-quantitative analysis the median FDG SUVmax was 6.4 (range 1.9-19.1), median FMISO SUVmax was 2.5 (range 1.4-3.7) and median FMISO TBR was 1.8 (1.1-2.5). There was a positive correlation between intensity of metabolic activity and hypoxia (r=0.72, p=0.001). Lesion by lesion analysis demonstrated a positive correlation between tumor thickness and FMISO activity (r=0.77, p<0.001).

Conclusion: This pilot study confirms that MPM is a tumor with significant areas of hypoxia, particularly in dominant tumor masses. The relationship of tumor hypoxia to effectiveness of chemotherapy and/or radiation therapy warrants prospective assessment.

Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.
Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma. L. Santarelli, S. Staffolani, E. Strafella, et al. 2015;90(3):457-64. PubMed · Publisher

Abstract

Objectives: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage.

Materials And Methods: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated.

Results And Conclusion: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Demographics, management and survival of patients with malignant pleural mesothelioma in the National Lung Cancer Audit in England and Wales. P. Beckett, J. Edwards, D. Fennell, et al. 2015;88(3):344-8. PubMed · Publisher

Abstract

Introduction And Methods: Malignant pleural mesothelioma (MPM) is an uncommon cancer with poor survival. We have used data collected for the UK National Lung Cancer Audit to assess current practice and to highlight regional variation in the management of mesothelioma patients, as well as to describe survival patterns in subgroups.

Results: Our data on 8740 cases seen in hospitals in England and Wales is the largest cohort of MPM in the literature and represents approximately 80% of the total incident cases. 83% are male and median age is 73 years. Performance status is recorded in 81% and of these approximately 70% are PS 0-2. Stage is poorly recorded and unreliable in this dataset. The patient pathway is similar to lung cancer with approximately one-fifth having a non-elective referral to secondary care. A histo-cytological diagnosis is made in 87% and varies across organisations. Only 67% have anti-cancer treatment, and this also varies across organisations, but there has been an annual increase in the proportion receiving chemotherapy. Overall median survival was 9.5 months, with a 1YS of 41.4% and 3YS of 12.0%, but was strongly linked to performance status and histological subtype. Median survival also varied by cancer network from 209 days to 349 days, but appeared to increase from of 9.2 months in 2008 to 10.5 months in 2012.

Conclusion: Our data provide a large scale, detailed assessment of MPM epidemiology, treatment choices and outcomes. Incidence is increasing in line with predictions and uptake of treatments has generally mirrored publication of key MPM treatment trials, in particular increasing use of chemotherapy but low uptake of radical surgery. However, there is significant variation in care patterns and outcomes that may reflect limited expertise in area with low incidence. Initiatives to improve outcomes should include improved recording of clinical stage.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Imaging in pleural mesothelioma: A review of the 12th International Conference of the International Mesothelioma Interest Group. S.G. Armato, J. Coolen, A.K. Nowak, et al. 2015;90(2):148-54. Review PubMed · Publisher

Abstract

Imaging of malignant pleural mesothelioma is essential to patient management, prognostication, and response assessment. From animal models to clinical trials, the gamut of research activities and clinical standards relies on imaging to provide information on lesion morphology and the growing number of physiologic characteristics amenable to capture through imaging techniques. The complex morphology, growth pattern, and biological mechanisms of mesothelioma, however, present challenges for image acquisition and interpretation. Nevertheless, novel approaches to image acquisition and subsequent image analysis have expanded the opportunities for (as well as the need for) imaging in this disease. This paper summarizes the imaging-based research presented orally at the 2014 International Conference of the International Mesothelioma Interest Group (iMig) in Cape Town, South Africa, October 2014. Presented topics include the imaging of hypoxia in a murine model through positron emission tomography (PET), the use of diffusion-weighted magnetic resonance imaging (MRI) to assess the histologic composition of biphasic mesothelioma and to assess early response to chemotherapy, the correlation of CT-based tumor volume with the volume of the post-surgical tumor specimen, the development of volumetric tumor response criteria, and pre-treatment tumor volume growth considerations for tumor response assessment.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Intratumoral macrophage phenotype and CD8+ T lymphocytes as potential tools to predict local tumor outgrowth at the intervention site in malignant pleural mesothelioma. R. Cornelissen, L.A. Lievense, J.L. Robertus, et al. 2015;88(3):332-7. PubMed · Publisher

Abstract

Objectives: In patients with malignant pleural mesothelioma (MPM), local tumor outgrowth (LTO) after invasive procedures is a well-known complication. Currently, no biomarker is available to predict the occurrence of LTO. This study aims to investigate whether the tumor macrophage infiltration and phenotype of and/or the infiltration of CD8+ T-cells predicts LTO.

Materials And Methods: Ten mesothelioma patients who developed LTO were clinically and pathologically matched with 10 non-LTO mesothelioma patients. Immunohistochemistry was performed on diagnostic biopsies to determine the total TAM (CD68), the M2 TAM (CD163) and CD8+ T-cell count (CD8).

Results: The mean M2/total TAM ratio differed between the two groups: 0.90±0.09 in the LTO group versus 0.63±0.09 in patients without LTO (p<0.001). In addition, the mean CD8+ T-cell count was significantly different between the two groups: 30 per 0.025 cm2 (range 2-60) in the LTO group and 140 per 0.025 cm2 (range 23-314) in the patients without LTO (p<0.01).

Conclusion: This study shows that patients who develop LTO after a local intervention have a higher M2/total TAM ratio and lower CD8+ cell count at diagnosis compared to patients who did not develop this outgrowth. We propose that the M2/total TAM ratio and the CD8+ T-cell amount are potential tools to predict which MPM patients are prone to develop LTO.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Non-coding RNA repertoires in malignant pleural mesothelioma. L. Quinn, S.P. Finn, S. Cuffe, et al. 2015;90(3):417-26. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. There are limited treatment options, with no second line standard of care for those who fail first line chemotherapy. Recent advances have been made to characterise the underlying molecular mechanisms of mesothelioma, in the hope of providing new targets for therapy. With the discovery that non-coding regions of our DNA are more than mere junk, the field of research into non-coding RNAs (ncRNAs) has exploded in recent years. Non-coding RNAs have diverse and important roles in a variety of cellular processes, but are also implicated in malignancy. In the following review, we discuss two types of non-coding RNAs, long non-coding RNAs and microRNAs, in terms of their role in the pathogenesis of MPM and their potential as both biomarkers and as therapeutic targets in this disease.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Predictors of lung cancer among former asbestos-exposed workers. B. Świątkowska, Z. Szubert, W. Sobala, et al. 2015;89(3):243-8. PubMed · Publisher

Abstract

Objectives: Despite extensive literature concerning the risk of lung cancer incidence among asbestos workers there is still lack of data specifying the association between the level of exposure and the frequency of cancer occurrence. The aim of the analysis was to assess the influence of smoking and selected factors related to occupational exposure on the risk of the incidence of lung cancer among the workers who were exposed to asbestos dust in the past.

Material And Methods: The assessment was performed based on the case-control studies carried out within a cohort including 7,374 former workers of asbestos processing plants, examined over the years 2000-2013. Analysis of the material was based on the calculation of the odds ratio (OR) using conditional logistic regression modeling, adjusted for cigarette smoking, cumulative exposure, branch and time since last exposure.

Results: During the survey period there were 165 cases of lung cancer. Among the individuals who smoked, the relative risk of lung cancer incidence was twice as high in the persons smoking more than 20 pack-years (OR=2.23; 95% CI: 1.45-3.46) than it was in the case of the non-smokers. Analysis revealed that the risk of lung cancer in the group with the highest exposure was two times higher in comparison with the low cumulative asbestos exposure (OR=1.99; 95% CI: 1.22-3.25). The risk continued to increase until 30 years after cessation of asbestos exposure and started to decline many years after the last exposure. Influence of the mentioned above characteristics is particularly visible for tumors located in the lower parts of the lungs.

Conclusion: Our findings confirm the strong evidence that the lung cancer risk is associated with asbestos exposure and it increases along with the increasing exposure. A strategy of smoking cessation among the individuals exposed to asbestos dust would potentially have health promoting effects.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Prevalence of BRCA-1 associated protein 1 germline mutation in sporadic malignant pleural mesothelioma cases. A. Rusch, G. Ziltener, K. Nackaerts, et al. 2015;87(1):77-9. PubMed · Publisher

Abstract

Objective: 23% of mesothelioma tumor specimens have a mutation in the BRCA1-associated protein 1 (BAP1) gene and germline BAP1 mutations predispose to malignant pleural mesothelioma (MPM). Our aim was to investigate germline BAP1 mutations in sporadic MPM patients.

Materials And Methods: Exonic DNA from peripheral blood leucocytes of 78 MPM patients was screened for germline BAP1 mutation.

Results: One out of 78 patients showed a germline synonymous mutation in exon 11. In all other patients wild-type sequence without any single-nucleotide polymorphisms was detected.

Conclusions: Taking into account previous similar screenings, the prevalence of germline BAP1 mutations in sporadic MPM patients can be estimated around 1-2%, suggesting a minor role of germline BAP1 mutation in the pathogenesis of sporadic MPM.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Prognostic significance of the lymphocyte-to-monocyte ratio in patients with malignant pleural mesothelioma. T. Yamagishi, N. Fujimoto, H. Nishi, et al. 2015;90(1):111-7. PubMed · Publisher

Abstract

Objectives: Chronic inflammation plays a key role in the pathogenesis of malignant pleural mesothelioma (MPM) as a result of asbestos exposure. Several inflammation-based prognostic scores including the lymphocyte-to-monocyte ratio (LMR), Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) reportedly predict survival in many malignancies, while the role of LMR in MPM remains unclear. The aim of this study was to evaluate the clinical value of LMR and to compare the prognostic value of these inflammation-based scores in predicting overall survival (OS) in MPM.

Materials And Methods: One hundred and fifty patients with histologically proven MPM were included in this retrospective study. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for OS. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system.

Results: An elevated LMR was significantly associated with prolonged OS. Patients with LMR <2.74 had significantly poor survival compared with LMR ≥2.74 (median, 5.0 versus 14.0 months; p=0.000). The LMR consistently had a higher AUC value at 6 months (0.722), 12 months (0.712), and 24 months (0.670), compared with other scores. Multivariate analysis showed that the LMR was independently associated with OS.

Conclusions: The LMR is an independent prognostic marker for OS in patients with MPM and is superior to other inflammation-based prognostic scores with respect to prognostic ability.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Radiologic-pathologic correlation of mesothelioma tumor volume. S.G. Armato, P. Li, A.N. Husain, et al. 2015;87(3):278-82. PubMed · Publisher

Abstract

Objectives: Tumor volume promises to become a more important factor in patient management. Mesothelioma, with its unique morphology and complex growth pattern, presents a challenging target for tumor volumetrics derived from computed tomography (CT) scans. This study evaluated the validity of image-based mesothelioma tumor volume against the physical volume of the tumor bulk captured by the images.

Materials And Methods: Twenty-eight patients underwent CT scanning prior to pleurectomy/decortication with an intent to achieve a macroscopic complete resection. A radiologist manually outlined the tumor border in all CT sections in which tumor appeared in the pre-surgery scan. CT-based tumor volume was computed as the number of image pixels enclosed by all tumor outlines across all sections in the scan multiplied by the physical dimensions of the voxel of tissue captured by each image pixel. The gross tumor specimen volume was measured ex vivo through a water-displacement technique. Correlation between CT volume and pathology volume was calculated.

Results: A correlation coefficient r-squared value of 0.66 was found between CT-based tumor volume and gross tumor specimen volume. Differences between the mean volume (either CT volume or pathology volume) across tumors of different T stages did not achieve statistical significance.

Conclusion: Despite a modest correlation between CT-based tumor volume and gross tumor specimen volume, image-based volumetry for mesothelioma is not straightforward-perhaps, in part, due to the challenges of distinguishing tumor borders from adjacent structures and perhaps, in part, due to a complex pathologic reference standard.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Research priorities in mesothelioma: A James Lind Alliance Priority Setting Partnership. R.J. Stephens, C. Whiting, K. Cowan, et al. 2015;89(2):175-80. PubMed · Publisher

Abstract

Background: In the UK, despite the import and use of all forms of asbestos being banned more than 15 years ago, the incidence of mesothelioma continues to rise. Mesothelioma is almost invariably fatal, and more research is required, not only to find more effective treatments, but also to achieve an earlier diagnosis and improve palliative care. Following a debate in the House of Lords in July 2013, a package of measures was agreed, which included a James Lind Alliance Priority Setting Partnership, funded by the National Institute for Health Research. The partnership brought together patients, carers, health professionals and support organisations to agree the top 10 research priorities relating to the diagnosis, treatment and care of patients with mesothelioma.

Methods: Following the established James Lind Alliance priority setting process, mesothelioma patients, current and bereaved carers, and health professionals were surveyed to elicit their concerns regarding diagnosis, treatment and care. Research questions were generated from the survey responses, and following checks that the questions were currently unanswered, an interim prioritisation survey was conducted to identify a shortlist of questions to take to a final consensus meeting.

Findings: Four hundred and fifty-three initial surveys were returned, which were refined into 52 unique unanswered research questions. The interim prioritisation survey was completed by 202 responders, and the top 30 questions were taken to a final meeting where mesothelioma patients, carers, and health professionals prioritised all the questions, and reached a consensus on the top 10.

Interpretation: The top 10 questions cover a wide portfolio of research (including assessing the value of immunotherapy, individualised chemotherapy, second-line treatment and immediate chemotherapy, monitoring patients with pleural thickening, defining the management of ascites in peritoneal mesothelioma, and optimising follow-up strategy). This list is an invaluable resource, which should be used to inform the prioritisation and funding of future mesothelioma research.

Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Response evaluation in mesothelioma: Beyond RECIST. L. Cheng, N. Tunariu, D.J. Collins, et al. 2015;90(3):433-41. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) typically demonstrates a non-spherical growth pattern, so it is often difficult to accurately categorize change in tumour burden using size-based tumour response criteria (e.g., WHO (World Health Organisation), RECIST (Response Evaluation Criteria in Solid Tumours) and modified RECIST). Functional imaging techniques are applied to derive quantitative measurements of tumours, which reflect particular aspects of the tumour pathophysiology. By quantifying how these measurements change with treatment, it is possible to observe treatment effects. In this review, we survey the existing roles of CT and MRI for the management of MPM, including the currently applied size measurement criteria for the assessment of treatment response. New functional imaging techniques, such as positron emission tomography (PET), diffusion-weighted MRI (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) that may potentially improve the assessment of treatment response will be highlighted and discussed.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Second line therapy in malignant pleural mesothelioma: A systematic review. W.A. Buikhuisen, B.I. Hiddinga, P. Baas, et al. 2015;89(3):223-31. Meta-analysis · Systematic review PubMed · Publisher

Abstract

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 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.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Treatment patterns and survival analysis in 9014 patients with malignant pleural mesothelioma from Belgium, the Netherlands and England. R.A. Damhuis, A. Khakwani, H. De Schutter, et al. 2015;89(2):212-7. PubMed · Publisher

Abstract

Introduction: Pleural mesothelioma has a dismal prognosis and is refractory to local treatment. Combination chemotherapy can increase median survival by several months and was gradually introduced in the period 2003-2006. Elderly patients may be unfit for chemotherapy but little is known about age-related treatment practice. To determine treatment patterns and current survival outcome, three large population-based registries were queried in a uniform manner.

Methods: Data from the Belgian Cancer Registry, the Netherlands Cancer Registry and the UK National Lung Cancer Audit were analyzed for patients diagnosed with pleural mesothelioma since 2007. Treatment patterns and survival rates were compared between countries and age-groups.

Results: The study included 900, 2306 and 5808 patients from Belgium, the Netherlands and England, respectively. Fifty-nine percent of patients were 70 years or older and 84% were men. Chemotherapy use decreased with advancing age and was used more often in Belgium (60%) than in the Netherlands (41%) and England (37%). For patients aged 70-79 years, chemotherapy use was 55%, 36% and 34% in the respective countries. Median survival was 10.7 months in Belgium versus 9.2 months for the Netherlands and 9.5 months for England. Survival rates decreased with advancing age. On average, median survival was 5.6 months longer for patients treated with chemotherapy, irrespective of age.

Conclusions: Combined analysis of data from three countries with high mesothelioma rates demonstrates that chemotherapy has become standard treatment for younger patients. Elderly patients currently account for more than half of all cases and less toxic treatment options will be required to improve their prospects.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. C. Cao, D. Tian, J. Park, et al. 2014;83(2):240-5. Meta-analysis · Systematic review PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis. Surgical treatments of MPM with a curative intent include extrapleural pneumonectomy and extended pleurectomy/decortication (P/D). This meta-analysis aimed to compare the perioperative and long-term outcomes of EPP and extended P/D for selected surgical candidates.

Methods: A systematic review of the literature was performed on six electronic databases to identify all relevant data on comparative outcomes of extended P/D and EPP in a multimodality setting. Endpoints included perioperative mortality and morbidity, as well as long-term overall survival.

Results: Seven relevant studies with comparative data on EPP (n=632) versus extended P/D (n=513) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (2.9% vs. 6.8%, p=0.02) and morbidity (27.9% vs. 62.0%, p<0.0001) for patients who underwent extended P/D compared to EPP. Median overall survival ranged between 13-29 months for extended P/D and 12-22 months for EPP, with a trend favouring extended P/D.

Conclusions: Although it must be emphasized that patient selection and treatment strategies differ between EPP and extended P/D, a number of comparative studies have recently been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that selected patients who underwent extended P/D had lower perioperative morbidity and mortality with similar, if not superior, long-term survival compared to EPP, in the context of multi-modality therapy. This may represent an important paradigm shift in the surgical management of MPM.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Cytokeratin 19 expression in primary thoracic tumors and lymph node metastases. K. Masai, K. Nakagawa, A. Yoshida, et al. 2014;86(3):318-23. PubMed · Publisher

Abstract

Background: The use of one-step nucleic acid amplification (OSNA), which allows for the rapid intraoperative detection of lymph node (LN) metastasis, is becoming more widely accepted in breast cancer. To provide basic data for the development of this method for lung tumors, we conducted a large-scale investigation of cytokeratin (CK) 19 expression in thoracic tumors.

Patients And Methods: We examined CK19 expression in specimens from a total of 801 surgically resected samples of primary lung adenocarcinoma (ADC), squamous cell carcinoma (SQC), large-cell carcinoma (LCC), pleomorphic carcinoma (PC), large cell neuroendocrine carcinoma (LCNEC), small cell carcinoma (SCC), and carcinoid tumor (CT) as well as pleural malignant mesothelioma and lung metastatic deposits from breast cancer using tissue microarrays (TMAs) and whole sections. We also compared the CK19 expression status between primary sites and LN metastatic deposits.

Results: The overall rate of CK19 expression as observed on TMAs and whole sections in the 801 analyzed cases was 88.0%. CK19 expression was detected in 94.6% of ADCs, 93.6% of SQCs, 54.5% of LCCs, 54.8% of PCs, 77.4% of LCNECs, 31.8% of SCCs, 34.0% of CTs, and 92.9% of malignant mesotheliomas. Expression of CK19 was also detected in 90.9% of lung metastatic deposits from breast carcinomas. CK19 expression was maintained between CK19-positive primary sites and the corresponding LN metastatic deposits. Of note, a portion of CK19-negative primary tumors showed upregulation of CK19 protein expression in LN metastases.

Conclusions: Most thoracic tumors, except for PCs, CTs, and SCCs, were positive for CK19. We also found that CK19 expression was maintained between CK19-positive primary tumors and the corresponding LN metastatic deposits. These results may be useful in the development of the OSNA method for the intraoperative detection of LN metastasis in non-small cell lung cancer (NSCLC).

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Effect of NSAIDS and COX-2 inhibitors on the incidence and severity of asbestos-induced malignant mesothelioma: evidence from an animal model and a human cohort. C. Robinson, H. Alfonso, S. Woo, et al. 2014;86(1):29-34. PubMed · Publisher

Abstract

Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors have been associated with lower incidence rates of some cancers. Because asbestos can cause chronic inflammation at the pleural and peritoneal surfaces we hypothesised that NSAID and COX-2 inhibitors would inhibit the development of asbestos-induced mesothelioma.

Materials And Methods: A murine model of asbestos-induced mesothelioma was used to test this hypothesis by providing the NSAID, aspirin, daily in the feed at 50mg/kg or 250 mg/kg. In a parallel study, the relationship between the use of NSAID and COX-2 inhibitors and mesothelioma was investigated in a human cohort of 1738 asbestos exposed people living or working in Wittenoom, Western Australia (a crocidolite mine site).

Results: Aspirin did not alter the rate of disease development or increase the length of time that mice survived. Aspirin had a small but significant effect on disease latency (the time between asbestos exposure and first evidence of disease; p<0.05) but disease progression was not affected by the continued presence of the drug. In the Wittenoom cohort, individuals who reported use of NSAIDs, COX-2 inhibitors or both did not have a lower incidence of mesothelioma (HR=0.85; 95% CI=0.53-1.37, p=0.50), (HR=0.69; 95% CI=0.21-2.30, p=0.55) and (HR=0.43; 95% CI=0.16-1.13, p=0.087) respectively.

Conclusion: We conclude that NSAIDs and COX-2 inhibitors do not moderate mesothelioma development or progression in a human cohort exposed to asbestos and this result is confirmed in an autochthonous mouse model.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Efficacy of phase 1 trials in malignant pleural mesothelioma: description of a series of patients at a single institution. J. Raphael, G. Le Teuff, A. Hollebecque, et al. 2014;85(2):251-7. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is a locally aggressive disease with a poor prognosis. After failure of first line platinum-based chemotherapy, there is no widely approved salvage regimen. New strategies for treatment are needed and phase 1 trials appear as a rationale alternative.

Materials And Methods: MPM patients were enrolled in 20 different phase 1 trials between March 2005 and January 2012, and their data analyzed retrospectively. The primary endpoint was response rate and secondary endpoints were toxicity profile, overall survival (OS) and progression free survival (PFS). OS and PFS were estimated using Kaplan-Meier and their association with baseline characteristics was investigated through a log-rank test. The drugs described were divided into 5 groups based on their mechanism of action.

Results: Forty-five patients were analyzed with a median follow up of 20.5 months. The best tumor response was as follows: 4% of patients had a RECIST partial response, 60% had stable disease, 24% had progressive disease and 11% were not evaluable. Grade ≥3 toxicities were observed in 19 (42%) patients. Median OS and PFS were estimated to 6 months (95% CI=[4.2-10.5]) and 2 months (95% CI=[1.3-2.7]), respectively. The cellular motility inhibitors group appeared as the most promising class to be developed in a phase 2 setting.

Conclusion: Including MPM patients in phase I trials beyond first line of treatment can result in modest clinical benefits with an acceptable toxicity profile. Several molecular pathways involved in MPM have been identified and further novel biologic therapies need to be tested.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Exposure-specific lung cancer risks in Chinese chrysotile textile workers and mining workers. X. Wang, S. Lin, E. Yano, et al. 2014;85(2):119-24. PubMed · Publisher

Abstract

Objective: Whether there is a difference in the exposure-response slope for lung cancer between mining workers and textile workers exposed to chrysotile has not been well documented. This study was carried out to evaluate exposure-specific lung cancer risks in Chinese chrysotile textile workers and mining workers.

Subjects And Methods: A chrysotile mining worker cohort and a chrysotile textile worker cohort were observed concurrently for 26 years. Information on workers' vital status, occupational history and smoking habits were collected, and causes and dates of deaths were verified from death registries. Individual cumulative fiber exposures were estimated based on periodic dust/fiber measurements from different workshops, job title and duration, and categorized into four levels (Q1-Q4). Standardized mortality ratios (SMRs) for lung cancer were calculated and stratified by industry and job title with reference of the national rates. Cox proportional hazard models were fit to estimate the exposure-specific lung cancer risks upon adjustment for age and smoking, in which an external control cohort consisting of industrial workers without asbestos exposure was used as reference group for both textile and mining workers.

Results: SMRs were almost consistent with exposure levels in terms of job titles and workshops. A clear exposure-response relationship between lung cancer mortality and exposure levels was observed in both cohorts. At low exposure levels (Q1 and Q2), textile workers displayed higher death risks of lung cancer than mining workers. However, similarly considerably high risks were observed at higher exposure levels, with hazard ratios of over 8 and 11 at Q3 and Q4, respectively, for both textile and mining workers, after both age and smoking were adjusted.

Conclusion: The chrysotile textile workers appeared to have a higher risk of lung cancer than the mining workers at a relatively low exposure level, but no difference was observed at a high exposure level, where both cohorts displayed a considerably high risk.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
How useful is GLUT-1 in differentiating mesothelial hyperplasia and fibrosing pleuritis from epithelioid and sarcomatoid mesotheliomas? An international collaborative study. A.N. Husain, M.K. Mirza, A. Gibbs, et al. 2014;83(3):324-8. PubMed · Publisher

Abstract

Objective: Mesothelial hyperplasia (MH) and fibrosing pleuritis (FP) can be difficult to distinguish from epithelioid (MM-E) and sarcomatoid (MM-S) malignant pleural mesotheliomas. GLUT-1 has shown variable results regarding its sensitivity and specificity when used to evaluate mesothelial proliferations. We evaluated the utility of GLUT-1 immunostaining in differentiating MH and FP from MM-E and MM-S.

Materials And Methods: In this retrospective study, diagnostically well-characterized cases (MH=31, FP=29, MM-E=41, MM-S=29) were collected and manually stained for GLUT-1. All slides were visually scored by 2 pathologists; using the following system: 0%, 1+ 1-25%, 2+ 26-50% and 3+ >51% cells staining.

Results: All benign cases (n=60) were negative for GLUT-1 while 45 of 78 (58%) MM [21 of 41 (50%) MM-E, 21 of 29 (72%) MM-S and 3 of 3 biphasic mesothelioma (100%)] had 1+ to 3+ staining. Of the MM-E, 10 had 1+, and 11 had 2+ staining; of the MM-S 3 had 1+, 15 had 2+ and 3 had 3+ staining. Both sarcomatoid and epithelioid components of the 3 biphasic mesotheliomas revealed 1+ staining. All 5 desmoplastic MM were negative.

Conclusions: Positive staining with GLUT-1 is helpful since it is present in half of MM-E and three-quarter of MM-S. Although all reactive mesothelial lesions were negative, the absence of immunoreactivity does not exclude the diagnosis of MM. As with all IHC stains used for diagnostic purposes, GLUT-1 has to be a part of a panel, and the results interpreted in the context of clinical, radiological and histological findings.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Identification of actionable mutations in malignant pleural mesothelioma. T. Shukuya, M. Serizawa, M. Watanabe, et al. 2014;86(1):35-40. PubMed · Publisher

Abstract

Background: Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood.

Patients And Methods: Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 and amplifications in EGFR, MET, PIK3CA, FGFR1, and FGFR2. In addition, 21 patients' samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes.

Results: Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients' samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc.) by deep sequencing.

Conclusions: Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Radical pleurectomy/decortication followed by high dose of radiation therapy for malignant pleural mesothelioma. Final results with long-term follow-up. E. Minatel, M. Trovo, J. Polesel, et al. 2014;83(1):78-82. PubMed · Publisher

Abstract

Purpose: We have previously shown the feasibility of delivering high doses of radiotherapy in malignant pleural mesothelioma (MPM) patients who underwent radical pleurectomy/decortication (P/D) or surgical biopsy. In this report, we present the long-term results of MPM patients treated with radical P/D followed by high doses of radiotherapy.

Methods And Materials: Twenty consecutive MPM patients were enrolled in this prospective study and underwent radical P/D followed by high dose radiotherapy. The clinical target volume was defined as the entire hemithorax excluding the intact lung. The dose prescribed was 50 Gy in 25 fractions. Any FDG-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. Nineteen patients received cisplatin/pemetrexed chemotherapy. Kaplan-Meier analysis was used to calculate rates of overall survival (OS), progression-free survival (PFS), and loco-regional control (LRC).

Results: The median follow-up was of 27 months. The median OS and PFS were 33 and 29 months, respectively. The median LRC was not reached. The Kaplan-Meier estimates of OS at 2 and 3 years were 70% and 49%, respectively. The estimates of PFS at 2 and 3 years were 65% and 46%, respectively. The estimates of LRC at 2 and 3 years were 68% and 59%, respectively. The predominant pattern of failure was distant: 7 patients developed distant metastases as the first site of relapse, whereas only 3 patients experienced an isolated loco-regional recurrence. No fatal toxicity was reported. Five Grades 2-3 pneumonitis were documented.

Conclusions: High dose radiation therapy following radical P/D led to excellent loco-regional control and survival results in MPM patients. A median OS of 33 months and a 3-year OS rate of 49% are among the best observed in recent studies, supporting the idea that this approach represents a concrete therapeutic option for malignant pleural mesothelioma.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Radiotherapy for the treatment of pain in malignant pleural mesothelioma: a systematic review. N. Macleod, A. Price, N. O'Rourke, et al. 2014;83(2):133-8. Systematic review PubMed · Publisher

Abstract

Radiotherapy is commonly used to treat pain in malignant pleural mesothelioma (MPM). The purpose of this systematic review is to examine the evidence for this practice. Medline (1946-2013), Embase (1974-2013) and Central (The Cochrane Library Issue 9, 2012) databases were searched. Eligible studies met the following criteria: MPM (histological or radiological diagnosis), radiotherapy given with the intent of improving pain, response rates to radiotherapy reported, dose and fractionation reported and the relationship between radiotherapy and pain response explored. All studies had independent review and were graded according to evidence level. Eight studies met the eligibility criteria. Two studies were prospective single arm phase II studies while the remainder were retrospective case series. All were graded as either Level 2 or Level 3 evidence. Due to marked heterogeneity among studies, quantitative synthesis of results was not possible. No high quality evidence currently exists to support radiotherapy in treating pain in MPM. Studies focusing on clear pain endpoints and improving target delineation are needed. Such studies should also use modern radiotherapy techniques and concentrate on dose escalation.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma. L.M. Krug, A.J. Wozniak, H.L. Kindler, et al. 2014;85(3):429-34. Randomized trial PubMed · Publisher

Abstract

Background: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin.

Methods: Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months.

Results: 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501.

Conclusions: While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Stage distribution and performance status of newly diagnosed patients in a UK regional mesothelioma centre. S. Khan, M. Evison, M. Alaloul, et al. 2014;85(1):99-100. Letter PubMed · Publisher
Surgery for malignant pleural mesothelioma: why, when and what?. L. Lang-Lazdunski. 2014;84(2):103-9. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma is a fatal cancer developing in the pleural cavity, linked to asbestos exposure. Various therapies have been tried in the past 50 years including surgery, radiotherapy, chemotherapy, immunotherapy and more recently, targeted therapy. Radical surgery remains controversial in malignant pleural mesothelioma and two procedures have been offered in the past to obtain maximal cytoreduction: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). Despite growing evidence that EPP might be detrimental, many believe that radical surgery should still be part of multimodality therapy in patients with malignant pleural mesothelioma. Recent evidence suggests that P/D is well tolerated and produces low mortality and morbidity. The role of adjuvant intrapleural therapies remains to be determined and evaluated in large prospective trials. Pleurectomy/decortication does not jeopardize the chance of having chemotherapy, or chemoradiotherapy either. Many now believe that it should be the default procedure in multimodality regimens. However, this remains to be proven in a large randomized trial. Palliative surgery still has an important role to play in mesothelioma, in establishing or refining diagnosis and in controlling symptoms and improving quality of life in many patients whose life expectancy is limited. Recent progress in molecular analyses and biomarkers should help with patient selection for surgery, immunotherapy and systemic therapies in the near future.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Systematic review of response rates of sarcomatoid malignant pleural mesotheliomas in clinical trials. A.S. Mansfield, J.T. Symanowski, T. Peikert. 2014;86(2):133-6. Meta-analysis · Systematic review PubMed · Publisher · Free full text

Abstract

Rationale: Malignant pleural mesothelioma is an almost universally fatal malignancy primarily related to asbestos exposure. Based on the differences in immunologic markers and gene expression between histologic subtypes of mesothelioma, and our clinical impression that response rates vary by histology, we decided to examine the reported response rates of mesothelioma subtypes.

Objectives: Our objective was to compare the response rates of sarcomatoid mesotheliomas to the overall response rates in published clinical trials.

Methods: We searched PubMed for "mesothelioma" with the clinical trials filter selected. We included articles published between January 1, 2000 and March 20, 2014 in which subjects received first or second line systemic therapy for malignant pleural mesothelioma. Studies investigating multi-modality therapy including surgery were excluded. Response rates [including 95% confidence intervals (95% CI)] were estimated for the entire patient cohort and then separately for subjects with sarcomatoid tumors.

Measurements And Main Results: We reviewed 544 publications of which 41 trials met our inclusion criteria. Eleven of these trials did not include patients with sarcomatoid mesothelioma (27% of eligible studies). The remaining 30 publications included 1475 subjects, 1011 with epithelioid tumors (68.5%), 203 with biphasic tumors (13.8%), 137 with sarcomatoid tumors (9.3%) and 124 with unknown subtypes (8.4%). In total, there were 323 responses (21.9%, complete and partial responses, 95% CI: 16.3, 28.8) to systemic therapy across all histological subtypes. In patients with sarcomatoid tumors (n=137) 19 responses were observed. This accounted for 5.9% of all responses and yields a 13.9% (95% CI: 8.6, 21.6) response rate for patients with sarcomatoid tumors. Multiple biases likely affected this systematic review.

Conclusion: Response rates for different histological subtypes of malignant pleural mesothelioma are infrequently reported. Partial and complete responses to systemic therapies appear to be less common among patients with sarcomatoid tumors.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
The homeobox gene EMX2 is a prognostic and predictive marker in malignant pleural mesothelioma. E. Giroux Leprieur, T. Hirata, M. Mo, et al. 2014;85(3):465-71. PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. EMX2 is a homeobox transcription factor that may regulate key developmental pathways known to promote tumorigenesis. In this study, we evaluated the prognostic and predictive significance of EMX2 expression in MPM.

Materials And Methods: Fifty surgically resected MPM specimens were studied. Quantitative real-time RT-PCR was used to analyze EMX2 mRNA expression. Association of EMX2 levels with clinical outcomes was evaluated with using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model.

Results: EMX2 expression was significantly associated with IMIG stage (p<0.001) and smoking history (p=0.006). Cox hazard regression modeling identified low-EMX2 expression as a negative prognostic factor in progression-free survival by both univariate (p=0.002) and multivariate analysis (p=0.002). Kaplan-Meier analysis revealed significant differences in progression-free survival between low- and high-EMX expressing groups in all patients (p=0.001), and also when grouped by early (I/II) stage disease (p<0.001), patients undergoing pleurectomy (p<0.001) and patients with an epitheliod subtype (p<0.004). Furthermore, EMX2 expression predicted response to neoadjuvant chemotherapy. High-EMX2 expression was associated with decreased progression-free survival after neoadjuvant therapy, suggesting that induction therapy should be avoided in these patients.

Conclusions: EMX2 expression is downregulated in advanced cases of malignant pleural mesothelioma and may serve as an important prognostic and predictive molecular biomarker of progression-free survival.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. M.G. Zauderer, S.L. Kass, K. Woo, et al. 2014;84(3):271-4. PubMed · Publisher · Free full text

Abstract

Objectives: Pemetrexed-cisplatin is the only FDA-approved regimen for malignant pleural mesothelioma (MPM), and the impact on survival is modest. No drugs have been shown to improve survival as second-line therapy, yet vinorelbine and gemcitabine are prescribed based on the results of small phase II trials. To augment the existing limited data, we examined our institutional experience with vinorelbine and gemcitabine in patients with previously treated MPM.

Materials And Methods: We reviewed charts of patients with MPM treated with vinorelbine and/or gemcitabine as second- or third-line therapy between 2003 and 2010. Toxicity was graded according to the Common Terminology Criteria for Adverse Events Version 4.0. CT scans were reviewed with a reference radiologist according to modified RECIST criteria.

Results: Sixty patients were identified: 33 treated with vinorelbine, 15 gemcitabine, and 12 both agents. Eighty-three percent initially received pemetrexed-platinum. Toxicity was substantial: 46% experienced at least one episode of grade 3-4 toxicity. Of 56 patients evaluable radiologically, there was 1 partial response (gemcitabine) giving a response rate of 2% (95% CI: 0-10%). Forty-six percent had stable disease. Median progression free survival was 1.7 months for vinorelbine and 1.6 months for gemcitabine. Median overall survival was 5.4 and 4.9 months, respectively.

Conclusions: Response to second- or third-line vinorelbine or gemcitabine is rare. The high rate of stable disease warrants the continued use of these agents in this setting, though the impact on survival is questionable. These data justify the choice of placebo control arms in randomized trials of novel agents in previously treated patients.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. P.A. Zucali, M. Perrino, E. Lorenzi, et al. 2014;84(3):265-70. PubMed · Publisher

Abstract

Background: Pemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients.

Methods: Vinorelbine 25 mg/m(2) was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity.

Results: Fifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as > 2L treatment. The median age was 69 years (range 45-80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR(0 vs. 1-2) 0.50; 95%CI: 0.3-0.8; p = 0.014) and PFS ≥ 6 months following first-line (FL) chemotherapy (HR(FL-PFS>6 ms vs. <6 ms) 0.50; 95%CI: 0.3-0.9; p = 0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients.

Conclusions: Vinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥ 6 months.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
18F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography fused imaging in malignant mesothelioma patients: looking from outside is not enough. E. Roca, S. Laroumagne, T. Vandemoortele, et al. 2013;79(2):187-90. Case report PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an uncommon neoplasm with a poor prognosis usually associated with asbestos exposure. 18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) has become an invaluable tool for the diagnosis, staging, and prognosis of this severe disease as it combines both anatomic and functional information in a single imaging procedure, allowing for improved management of this disease. For many authors, 18F-FDG-PET/CT is the cornerstone of the pre-therapeutic evaluation of mesothelioma patients, particularly when multimodal therapy (including extra-pleural pneumonectomy or omentectomy) is considered. However, while characteristic patterns have been reported as predictive of macroscopic pleural or peritoneal involvement, false negative findings are possible, both for pleural and peritoneal mesothelioma, during the initial diagnosis or during the patient's surveillance as illustrated by this report of three cases of suspected MM with negative PET/CT. This report highlights the limitations of PET/CT in the diagnostic evaluation of MM and the importance of histopathological confirmation by thoracoscopy and/or laparoscopy, which remain the most important diagnostic procedures in MM.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
A genome-wide association study for malignant mesothelioma risk. G. Cadby, S. Mukherjee, A.W. Musk, et al. 2013;82(1):1-8. PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a uniformly fatal tumour of mesothelial cells. MM is caused by exposure to asbestos however most individuals with documented asbestos exposure do not develop MM. Although MM appears to aggregate within families, the genetics of MM susceptibility is a relatively unexplored area. The aim of the current study was to identify genetic factors that contribute to MM risk. A genome-wide association analysis of 2,508,203 single nucleotide polymorphisms (SNPs) from 428 MM cases and 1269 controls from Western Australia was performed. Additional genotyping was performed on a sample of 778 asbestos-exposed Western Australian controls. Replication of the most strongly associated SNPs was undertaken in an independent case-control study of 392 asbestos-exposed cases and 367 asbestos-exposed controls from Italy. No SNPs achieved formal genome-wide statistical significance in the Western Australian study. However, suggestive results for MM risk were identified in the SDK1, CRTAM and RASGRF2 genes, and in the 2p12 chromosomal region. These findings were not replicated in the Italian study, although there was some evidence of replication in the region of SDK1. These suggestive associations will be further investigated in sequencing and functional studies.

Copyright © 2013. Published by Elsevier Ireland Ltd.
A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma. A.K. Nowak, C. Brown, M.J. Millward, et al. 2013;81(3):422-427. PubMed · Publisher

Abstract

BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Does CA125 binding to mesothelin impact the detection of malignant mesothelioma?. J. Creaney, I.M. Dick, H. Dare, et al. 2013;80(1):39-44. PubMed · Publisher

Abstract

The biomarker mesothelin is a useful diagnostic tool in malignant mesothelioma (MM) patients. It has high specificity but a sensitivity of only 50%. As mesothelin binds CA125, and as CA125 is often elevated in MM, we asked whether this binding affected measurable mesothelin levels in a relevant clinical setting. Mesothelin and CA125 concentrations were measured in the serum of 41 patients with MM. An assay was developed to detect mesothelin bound to CA125. Mesothelin was demonstrated to be bound by CA125 in 9 of 41 MM patients. This binding could be broken by the addition of sodium dodecyl sulphate and diethylenetriaminepenta acetic acid (DTPA) to the samples, however this did not lead to any change in the mesothelin level measured. We therefore conclude that binding of mesothelin to CA125 does not alter the measurement of mesothelin for the detection of MM.

Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.
Free drugs in clinical trials and their potential cost saving impact on the National Health Service: a retrospective cost analysis in Italy. F. Grossi, C. Genova, N.D. Gaitan, et al. 2013;81(2):236-40. PubMed · Publisher

Abstract

Background: The cost of new anti-cancer drugs has dramatically increased in recent years, and countermeasures are required in order to limit pharmaceutical expenses. Sponsored clinical trials that provide drugs free of charge may be a useful tool in order to reduce drug costs. The aim of this analysis is to evaluate the effect of clinical trials on pharmaceutical expenditure savings.

Methods: We evaluated the cost of drugs administered in clinical practice and in clinical trials (considering only the standard regimens that were administered also in clinical practice) in 2010 at the Lung Cancer Unit of the National Institute for Cancer Research in Genoa, Italy. The cost of drugs was calculated on the price charged at our Institute in 2010. The supposed cost of experimental treatment replacing standard therapy was converted in the cost of the treatments that would have been chosen in clinical practice, considering histology, line of treatment and number of administered cycles.

Results: From 1/1/2010 to 12/31/2010, 196 patients affected by lung cancer or pleural mesothelioma were treated. 152 patients (78%) received treatment in clinical practice or in non-sponsored trials (18 patients in 4 trials), while 44 (22%) were treated in one of the 12 sponsored clinical trials recruiting in 2010. Globally, 606 cycles of treatment would have been administered to patients, of which 436 (72%) were administered in clinical practice or in non-sponsored trials and 170 (28%) were administered in pharmaceutical company sponsored clinical trials. The overall cost of those anti-neoplastic drugs, based on the prices charged at our Institute in 2010, was €799 803. The cost of drugs administered in clinical practice or in non-sponsored trials was €556 649 (70%), whereas the cost of standard drugs administered in clinical trials was €243 154 (30%). The grants provided by pharmaceutical companies were evaluated and amounted to €235 965.

Conclusions: The participation in sponsored clinical trials in which drugs are provided free of charge offers substantial cost savings for the National Health Service; moreover, the grants received for each enrolled patient produced additional income.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Imaging in pleural mesothelioma: a review of the 11th International Conference of the International Mesothelioma Interest Group. S.G. Armato, Z.E. Labby, J. Coolen, et al. 2013;82(2):190-6. Review PubMed · Publisher

Abstract

Imaging of malignant pleural mesothelioma (MPM) is essential to the diagnosis, assessment, and monitoring of this disease. The complex morphology and growth pattern of MPM, however, create unique challenges for image acquisition and interpretation. These challenges have captured the attention of investigators around the world, some of whom presented their work at the 2012 International Conference of the International Mesothelioma Interest Group (iMig 2012) in Boston, Massachusetts, USA, September 2012. The measurement of tumor thickness on computed tomography (CT) scans is the current standard of care in the assessment of MPM tumor response to therapy; in this context, variability among observers in the measurement task and in the tumor response classification categories derived from such measurements was reported. Alternate CT-based tumor response criteria, specifically direct measurement of tumor volume change and change in lung volume as a surrogate for tumor response, were presented. Dynamic contrast-enhanced CT has a role in other settings, but investigation into its potential use for imaging mesothelioma tumor perfusion only recently has been initiated. Magnetic resonance imaging (MRI) and positron-emission tomography (PET) are important imaging modalities in MPM and complement the information provided by CT. The pointillism sign in diffusion-weighted MRI was reported as a potential parameter for the classification of pleural lesions as benign or malignant, and PET parameters that measure tumor activity and functional tumor volume were presented as indicators of patient prognosis. Also reported was the use of PET/CT in the management of patients who undergo high-dose radiation therapy. Imaging for MPM impacts everything from initial patient diagnosis to the outcomes of clinical trials; iMig 2012 captured this broad range of imaging applications as investigators exploit technology and implement multidisciplinary approaches toward the benefit of MPM patients.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Legal claims for malignant mesothelioma: dealing with all cases. S. van der Bij, P. Baas, M.J. van de Vijver, et al. 2013;80(2):153-8. PubMed · Publisher

Abstract

Background: Apart of medical reasons, a definitive diagnosis of malignant mesothelioma may be required as a basis for a claim of financial compensation although a pathological source of conclusive evidence is missing. Clinical assessment of all available data is then the only option to come to a final conclusion. We evaluated the diagnostic work-up of a large cohort of Dutch patients who applied for financial compensation due to mesothelioma. We determined how often a pathological or clinical diagnosis can be made, and which factors are associated with making the final diagnosis malignant mesothelioma.

Methods: A flow diagram of the diagnostic work-up was constructed for patients that applied to the Dutch institute for asbestos victims between 2005 and 2008 (N=1498). Both pathological and clinical factors that may influence the diagnostic outcome were assessed.

Results: In 97 of the 1498 patients (6%) no pathologic diagnosis could be established because of an uncertain diagnosis (N=54), inadequate (N=22) or unavailable tumor samples (N=21). A final pathological diagnosis of malignant mesothelioma could most often be made when biopsy samples were available compared to those in whom only cytological material was available. In patients in who no conclusive diagnosis could be made, clinical assessment was performed. Eighty percent of patients (66/83) who were clinically assessed were considered to have mesothelioma. None of the clinical features analyzed were strongly associated with a confirmed diagnosis of malignant mesothelioma.

Discussion: Our study shows that only in a small number of the patients who applied no pathologic diagnosis could be obtained. Based on judgment of clinical experts in the majority of these cases a near to certain diagnosis could be made. Moreover, it is reasonable to obtain biopsy material from patients to increase the chance to obtain a confirmed diagnosis. Therefore, it is important to refer patients early for diagnostic procedures.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Pemetrexed-induced neutropenic enteritis and severe cutaneous hyperpigmentation in a patient with malignant pleural mesothelioma. K. Buchinger, R. Stahel, V. Niggemeier, et al. 2013;80(3):347-9. PubMed · Publisher

Abstract

Neutropenic enteritis (NE) or enterocolitis (NEC) is a rare, but potentially life-threatening side effect of neutropenia-inducing chemotherapy agents. Generally, its occurrence is attributed to leukemia-associated chemotherapies. Two cases of NE have been reported after the appliance of pemetrexed for treatment of non-small cell lung cancers. To our knowledge, NE has never been reported due to treatment with pemetrexed for malignant pleural mesothelioma (MPM). We present a case of MPM in a 77-year-old male suffering from severe NE one week after the seventeenth cycle of pemetrexed in the course of maintenance therapy for MPM, which could be treated successfully with antibiotic coverage and supportive measures. Concomitantly the patient showed a severe hyperpigmentation of his entire integument sparing the palms of both hands and the soles of his feet. After exclusion of alternative causes of skin hyperpigmentation, a pemetrexed-induced cutaneous hyperpigmentation was assumed according to two previous case reports. A combination of both pemetrexed-induced side effects in one patient has not been reported to date.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma. J. Creaney, I.M. Dick, A. Segal, et al. 2013;82(3):491-8. PubMed · Publisher

Abstract

Background: Malignant mesothelioma (MM), a primarily asbestos-induced tumour, has a poor prognosis, with over-all 5-year survival less than 5%. Tumour biomarkers are being intensely investigated in MM as aids to diagnosis and prognosis. Hyaluronic acid (HA) is produced in MM but its role in prognostication remains uncertain.

Materials And Methods: HA concentrations were determined in matching serum and pleural effusion of 96 MM patients, 26 lung cancer patients and 42 patients with benign effusions resulting from infectious, cardiac, renal, liver and rheumatoid diseases and compared to the current 'best practice' biomarker, mesothelin. Liver and kidney function were determined for each patient. Diagnostic accuracy was determined by area under the receiver operator characteristic curve (AUC) analysis following logistic regression modelling. Difference in survival between groups was determined by both log-rank test and Cox proportional hazards regression modelling.

Results: For effusion HA, the AUC (IQ range) was 0.89 (0.82-0.94) and for effusion mesothelin, it was 0.85 (0.78-0.90). Serum HA was not diagnostically useful. A combined measure of effusion HA, and serum and effusion mesothelin had an AUC of 0.92 (0.86-0.96), which was significantly higher than effusion mesothelin alone. Effusion HA had a biphasic distribution in MM patients, dichotomised at a concentration of 75 mg/L. The median survival of MM patients with high effusion HA was 18.0 (13.7-22.4) months, significantly longer than those with low HA effusion levels (12.6 months (8.4-16.8), p=0.004). Serum HA, and effusion and serum mesothelin were not significant prognostic indicators.

Conclusion: This study demonstrates that a combined biomarker panel has greater diagnostic accuracy than effusion mesothelin alone, and that significant prognostic information is provided by effusion HA.

Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.
Radical pleurectomy and chemoradiation for malignant pleural mesothelioma: the outcome of incomplete resections. S. Bölükbas, M. Eberlein, A. Fisseler-Eckhoff, et al. 2013;81(2):241-6. PubMed · Publisher

Abstract

Background: The type of surgery (radical pleurectomy (RP) vs. extrapleural pneumonectomy (EPP)) remains controversial for malignant pleural mesothelioma (MPM). Macroscopic complete resection (MCR) is a key prognostic factor. It is unclear, if patients undergoing incomplete RP within a standardized multimodality treatment protocols have any advantage in terms of survival and if EPP could theoretically have avoided incomplete resections (R2).

Methods: Eighty-eight patients underwent RP followed by chemoradiation from 2002 to 2011 within a prospective multimodality treatment study at a single institution. MCR were compared to R2 within this patient cohort retrospectively. EPP eligibility was assessed retrospectively based on preoperative cardiopulmonary testing and theoretical feasibility to achieve MCR. Kaplan-Meier analyses, log-rank test and Cox regression analyses were used to estimate survival and to determine predictors of survival.

Results: For the complete patient cohort, median survival (MS) was 26.3 months (mo). MCR could be achieved in 64.8% (57/88). Compared to MCR patients, R2-patients (n = 31, 35.2%) had an inferior overall survival (MS 13 vs. 33 mo, P < .0001), shorter progression-free-survival (MS 9 vs. 16 mo, P < .0001) and inferior survival after disease progression (MS 4 vs. 11 mo; P < .0001), respectively. R2 was associated with advanced p-T-Status (P < .0001), p-N-Status (P = 0.046) and p-IMIG stage (P < .0001). No difference could be observed with regard to age, histology, laterality, surgical morbidity and mortality, respectively. Only 3 out of 88 patients (3.4%) would have been eligible for EPP to achieve MCR. Not resectable T4-disease and impaired cardiopulmonary reserves were the main reasons for ineligibility for EPP in 35.5% (11/31) and 48.4% (15/31), respectively.

Conclusions: R2 in patients undergoing RP is associated with inferior outcomes. Only very selected cases would have qualified for EPP to achieve MCR. EPP might be an important surgical extension in selected patients to achieve MCR. There is a need for further investigation of effective intrapleural additive treatment options for patients undergoing R2.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

In plain English

This study looked at 88 patients with malignant pleural mesothelioma treated at one hospital in Wiesbaden, Germany, between 2002 and 2011. All had radical pleurectomy, an operation that removes the tumor while keeping the lung. The treatment plan then called for cisplatin/pemetrexed chemotherapy and radiotherapy; 74 of the 88 (84%) completed all three treatments. Looking back, the authors compared the 57 patients (64.8%) whose visible tumor was fully removed with the 31 (35.2%) whose tumor was not. Median overall survival was 33.2 months after complete removal and 12.9 months after incomplete removal. Incomplete removal was more common with more advanced tumor stage and lymph node spread. On retrospective review, only 3 of the 88 patients (3.4%) were judged suitable for extrapleural pneumonectomy, a larger operation that also removes the lung, as a way to achieve complete removal. The authors concluded that incomplete removal was associated with worse outcomes. They noted that the study was retrospective, came from one hospital, and was small. They also noted that the worse outcomes might reflect the advanced stage itself. The article did not discuss asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.
Systematic review of pleurectomy in the treatment of malignant pleural mesothelioma. C. Cao, D.H. Tian, K.A. Pataky, et al. 2013;81(3):319-327. Meta-analysis · Systematic review PubMed · Publisher

Abstract

Introduction: Pleurectomy/decortication (P/D) in the treatment of malignant pleural mesothelioma includes a number of procedures with different clinical indications and therapeutic intents. To unify the nomenclature, IMIG and IASLC recently defined P/D-related procedures according to surgical technique, including 'extended P/D', 'P/D' and 'partial pleurectomy'. The present systematic review aimed to assess the safety and efficacy of these techniques.

Methods: A systematic review of relevant studies was performed by electronic search of five online databases from 1985 to 2012 by two independent reviewers according to predefined selection criteria.

Results: Thirty-four studies involving 1916 patients who underwent pleurectomy were included for quantitative analysis. These included 12 studies on 'extended P/D', 8 studies on 'P/D' and 14 studies on 'partial pleurectomy'. Perioperative mortality ranged from 0% to 11% and perioperative morbidity ranged from 13% to 43%. Median overall survival ranged from 7.1 to 31.7 months and disease-free survival ranged from 6 to 16 months. One study reported on quality-of-life outcomes using a standardized questionnaire suggesting superior outcomes for 'extended P/D' compared to extrapleural pneumonectomy.

Conclusions: Results of the present systematic review suggested similar perioperative mortality outcomes between different P/D techniques but a trend towards higher morbidity and length of hospitalization for patients who underwent 'extended P/D'. However, overall and disease-free survival appeared to favour 'extended P/D' compared to less aggressive techniques. Future studies on P/D should adhere to recent definitions to enable accurate analysis of similar procedures. Direct comparisons of pleurectomy to extrapleural pneumonectomy remain challenging, and should be restricted to 'extended P/D' procedures only.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma. T. Muraoka, J. Soh, S. Toyooka, et al. 2013;82(3):485-90. PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP).

Materials And Methods: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined.

Results: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 °C which was the mean ± 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P=0.03) or HVs (P<0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77.

Conclusions: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
The role of epigenetics in malignant pleural mesothelioma. F. Vandermeers, S. Neelature Sriramareddy, C. Costa, et al. 2013;81(3):311-318. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an almost invariably fatal cancer of the pleura due to asbestos exposure. Increasing evidence indicates that unresponsiveness to chemotherapy is due to epigenetic errors leading to inadequate gene expression in tumor cells. The availability of compounds that modulate epigenetic modifications, such as histone acetylation or DNA methylation, offers new prospects for treatment of MPM. Here, we review latest findings on epigenetics in mesothelioma and present novel strategies for promising epigenetic therapies.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Tumor-associated macrophages in thoracic malignancies. L.A. Lievense, K. Bezemer, J.G. Aerts, et al. 2013;80(3):256-62. Review PubMed · Publisher

Abstract

Tumor-associated macrophages (TAMs) can be abundantly present in numerous cancer types. Under influence of various stimuli in the tumor microenvironment TAMs develop into a tumor-inhibitory (M1) or tumor-promoting (M2) phenotype. Recently, the role of TAMs in tumor biology and their prognostic value in cancer has become a major topic of interest. In this review we will discuss the importance of TAMs in the pathogenesis and clinical outcome of lung cancer and mesothelioma patients. In addition, the potential of TAMs as therapeutic targets will be discussed.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Two malignancies or an unusual presentation of a pleural malignancy?. B.J. Knipscheer, R.C. Kromontono, P.C. de Bruin, et al. 2013;81(2):306-7. Case report PubMed · Publisher

Abstract

Malignant mesothelioma is primarily located in the pleura. Progression usually involves adjacent tissue invasion. Both lymphatic and haematogenous spreads are possible, but rare. Bone involvement usually means locally invasive disease and rarely bone marrow metastases. In this report we presented two patients with a mesothelioma and bone marrow metastases.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma. J.E. Dowell, F.R. Dunphy, R.N. Taub, et al. 2012;77(3):567-71. PubMed · Publisher

Abstract

Introduction: Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM.

Methods: Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m(2)), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance. The primary endpoint was progression-free survival rate at 6 months.

Results: 53 patients were enrolled at 4 centers; 52 were evaluable for this analysis. The progression-free survival rate at 6 months was 56% and the median progression-free survival was 6.9 months (95% confidence interval [CI], 5.3-7.8 months). The partial response rate was 40% and 35% of patients had stable disease. Median overall survival was 14.8 months (95% CI; 10.0-17.0 months). Grade 3/4 toxicities included neutropenia in 11%, hypertension in 6%, and venous thromboembolism in 13% of patients.

Conclusion: This trial evaluating the addition of bevacizumab to cisplatin and pemetrexed in patients with previously untreated, advanced MM failed to meet the primary endpoint of a 33% improvement in the progression-free survival rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.

Published by Elsevier Ireland Ltd.
An electronic nose distinguishes exhaled breath of patients with Malignant Pleural Mesothelioma from controls. S. Dragonieri, M.P. van der Schee, T. Massaro, et al. 2012;75(3):326-31. PubMed · Publisher

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is a tumour of the surface cells of the pleura that is highly aggressive and mainly caused by asbestos exposure. Electronic noses capture the spectrum of exhaled volatile organic compounds (VOCs) providing a composite biomarker profile (breathprint).

Objective: We tested the hypothesis that an electronic nose can discriminate exhaled air of patients with MPM from subjects with a similar long-term professional exposure to asbestos without MPM and from healthy controls.

Methods: 13 patients with a histology confirmed diagnosis of MPM (age 60.9±12.2 year), 13 subjects with certified, long-term professional asbestos exposure (age 67.2±9.8), and 13 healthy subjects without asbestos exposure (age 52.2±16.2) participated in a cross-sectional study. Exhaled breath was collected by a previously described method and sampled by an electronic nose (Cyranose 320). Breathprints were analyzed by canonical discriminant analysis on principal component reduction. Cross-validated accuracy (CVA) was calculated.

Results: Breathprints from patients with MPM were separated from subjects with asbestos exposure (CVA: 80.8%, sensitivity 92.3%, specificity 85.7%). MPM was also distinguished from healthy controls (CVA: 84.6%). Repeated measurements confirmed these results.

Conclusions: Molecular pattern recognition of exhaled breath can correctly distinguish patients with MPM from subjects with similar occupational asbestos exposure without MPM and from healthy controls. This suggests that breathprints obtained by electronic nose have diagnostic potential for MPM.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Analysis of "dry" mesothelioma with ultrasound guided biopsies. J.A. Stigt, J.E. Boers, H.J. Groen. 2012;78(3):229-33. PubMed · Publisher

Abstract

Background: Image-guided sampling of the thickened pleura is a sensitive approach in patients with malignant pleural mesothelioma with pleural effusion. Malignant pleural mesothelioma presenting without effusion however is more of a diagnostic challenge. In this study we report the diagnostic yield and complications of ultrasound-guided cutting needle biopsies in this particular category of patients.

Methods: A retrospective database analysis from September 2007 until January 2012 was performed in 56 patients with malignant pleural mesothelioma. Clinical characteristics and results of diagnostic evaluations were analysed.

Results: Of the 56 patients with malignant pleural mesothelioma, 20 patients presented without pleural effusion of with locular effusion. Ultrasound-guided cutting needle biopsy was performed in 14/20 patients with a diagnostic accuracy of 80%. Only 1 patient had mild haemoptysis immediately following biopsies.

Conclusion: Diagnosing patients with pleural thickenings suspect for malignant mesothelioma without pleural effusion or with loculated pleural effusion is effective and safe with ultrasound-guided cutting needle biopsies.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Cancer mortality among Chinese chrysotile asbestos textile workers. X.R. Wang, I.T. Yu, H. Qiu, et al. 2012;75(2):151-5. PubMed · Publisher

Abstract

To determine mortality associated with exposure to chrysotile asbestos, a cohort of asbestos workers from an asbestos textile factory in China was followed prospectively from 1972 to 2008. A total 577 workers were successfully followed, achieving a follow-up rate of 98.5% over 37 years. Employment data and smoking information were obtained from factory and individual workers. Vital status was ascertained from factory personnel records and the municipal death registry. Workers were categorized into high, medium and low exposure groups in terms of their job titles and workshops. Follow-up generated 17,508 person-years, with 259 deaths from all causes, 96 all cancers and 53 lung cancers and 2 mesotheliomas. The highest cancer mortality was observed in the high exposure group, with 1.5-fold age-adjusted mortality from all cancers and 2-fold from lung cancer compared to the low exposure group. Age and smoking adjusted hazard ratio in the high exposure group was 2.99 (95%CI, 1.30, 6.91) for lung cancer and 2.04 (1.12, 3.71) for all cancers. Both smokers and nonsmokers at the high exposure level had a high death risk of lung cancer, with a clearer exposure-response trend seen in smokers. This study confirmed increased mortality from lung cancer and all cancers in asbestos workers, and the cancer mortality was associated with exposure level.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium. N.P. Campbell, R. Kunnavakkam, N. Leighl, et al. 2012;78(1):76-80. PubMed · Publisher · Free full text

Abstract

Introduction: Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1, -2, and -3.

Methods: We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily.

Results: Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥grade 3 hypertension (8.5 vs. 4.1 months, p=0.024).

Conclusion: This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM). S. Cedrés, M.A. Montero, P. Martinez, et al. 2012;77(1):192-8. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM.

Patients And Methods: Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil-lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis.

Results: Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p = 0.04) and overall survival (OS: 23.4 vs 5.6 months; p = 0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p = 0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p = 0.02 and p = 0.04 respectively), but pS6 only showed a trend (p = 0.8).

Conclusions: This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. O. Rena, C. Casadio. 2012;77(1):151-5. PubMed · Publisher

Abstract

The effects on long-term post-operative quality of life (QoL) and disease-control in malignant pleural mesothelioma (MPM) of extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are compared. Seventy-seven patients affected by early-stage MPM received EPP (40) or P/D (37) associated with multimodal treatment between 1998 and 2009 at our institution. The last consecutive 39 (19 EPP and 20 P/D) were asked to answer the EORTC-QLQ-C30 questionnaire at baseline and at 6- and 12-months after treatment completion to evaluate the impact on QoL of both procedures. QoL evaluation was stopped at recurrence demonstration. Twenty-five (62%) EPP vs 9 (24%) P/D patients (p = 0.002) had in-hospital major complications, and 2/40 (5%) EPP vs no one P/D patients died after surgery. Both procedures caused a significant impairment of all the considered variables of the EORTC-QLQ-C30 questionnaire after treatment completion; only P/D patients returned at baseline levels after 12 months. EPP patients had a worse long-term post-operative QoL when compared with P/D. Median post-operative disease-free period was longer for EPP patients (14 vs 11 months) whereas the residual life to death period after recurrence detection was significantly longer for P/D patients (13 vs 9 months) (p = 0.01). Median long-term survival was longer, even not significant, for P/D patients (25 vs 20 months). MPM patients submitted to EPP had a higher post-operative complication rate, a worse long-term QoL, a shorter residual life time after recurrent disease, despite a similar long-term survival when compared to P/D.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Health-related quality of life in patients with lung cancer: validation of the Mexican-Spanish version and association with prognosis of the EORTC QLQ-LC13 questionnaire. Ó. Arrieta, C. Núñez-Valencia, L. Reynoso-Erazo, et al. 2012;77(1):205-11. PubMed · Publisher

Abstract

Introduction: Lung cancer (LC) is the first cause of cancer-related mortality worldwide and health-related quality of life (HRQL) is a fundamental outcome for evaluating treatment results. Our objective was to validate the Mexican-Spanish versions of the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life QLQ-LC13 disease-specific questionnaire module in Mexican patients with LC; and to explore the possible prognostic role of HRQL data.

Methods: Translation procedures followed EORTC guidelines. Both instruments were completed by patients with LC. Tests for reliability and validity were performed. A subset of patients was administered HRQL evaluations before and after chemotherapy. HRQL was associated with prognosis in chemotherapy-naïve patients. The protocol was approved by the Institute's Ethics Committee.

Results: One hundred fifty three patients (mean age, 60.3 years; 84 females and 69 males) completed both questionnaires. Compliance rates were high, and the questionnaires were well accepted. Nine of 10 multi-item scales of both questionnaires presented Cronbach's alpha coefficients > 0.7. Multi-trait scaling analysis demonstrated good convergent and discriminant validity. Patients with better Karnofsky or Eastern Cooperative Oncology Group (ECOG) performance status reported better functional HRQL scores. Different scales in the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires were accurately related with clinical characteristics. Functional as well as disease-symptom scales improved after chemotherapy, but treatment side-effects scales worsened in test-retest analysis. Better role functioning and absence of thoracic pain scales were associated with longer overall survival (OS) (p = 0.009 and p = 0.035, respectively).

Conclusion: The Mexican-Spanish versions of the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires are reliable and valid for HRQL measurement in Mexican patients with LC and can be used in clinical trials.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
High association of peroxiredoxins with lung cancer. Y. Soini, V.L. Kinnula. 2012;78(2):167. Letter · Comment PubMed · Publisher

Summary

In this letter to the editor, the authors commented on an article by Rostila et al. that examined peroxiredoxins (PRX) 1 and 2 and tropomyosin 4 as potential biomarker proteins in the serum of patients with lung cancer and of individuals exposed to asbestos fibers and/or tobacco smoke. They summarized Rostila et al.'s data postulating that PRX1 is upregulated in lung cancer while PRX2 is likely downregulated, and the report that serum PRX1 and PRX2 levels were inversely associated with smoking, and PRX1 with lung cancer. The letter writers stated that these results were in line with their own earlier work on mesotheliomas, in which all six mammalian PRXs were studied and found to be over-expressed. They noted that Rostila et al. had not cited their earlier studies of PRXs in human lung and in various lung cancers. In that lung cancer study, PRXs 1, 2, 4 and 6 were elevated, expression varied considerably between tumor subtypes, and some PRXs (mainly 2 and 6) were associated with cancer grade or progression. The authors described the regulation of PRX1 by NRF2. They cited their recent findings that NRF2 expression was associated with poor prognosis in lung cancer, and that sulfiredoxin predicted poor outcome in patients receiving cytotoxic drugs or radiation therapy and was associated with smoking history. They agreed that PRXs 1 and 2 and tropomyosin 4 are worthy of further research in lung cancer and other pulmonary diseases.

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Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy. B. Fischer, C. Frei, U. Moura, et al. 2012;78(1):23-9. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a relatively chemoresistant malignancy. Diverse biological targets are under investigation to develop new therapeutic options. One of these targets, namely the phosphoinositide-3-kinase (PI3K) pathway, has been shown to be a regulator of the side population (SP) phenotype in different cancers. The SP phenotype is due to drug efflux abilities providing drug-resistant properties. The presence of a SP fraction in MPM was recently observed in our laboratory. The aim of this study was to investigate the role of the PI3K pathway in the regulation of the SP phenotype in MPM. Treatment of overnight serum-starved cells with IGF increased phosphorylation of downstream target AKT, S6 and 4EBP1 and SP fraction in ZL55, ZL34 and SDM103T2 MPM cell lines. The PI3K/mTOR inhibitor NVP-BEZ235 and PI3K inhibitor wortmannin reduced the phosphorylation of downstream target AKT, S6 and 4EBP1 and decreased the SP fraction. Chemotherapy resistance mediated by drug efflux was tested by treating the cells with mitoxantrone. NVP-BEZ235 increased mitoxantrone cytotoxicity and this effect was mimicked by fumitremorgin C, a specific ABCG2 inhibitor, although not to the same extent, indicating that ABCG2-mediated drug efflux participates to chemoresistance. The involvement of ABCG2 in drug efflux was confirmed by determination of ABCG2-mediated decrease of intracellular mitoxantrone accumulation and silencing experiments. NVP-BEZ235-mediated decrease in drug efflux was associated with a significant decrease of ABCG2 present at the cell surface in ZL55 and SDM103T2 cells. In conclusion, the PI3K pathway is playing an important role in regulating the SP phenotype in MPM cells and inhibition of this activity may contribute to a more efficient cancer treatment.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Mesothelioma and lung cancer mortality: a historical cohort study among asbestosis workers in Hong Kong. M. Chen, L.A. Tse, R.K. Au, et al. 2012;76(2):165-70. PubMed · Publisher

Abstract

Objectives: To investigate the mortality pattern among a cohort of workers with asbestosis in Hong Kong, with special emphases on mesothelioma and lung cancer.

Methods: All 124 male workers with confirmed asbestosis in Hong Kong during 1981-2008 were followed up to December 31, 2008 to ascertain the vital status and causes of death. Standardized mortality ratio (SMR) for each underlying cause of death was calculated by using person-year method. Axelson's indirect method was applied to adjust for the potential confounding effect of cigarette smoking.

Results: A total of 86 deaths were observed after 432.8 person-years of observations. The SMR for overall mortality (6.06, 95% CI: 4.90-7.51) increased significantly. The elevated risk of deaths from all cancers (7.53, 95% CI: 5.38-10.25) was mainly resulted from a significantly excess risk from lung cancer (SMR=7.91, 95% CI: 4.32-13.29, 14 deaths) and mesothelioma (SMR=6013.63, 95% CI: 3505.95-9621.81, 17 deaths). The SMR for lung cancer retained statistically significant after adjustment of smoking. An increased smoking adjusted SMR was also suggested for all heart diseases (2.32, 95% CI: 0.93-4.79, 7 deaths) and acute myocardial infarction (3.10, 95% CI: 0.84-7.94, 4 deaths), though the statistical significance was borderline. We found a positive association with net years of exposure to asbestos for mesothelioma and lung cancer.

Conclusions: Our study provided further evidence on the carcinogenesis of asbestos/asbestosis with the risk of deaths from lung cancer and mesothelioma. This study also provided a preliminary support for a possible link between asbestosis and heart disease, but power is limited.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma. S. Al-Taei, J. Salimu, J.F. Lester, et al. 2012;77(2):312-8. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is resistant to conventional treatments. Novel, targeted treatments are hampered by the relative lack of MPM-associated tumour antigens. The aim of this study was to evaluate the level of expression and the relevance of 5T4 as a tumour-associated antigen in MPM. 5T4 expression was assessed by Western blotting, flow cytometry, immuno-cytochemistry and -histochemistry in 11 mesothelioma cell lines, 21 tumour biopsies, and ex vivo tumour cells obtained from the pleural fluid (PF) of 10 patients. 5T4 antibody levels were also determined in the plasma of patients and healthy donors. The susceptibility of MPM cells to 5T4-specific T-cell-mediated killing was determined using an HLA-A2(+), CD8(+) T-cell line, developed against the 5T4(17-25) peptide. We report here that cell surface 5T4 expression was detected in all mesothelioma cell lines and PF cell samples. Mesothelin and CD200, a suggested mesothelioma marker, were co-expressed with 5T4 on tumour cells in PF. Immunohistochemistry confirmed overexpression of 5T4, similar to mesothelin, on tumour cells but not on reactive stroma in all tissue sections tested. Median 5T4 antibody levels were 46% higher in patient than in healthy donor plasma, indicating immune recognition. Importantly, 5T4-specific CD8(+) T-cells were able to kill four out of six HLA-A2(+) MPM cell lines but not an HLA-A2(-) cell line, demonstrating immune recognition of MPM-associated 5T4 antigen at the effector T-cell level. We conclude that 5T4 is a potential new antigen for targeted therapies such as immunotherapy in MPM, as it is overexpressed on mesothelioma cells and recognised by 5T4-specific cytotoxic T-cells. Our findings have been translated into a Phase II clinical trial applying 5T4-targeted therapies in MPM patients.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Perineal and colonic metastases in two cases of malignant mesothelioma. B. Grewal, G. Reid, H. Lord. 2012;77(1):235-8. Case report PubMed · Publisher

Abstract

Two patients with rare sites of metastatic pleural mesothelioma are presented and the literature on similar cases is examined. One patient developed colonic metastases from a sarcomatoid mesothelioma. Another patient with epithelioid mesothelioma developed perineal metastases.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Peroxiredoxins and tropomyosins as plasma biomarkers for lung cancer and asbestos exposure. A. Rostila, A. Puustinen, T. Toljamo, et al. 2012;77(2):450-9. PubMed · Publisher

Abstract

The prognosis of lung cancer is poor due to late diagnosis, the lack of established screening programs, and the paucity of early biomarkers for high-risk populations. Plasma proteome analysis was used to identify novel biomarkers for diagnosing lung cancer, and to unravel the mechanisms of underlying pathogenesis. Plasma proteins obtained from asbestos-exposed lung cancer cases detected by CT screening, asbestos-exposed subjects, clinical lung cancer patients, and healthy tobacco smokers, 5-6 cases in each group, were separated by two-dimensional gel electrophoresis, and identified with tandem mass spectrometry (LC-MS/MS). Nine proteins were selected for immunological confirmation in a test or validation set of plasma samples from an additional 49 clinical lung cancer cases, 66 asbestos-exposed patients, and 107 healthy tobacco smokers. Twenty-eight unique proteins were differentially expressed between the four study groups (p<0.05). Peroxiredoxin 1 (PRX1) was detected as a novel plasma marker for lung cancer (p=0.001). We also confirmed the previously found association of serum amyloid A with lung cancer (p<0.001). High plasma levels of tropomyosin 4 (TPM4: p<0.001) and peroxiredoxins 1 and 2 (PRX2: p<0.001) correlated with asbestos exposure or a diagnosis of asbestosis. PRX1 and PRX2 exhibited an inverse correlation with tobacco smoking (p<0.001). Plasma peroxiredoxins 1 and 2, and tropomyosin 4 were shown to associate with asbestos-exposure, and peroxiredoxin 1 with lung cancer. High plasma levels of peroxiredoxin 1 may result from genetic damage caused by reactive oxygen species. This study has identified several biomarkers worthy of further investigation in lung cancer and asbestos-related diseases.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Primum non nocere? Does this also apply to mesothelioma?. P. Baas. 2012;77(1):1. Editorial PubMed · Publisher
Proteomic surfaceome analysis of mesothelioma. A. Ziegler, F. Cerciello, C. Bigosch, et al. 2012;75(2):189-96. PubMed · Publisher

Abstract

Identification of new markers for malignant pleural mesothelioma (MPM) is a challenging clinical need. Here, we propose a quantitative proteomics primary screen of the cell surface exposed MPM N-glycoproteins, which provides the basis for the development of new protein-based diagnostic assays. Using the antibody-independent mass-spectrometry based cell surface capturing (CSC) technology, we specifically investigated the N-glycosylated surfaceome of MPM towards the identification of protein-marker candidates discriminatory between MPM and lung adenocarcinoma (ADCA). Relative quantitative CSC analysis of MPM cell line ZL55 in comparison with ADCA cell line Calu-3 revealed a bird's eye view of their respective surfaceomes. In a secondary screen of fifteen MPM and six ADCA, we used high throughput low density microarrays (LDAs) to verify specificity and sensitivity of nineteen N-glycoproteins overregulated in the surfaceome of MPM. This proteo-transcriptomic approach revealed thy-1/CD90 (THY1) and teneurin-2 (ODZ2) as protein-marker candidates for the discrimination of MPM from ADCA. Thy-1/CD90 was further validated by immunohistochemistry on frozen tissue sections of MPM and ADCA samples. Together, we present a combined proteomic and transcriptomic approach enabling the relative quantitative identification and pre-clinical selection of new MPM marker candidates.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma. B. Woods, N. Paracha, D.A. Scott, et al. 2012;75(2):261-7. PubMed · Publisher

Abstract

Introduction: The National Institute for Health and Clinical Excellence (NICE) has previously recommended pemetrexed plus cisplatin for the treatment of patients with advanced malignant pleural mesothelioma (MPM) and WHO performance status 0-1. Subsequent to this appraisal, randomised controlled trial (RCT) data for raltitrexed plus cisplatin and comparing chemotherapy to active symptom control (ASC) has become available, allowing a more complete analysis of the comparative efficacy and cost-effectiveness of first-line chemotherapy in MPM.

Methods: An adjusted indirect comparison is used to estimate the relative efficacy of raltitrexed plus cisplatin and pemetrexed plus cisplatin. A cost-effectiveness model is used to assess the lifetime costs and health outcomes associated with these comparators and ASC. Patient level data from the EORTC 08983 trial are used to estimate baseline progression and survival rates. Relative treatment effects are taken from RCTs; cost and utility data from the literature.

Results: Raltitrexed plus cisplatin and pemetrexed plus cisplatin were not found to be statistically significantly different with respect to overall response, progression free survival or overall survival. The cost-effectiveness analysis found raltitrexed plus cisplatin to be cost-effective at a cost per quality adjusted life year of £13,454 compared to cisplatin and £27,360 compared to ASC. Pemetrexed plus cisplatin is dominated by raltitrexed plus cisplatin as the raltitrexed combination offers marginally higher quality adjusted life years (QALYs) and life years (LYs) at a substantially lower total cost.

Conclusion: Raltitrexed plus cisplatin is a cost-effective first-line treatment for MPM. This conclusion was maintained across a number of sensitivity analyses.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Safety and effectiveness of pemetrexed in patients with malignant pleural mesothelioma based on all-case drug-registry study. K. Kuribayashi, S. Voss, S. Nishiuma, et al. 2012;75(3):353-9. PubMed · Publisher

Abstract

Background: Pemetrexed in combination with cisplatin (Pem/Cis) is the only approved chemotherapeutic regimen for malignant pleural mesothelioma (MPM). At the time of launch, limited safety information was available. The purpose of this postmarketing all-case registry study was to investigate the safety and effectiveness of pemetrexed in patients with MPM.

Methods: From January 2007 to May 2008, MPM patients to be treated with pemetrexed in Japan were registered to this study to monitor its safety and effectiveness. Supply of pemetrexed was restricted to institutions with experienced medical oncologists based on predetermined criteria.

Results: Of 953 patients registered, data from 903 patients were eligible for analysis. Most patients were male, with median age of 65 years and 68.5% had a history of asbestos exposure. More than 90% of patients received the first cycle of Pem/Cis treatment; median number of treatment cycles was 4.0. Treatment-associated death was reported in 0.8% of patients. The incidence of Interstitial lung disease (ILD) associated with Pem/Cis during the observation period was 0.9%. The frequency of ILD in patients with pre-existing asbestosis was higher than that in patients without it. For tumor response, the overall response rate was 25.0% (95% confidence interval (CI): 22.2-28.0%). The six-month survival rate estimated by the Kaplan-Meier method was 75.9%.

Conclusions: This large scale all case registry study appeared to have enrolled a major portion of Japanese MPM patients. Treatment with pemetrexed was generally well tolerated and showed safety and effectiveness comparable to prior clinical trials.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. P.A. Zucali, M. Simonelli, G. Michetti, et al. 2012;75(3):360-7. PubMed · Publisher

Abstract

The pemetrexed-cisplatin chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). The second-line (SL) chemotherapy is considered, but the optimal treatment has not been defined yet. The aim of this study was to evaluate the clinical outcomes of SL-therapy in a series of MPM-patients included in a retrospective multicenter database. Clinical records of MPM-patients who received SL-treatment from 1996 to 2008 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL, stratified for patient characteristics, FL-outcomes, and type of SL. Out of 423 patients, 181 with full clinical data were identified. Patients' characteristics: median-age 64 years (range: 36-85); male gender 115 (63.5%); good EORTC-score 109 (60.2%); epithelial histology 135 (74.6%). After FL, 147 (81.2%) patients achieved disease-control (DC) and 45 had a time-to-progression≥12 months (TTP≥12). After SL, 95 patients (52.6%) achieved DC (21 response; 74 stable-disease); median PFS and OS were 4.3 and 8.7 months, respectively. According to multivariate analysis, DC after SL-therapy was significantly related to pemetrexed-based treatment (OR: 2.46; p=0.017) and FL-TTP≥12 (OR: 3.50; p=0.006). PFS was related to younger age (<65 years) (HR: 0.70; p=0.045), ECOG-PS0 (HR: 0.67; p=0.022), and FL-TTP≥12 (HR: 0.45; p<0.001). OS was significantly related to ECOG-PS0 (HR: 0.43; p<0.001) and to FL-TTP≥12 (HR: 0.54; p=0.005). In pemetrexed pre-treated patients, re-treatment with a pemetrexed/platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p<0.001). In conclusion, SL-chemotherapy seems to be active in MPM-patients, particularly in younger patients with ECOG-PS0 and prolonged TTP after FL-pemetrexed-based chemotherapy. In selected patients, re-challenge with pemetrexed-based regimens, preferentially associated with platinum-compound, appears to be an option for SL-setting. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer. T. Ueno, K. Tsukuda, S. Toyooka, et al. 2012;76(1):26-31. PubMed · Publisher

Abstract

The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24,100 nM) than the NSCLC cells (p=0.015). There was significant depletion of both the total and phosphorylated client proteins--EGFR, MET, HER2 and AKT--at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G0-G1 cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC.

Copyright Â© 2011 Elsevier Ireland Ltd. All rights reserved.
The predictive role of serum VEGF in an advanced malignant mesothelioma patient cohort treated with thalidomide alone or combined with cisplatin/gemcitabine. S.C. Kao, R. Harvie, F. Paturi, et al. 2012;75(2):248-54. PubMed · Publisher

Abstract

There is a need for new treatment strategies and prognostic markers for the management of malignant mesothelioma (MM). The activity of thalidomide/cisplatin/gemcitabine (arm A) or thalidomide alone (arm B) was investigated in two parallel phase II studies in patients with advanced MM, using 6 month progression free survival (PFS) as the principal end-point. The predictive role of pre-treatment and 8 week follow-up serum C-reactive protein (CRP), interlukin-6 (IL-6), interlukin-6 soluble receptor (sIL-6R), mesothelin (SMRP) and vascular endothelial growth factor (VEGF) was also assessed. The proportion of patients with stable disease for >6 months was similar in both studies (arm A 35%, arm B 29%) and toxicity was mainly grade I/II. In univariate analyses only pre-treatment VEGF and CRP were correlated with survival. At 8 weeks post treatment, increased survival was found with low (<median) VEGF and CRP compared with high (>median) VEGF and CRP (P<0.05). Change in VEGF over the first 8 weeks of treatment was also predictive for survival (P<0.05). When pre-treatment VEGF was >median, decreasing VEGF was associated with increased survival (P<0.05). In conclusion, thalidomide alone, or in combination with cisplatin/gemcitabine, controlled disease for >6 months in ∼30% of patients. Patients with decreasing VEGF during treatment had longest survival. Pre-treatment VEGF or CRP and early change in VEGF on treatment may predict treatment benefit and should be examined in future studies.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107). T. Jahan, L. Gu, R. Kratzke, et al. 2012;76(3):393-6. PubMed · Publisher · Free full text

Abstract

Introduction: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the efficacy and safety of vatalanib in previously untreated patients with malignant mesothelioma and to evaluate potential biomarkers of disease response (CALGB 30107).

Methods: Treatment consisted of vatalanib 1250 mg given orally once daily. CT scans were obtained at baseline and every 6 weeks thereafter. Baseline serum levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), thrombospondin-1 (TSP-1), and mesothelin were obtained. The primary endpoint was 3-month progression-free survival (PFS).

Results: Forty-seven patients enrolled at 19 centers. The median age was 75 years, and the majority of patients (79%) had an ECOG performance status of 1. Tumors were classified as epithelial (77%), sarcomatoid (10%), or mixed (9%) histology. Toxicity was mild; the most common grade 3/4 adverse events were neutropenia (2%), nausea (15%), elevated alanine aminotransferase (11%), hypertension (2%), and gastrointestinal bleeding (2%). Partial responses were observed in 6% of patients and stable disease in 72% of patients. The 3-month PFS rate was 55% (95% CI: 40%, 68%). The median PFS was 4.1 months. Median overall survival was 10.0 months. There was no correlation between serum levels of VEGF, PDGF, TSP-1, or mesothelin and treatment response, PFS, or survival.

Conclusions: Vatalanib as a single agent with this dose and schedule does not warrant further study in this disease.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
5-Aminolevulinic acid-induced fluorescence diagnosis of pleural malignant tumor. A.H. Ali, H. Takizawa, K. Kondo, et al. 2011;74(1):48-54. PubMed · Publisher

Abstract

Background: It is known that endogenously synthesized protoporphyrin IX (PpIX) following the administration of 5-aminolevulinic acid (5-ALA) is an effective photosensitizer for photodynamic diagnosis (PDD). We tested in vivo and in vitro susceptibility of human lung cancer and mesothelioma cells to photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) as a photosensitizer.

Methods: Human lung cancer cell lines A549, Ma44-3, FT821 and human mesothelioma cell lines MSTO-211H, NCI-H290, Y-MESO-14 were incubated with 0.03% 5-ALA for 4 h. After incubation, protoporphyrin IX (PpIX) fluorescence was detected using a fluorescence microscope. Pleural carcinosis was induced in severe combined immunodeficiency disease mice using the previous cell lines to test the efficacy of PDD in vivo. The mice were sacrificed 4 h after oral administration of 400 mg/kg of 5-ALA. We counted the visible tumors under white light then fluorescence light.

Results: In vitro, clear red fluorescence was observed in all cell lines. The mean fluorescence intensity was stronger in A549 and FT821 cells than Ma44-3 cells (165.59±26.49, 157.62±18.93 vs. 104.01±17.58). Also, MSTO-211H and NCI-H290 cells had stronger fluorescence intensity than Y-MESO-14 cells (142.51±26.85, 165.16±12.91 vs. 92.31±8.69). In vivo, the tumor detection rate of fluorescence diagnosis was 1.1-4.5 times higher than that of white light. The mean number of metastases detected by the PDD was significantly higher than that of white light for FT821 (p=0.004), Ma44-3 (p=0.006) and Y-MESO-14 cell lines (p=0.005), but not for A549, NCI-H290 and MSTO-211H cell lines. Small lesions were detected by fluorescence diagnosis even though the lesions were invisible macroscopically under white light.

Conclusion: Our results suggest the possibility of clinical application of fluorescence diagnosis with intrapleural malignant tumors.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Bioluminescence imaging for in vivo monitoring of local recurrence mesothelioma model. Y. Shi, A. Hollenstein, E. Felley-Bosco, et al. 2011;71(3):370-1. Letter PubMed · Publisher

Summary

This letter to the editor described a noninvasive way to monitor a rat model of local recurrence of malignant pleural mesothelioma (MPM) that the authors had established earlier. The rat mesothelioma cell line IL45, which came from experimental asbestos-exposed peritoneal mesothelioma in rats, was stably transfected with a luciferase-expressing vector, and luciferase-positive clones were pooled. Male Fischer 344 rats weighing 250–300 g were kept at the University Hospital Zurich. Two groups of 3 rats each were inoculated with 1 × 10^6 cells: one group received luciferase-expressing IL45 cells and the other received normal IL45 cells. Tumors were imaged with an IVIS 200 system at several time points. Bioluminescence signals were detected three days after tumor cell inoculation in rats given luciferase-expressing cells and increased over time. No signal was seen in rats given non-transfected cells. Six days after inoculation, a tumor nodule was present at the injection site in all cases and was macroscopically completely resected. At final evaluation 13 days after inoculation, the tumor had relapsed locally at the resection site in all animals. The recurrent tumor was sarcomatoid, like the parental tumor. Bioluminescence signals correlated well with caliper-measured tumor volumes (r2 = 0.9665). Tumor development did not differ between luciferase-expressing and non-luciferase-expressing tumors. The authors concluded that the model would be a useful tool for evaluating and optimizing preclinical cancer therapies.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Chemotherapy and targeted therapies for unresectable malignant mesothelioma. R.J. Kelly, E. Sharon, R. Hassan. 2011;73(3):256-63. Review PubMed · Publisher · Free full text

Abstract

The global burden of mesothelioma is expected to increase in the coming decades. As a result the development of more effective therapies with an emphasis on personalized treatments based on validated prognostic and predictive biomarkers is an essential requirement. Progress has been made in the last decade with the development of newer generation anti-folates leading to the current standard of care of pemetrexed and cisplatin in patients with unresectable disease. However, the median overall survival of patients with this combination treatment is only 12 months. There is no consensus regarding second line therapy for patients who have progressed or not responded to pemetrexed based therapies although gemcitabine in combination with a platinum compound or single agent vinorelbine is a reasonable option. The development of effective targeted agents that are active in mesothelioma has to date been disappointing. Strategies involving the addition of bevacizumab to pemetrexed and cisplatin in the frontline setting, the histone deacetylase inhibitor vorinostat as second line therapy and studies evaluating the utility of maintenance therapy in mesothelioma are all ongoing and appear promising. In addition clinical trials investigating immunotherapy and gene therapy in combination with chemotherapy could potentially improve the prognosis of patients with mesothelioma.

Published by Elsevier Ireland Ltd.
Influence of co-morbidity on renal function assessment by Cockcroft-Gault calculation in lung cancer and mesothelioma patients receiving platinum-based chemotherapy. R.A. Hubner, R. Goldstein, S. Mitchell, et al. 2011;73(3):356-60. PubMed · Publisher

Abstract

Background: Creatinine clearance (CrCl) estimation by Cockcroft-Gault calculation (CG) often replaces measurement of glomerular filtration rate (GFR) by [(51)Cr]-ethylenediaminetetraacetic acid clearance (EDTA). Co-morbidity, age, and renal impairment influence the accuracy of CG, whilst the relationship between CG and EDTA has been poorly assessed in lung cancer patients, a population significantly affected by these covariates.

Methods: Retrospective analysis of co-morbidity, nephrotoxic drug use, chemotherapy toxicity, and correlation between paired CG and EDTA, in 388 lung cancer and mesothelioma patients receiving platinum-based chemotherapy.

Results: Potentially nephrotoxic co-morbidity or medication use occurred in 47% of patients, and was twice as likely in those aged >70 years (OR=2.07; 95%CI: 1.25-3.44, p=0.003). Patients with co-morbidity or nephrotoxic medication use had a lower EDTA compared to those without these baseline factors (p=0.02), but were not significantly more likely to experience chemotherapy toxicity. CG and EDTA correlation was high (r(2)=0.68), but reduced in patients with ETDA<50 ml/min (r(2)=0.26, p=0.02) or >120 ml/min (r(2)=0.32, p=0.09), and in those with CG>120 ml/min (r(2)=0.20, p=0.01). The correlation between CG and EDTA was not significantly altered in patients with co-morbidity or nephrotoxic medication use. CG bias (mean percentage error) and precision (mean absolute percentage error, MAPE) were 7% and 26%, respectively, and precision was impaired in patients with abnormally raised serum creatinine (MAPE 65%, p<0.0001).

Conclusion: CG estimation of CrCl is accurate and safe in lung cancer patients with potentially nephrotoxic co-morbidity or concomitant medication, but should not be used when values are outside the range 50-120 ml/min, or with abnormally elevated serum creatinine.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Mesothelin and kidney function--analysis of relationship and implications for mesothelioma screening. N. Boudville, R. Paul, B.W. Robinson, et al. 2011;73(3):320-4. PubMed · Publisher

Abstract

Purpose: Malignant mesothelioma (MM) carries a poor prognosis and remains a major public health issue in many countries. Outcomes may be improved with earlier detection and this justifies screening the at-risk asbestos-exposed population. Soluble mesothelin is a potential biomarker for MM, but it has been observed to be elevated in patients with reduced kidney function. Defining the relationship between mesothelin concentrations and kidney function will allow more accurate interpretation of this assay.

Materials And Methods: A cross-sectional study consisting of 144 patients with chronic kidney disease (CKD) was conducted at Sir Charles Gairdner Hospital and Royal Perth Hospital in Western Australia. Only patients with CKD stages II-V were recruited while those with a history of renal transplant, dialysis, or malignancy were excluded. Serum and urine mesothelin and creatinine concentrations were determined.

Results: There were 33, 49, 31 and 31 patients in CKD stages II, III, IV and V, respectively recruited. Serum mesothelin increased significantly with increasing serum creatinine (p<0.0001), and worsening stage of CKD (p<0.0001). A significant correlation between urine mesothelin to creatinine ratio and serum mesothelin concentration was detected (p=0.002). No significant difference was found in urine mesothelin to creatinine ratios across the four CKD stage groups.

Conclusion: Serum mesothelin concentration is elevated in individuals with renal impairment. Renal function should therefore be taken into account during interpretation of this assay.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Mesothelioma at era of helical tomotherapy: results of two institutions in combining chemotherapy, surgery and radiotherapy. A. Sylvestre, M.A. Mahé, A. Lisbona, et al. 2011;74(3):486-91. PubMed · Publisher

Abstract

Purpose: There is a scarce clinical experience about adjuvant helical tomotherapy (HT) in patients affected by malignant pleural mesothelioma (MPM) even though it appears as a useful technique to treat complex volume as the pleural cavity, and seems to have better dose distribution than the "classic" intensity modulated radiotherapy (IMRT).

Methods And Materials: Twenty-four patients received adjuvant radiotherapy (RT) by HT from August 1st, 2007 to December 1st, 2009 at Curie Institute (Paris) and René Gauducheau Cancer Center (Nantes). Thirteen patients had neoadjuvant chemotherapy. Extrapleural pleuropneumonectomy (EPP) was done in 23 patients. Median dose to PTV was 50Gy [48.7-55.9Gy] (2Gy/fraction). Acute and long term toxicities, disease free survival (DFS), overall survival (OS) and relapses are presented.

Results: Average follow up after RT was 7 months. The disease was staged mostly as T2-T3, N1-N2. Nineteen patients had epithelial type histology. Most patients tolerated radiotherapy with grade 1-2 side effects: redness of the skin, light cough or dyspnea, fatigue, nausea and odynophagia, mild increase of the post-operative thoracic pain. Grade 3 pneumonitis was suspected in 2 patients. Two grade 5 pneumonitis were also suspected. Eleven patients had a follow up of more than 6 months and no long term side effects related with HT were noted. At 24 months, 51.8% of patients were free of disease. Thirty percent of patients relapsed, with 2 patients presenting local relapses. Two patients died from recurrence.

Conclusion: With limited follow up, HT has comparable toxicity to those observed with traditional IMRT. Higher radiation dose and good coverage results in excellent local control.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP. L.S. Kristensen, H.M. Nielsen, H. Hager, et al. 2011;71(2):130-6. PubMed · Publisher

Abstract

Silencing of the DNA repair gene O⁶-methylguanine DNA methyltransferase (MGMT) by promoter methylation is an early event in several human cancers. MGMT removes alkyl adducts from the O⁶ position of guanine thereby preventing G>A mutations in the genome. For this reason, MGMT promoter methylation predicts a favorable outcome for glioblastoma patients treated with alkylating agents. In this study, we investigated whether MGMT becomes silenced by promoter methylation in malignant pleural mesothelioma (MPM), an aggressive cancer of the pleura associated with a poor prognosis. Ninety-five samples from patients diagnosed with MPM were studied. These samples were genotyped for the MGMT rs16906252 promoter SNP using high-resolution melting, and methylation status was analyzed using SMART-MSP and confirmed by Sanger sequencing. The SMART-MSP assay was designed to provide information on the allelic methylation status in samples heterozygous for rs16906252. MGMT immunohistochemistry was performed on samples showing no methylation, monoallelic methylation, and biallelic methylation. Thirteen of the 95 MPM samples (13.7%) were methylation positive and a strong association with the T allele of the rs16906252 SNP (P<0.001) was observed. Detection of the protein was found to be dependent not only on the allelic methylation status but also on the methylation level, and complete silencing was observed in only one sample, showing biallelic methylation and a methylation level close to 100%. In conclusion, methylation of the MGMT promoter occurs in a subset of MPM patients and is associated with the T allele of the MGMT rs16906252 SNP. However, complete silencing of MGMT in MPM is a rare event.

Copyright Â© 2010 Elsevier Ireland Ltd. All rights reserved.
Pemetrexed re-challenge in pleural malignant mesothelioma: an option for a subset of patients initially treated with pemetrexed-platinum doublets in the first-line setting?. G. Zalcman, E. Bergot, E. Lechapt. 2011;72(1):1-2. Editorial PubMed · Publisher
Plasma versus serum levels of osteopontin and mesothelin in patients with malignant mesothelioma--which is best?. J. Creaney, D. Yeoman, A.W. Musk, et al. 2011;74(1):55-60. PubMed · Publisher

Abstract

Background: Blood-based markers for malignant mesothelioma (MM), particularly soluble mesothelin and osteopontin, are currently of great clinical interest. As there is some concern about the sensitivity of osteopontin in serum versus plasma, we compared them in the same patient population to mesothelin.

Methods: Soluble mesothelin and osteopontin concentrations were determined by commercial assays in blood samples from 66 patients with pleural MM, 47 patients with non-malignant asbestos-related lung or pleural disease, 42 patients with other benign pleural and lung diseases and 21 patients with lung cancer.

Results: Soluble mesothelin and osteopontin in serum and plasma were significantly elevated in MM patients compared to patients with benign lung and pleural disease. At a level of specificity of 95% relative to patients with benign disease, the sensitivity of mesothelin in serum and plasma at presentation with symptoms was 67%, and for osteopontin in the plasma was 40% and in the serum was 20% for MM patients. Combining the serum mesothelin and plasma osteopontin markers using a logistic regression model did not significantly increase the area under the receiver operator curve.

Conclusion: Plasma osteopontin has a superior diagnostic accuracy to serum. As the choice of blood sample type has limit effect on soluble mesothelin sensitivity, plasma should be collected for biomarker evaluation in patients suspected of having mesothelioma.

Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.
Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience. G. Pasello, S. Nicotra, G. Marulli, et al. 2011;73(3):351-5. PubMed · Publisher

Abstract

Background: The major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients.

Methods: Eligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS=0-2, adequate organ function, measurable disease. Chemotherapy was gemcitabine 1000 mg/m(2) days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75 mg/m(2) or carboplatin AUC 5 day 1 every 3 weeks, for 3-6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan.

Results: Since 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47-74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1-2 (15:2). The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13-168) and median time-to-treatment failure 15 weeks (range 3-75). Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%).

Conclusion: Gemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Premature senescence induced by DNA demethylating agent (Decitabine) as therapeutic option for malignant pleural mesothelioma. S. Amatori, I. Bagaloni, D. Viti, et al. 2011;71(1):113-5. Letter PubMed · Publisher

Abstract

The drug-dependent induction of premature senescence in neoplastic cells is considered per se an important tumor suppressive mechanism. DNA demethylating agents recently introduced in clinical trials, such as 5-aza-cytidine (Decitabine) and its derivatives, have been extensively characterized in recent years as antiproliferative compounds that act through multiple mechanisms, which have not yet been fully clarified. We recently analyzed the introduction of Decitabine in therapy for malignant pleural mesothelioma (MPM) observing that, despite the ability to induce profound biological effects in MPM cells, the drug failed to generate a massive apoptotic response. Since one of the most intriguing aspects of DNA demethylating agents is the possibility to accelerate the senescent response of tumor cells, we investigated the hypothesis of Decitabine inducing, in vitro, the premature aging of MPM cells.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Quantitative Perfusion Scintigraphy or Anatomic Segment Method in lung cancer resection. T. Holvoet, J.P. van Meerbeeck, C. Van De Wiele, et al. 2011;74(2):212-8. PubMed · Publisher

Abstract

Background: Quantitative Perfusion Scintigraphy (QPS) and Anatomic Segment Method (ASM) are two techniques for estimating postoperative pulmonary function. QPS is gold standard, but holds disadvantages.

Aim: Could ASM substitute QPS in the preoperative work-up of NSCLC?

Methods: Retrospective study in patients with NSCLC or mesothelioma undergoing resection. FEV1 and DL,CO were estimated by QPS and ASM and compared to pulmonary function measured 3 months after resection. Correlation tests and Bland-Altman analyses were performed.

Results: 40 patients (23 lobectomies, 14 pneumonectomies). Both methods correlated similarly with postoperative FEV(1) (QPSρ=0.69; ASMρ=0.75) and DL,CO (QPSρ=0.70; ASMρ=0.74). Correlation between both methods was high (ppoFEV(1)ρ=0.89; ppoDL,COρ=0.89). The same principles applied in a subgroup analysis of patients with COPD. Bland-Altman analyses showed that ASM underestimated postoperative FEV(1) and DL,CO more than QPS in all groups.

Conclusion: QPS and ASM are remarkably similar in predicting postoperative pulmonary function. As ASM underestimates pulmonary function more, it could be a safe alternative from a cost-benefit point of view. Based on these results, it appears that QPS could be restricted to patients in whom ASM suggests functional inoperability, although further prospective studies are necessary.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Rat mesothelioma cell proliferation requires p38δ mitogen activated protein kinase and C/EBP-α. J. Zhong, D. Lardinois, J. Szilard, et al. 2011;73(2):166-70. PubMed · Publisher

Abstract

Pleural malignant mesothelioma is a rare but deadly tumour mainly induced by asbestos inhalation. Despite the ban of asbestos in 1990 in 52 countries, mesothelioma cases still increase worldwide. In pleural mesothelioma, p38 mitogen activated protein kinases (MAPK) have been suggested to play a major role in carcinogenesis and aggressiveness of tumours. The aim of this study was to determine the role of the different four p38 MAPK isoforms and their effect on proliferation together with the underlying signalling pathways in a rat pleural mesothelioma cell line. Rat pleural mesothelioma cells were stimulated with platelet-derived growth factor (PDGF)-BB and/or transforming growth factor beta (TGF)-β. MAPK and transcription factor expression and activation was monitored in the cytosol and nucleus by immuno-blotting. Proliferation was determined by manual cell count and siRNAs were used to control MAPK and transcription factor expression and action. Only PDGF-BB, but not TGF-β1 induced proliferation via activated Erk1/2 and p38 MAPK. The p38α and δ isoforms were expressed in the cytosol, and upon activation p38δ translocated into the nucleus, while p38α remained in the cytosol. No other p38 isoform was expressed by rat mesothelioma cells. C/EBP-α was found in both the cytosol and the nucleus, while C/EBP-β was not expressed at all. PDGF-BB induced proliferation was suppressed by down-regulation of either Erk1/2, or p38δ MAPK, or C/EBP-α. Furthermore, TGF-β inhibited PDGF-BB induced proliferation by interruption of p38 MAPK signalling. From this rat model, we conclude that in pleural mesothelioma, p38δ in C/EBP-α mediate proliferation and thus may represent new targets in mesothelioma therapy.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma. G.L. Ceresoli, P.A. Zucali, F. De Vincenzo, et al. 2011;72(1):73-7. PubMed · Publisher

Abstract

The role of second-line therapy in patients with malignant pleural mesothelioma (MPM) progressing after first-line pemetrexed-based chemotherapy (PBC) is currently undefined. Recent case series have suggested a possible role of re-treatment with PBC. In this observational study, the activity and safety of this therapeutic option was assessed in a consecutive series of cases. Patients with complete response (CR), partial response (PR) or stable disease (SD) lasting for at least 3 months after first-line PBC were retreated with PBC, either as second-line (2L) or further-line (>2L) therapy. Descriptive analyses of progression-free survival (PFS), overall survival (OS), response rate and toxicity are reported. Between October 2004 and July 2009, 31 patients (21 males and 10 females) received re-treatment with PBC as 2L (18 patients) or beyond 2L therapy (13 patients). Median age was 65 years (range 37-81). Fifteen patients were re-treated with pemetrexed alone, and 16 with a pemetrexed/platinum combination. An objective response was achieved in 6 patients (one CR and 5 PRs), for a response rate of 19%. Nine patients (29%) had SD after treatment. Overall, the disease control rate (DCR) was 48%. Median PFS and overall survival (OS) after re-treatment with PBC were 3.8 months and 10.5 months, respectively. PFS and OS after re-treatment with PBC were correlated with PFS achieved after first-line PBC (FL-PFS). Patients with a FL-PFS >12 months had a median PFS after re-treatment of 5.5 months, while patients with a FL-PFS ≤12 months had a median PFS after re-treatment of 2.5 months; no patient in this group was progression-free at 1 year. Toxicity was mild, with grade 3 or 4 hematological toxicity occurring in 9.7% of patients. In conclusion, re-treatment with PBC should be considered as second-line therapy in MPM patients achieving a durable (>12 months) disease control with first-line PBC. Further prospective evaluation of this therapeutic option is warranted.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Surgery and mesothelioma: if not randomization, at least standardization and registration!. H. Pass. 2011;71(1):1-2. Editorial PubMed · Publisher

Summary

In this editorial, the author discussed how to answer questions about the surgical management of malignant pleural mesothelioma (MPM). He listed what he considered established facts: staging before surgery was unreliable, surgical mortality at high-volume centers had fallen, surgery alone was insufficient, morbidity remained high but manageable at experienced centers, and intrapleural therapies needed further refinement. He noted that a complete (R0) resection was possible in about 8% of cases, and that maximal cytoreduction lacked objective criteria for residual disease. He commented on a study by Bolukbas and colleagues of lung-sparing radical pleurectomy/decortication in 35 patients. Of these, 16 (46%) had Stage I/II disease, only 4 had extended operations, and median survival was 37 months for Stage I/II and 23 months for Stage III/IV. He argued that these results reflected patient selection. He doubted that a randomized trial comparing extrapleural pneumonectomy with radical pleurectomy/decortication was feasible. Instead, he called for standardized surgical terms, standardized pathology interpretation, prospective reporting of complications and adjunctive therapies, and a joint International Mesothelioma Interest Group and IASLC prospective registry. He also called for biomarker studies and archives of tissue and body fluids. He concluded that surgery was an important part of therapy for selected individuals, while acknowledging the lack of consensus in 2010. The author disclosed a pending patent on a microRNA for mesothelioma prognosis.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Survival after trimodality therapy for malignant pleural mesothelioma: Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy. S. Bölükbas, C. Manegold, M. Eberlein, et al. 2011;71(1):75-81. PubMed · Publisher

Abstract

Introduction: The role of surgery in the management of malignant pleural mesothelioma (MPM) is controversial and there are no established guidelines. We describe the feasibility and long-term outcomes associated with Radical Pleurectomy (RP) as surgical therapy modality in a standardized trimodality therapy concept of MPM.

Methods: From November 2002 to October 2007, 35 out of 102 consecutive patients with MPM were enrolled in our prospective database. They underwent trimodality therapy, including RP followed by 4 cycles of chemotherapy with Cisplatin (75 mg/m(2))/Pemetrexed (500 mg/m(2)) and radiotherapy 4-6 weeks after operation.

Results: Median age was 65 years. Nineteen patients were in advanced stages III and IV (54.3%). Tumor histology was epithelial in 27 patients (77.1%). Macroscopic complete resection could be achieved in 18 patients (51.4%). Surgical morbidity/mortality and trimodality treatment-related mortality were 20.0%, 2.9% and 5.8%, respectively. Thirty-three patients completed the trimodality therapy. Median follow-up was 21.7 months. Overall median survival was 30.0 months. One-, 2-, and 3-year-survival were 69%, 50% and 31%, respectively. Advanced stages III/IV (p=0.06), macroscopic incomplete resections (p=0.001), non-epithelial histology (p=0.55) and nodal metastases (p=0.19) were associated with poorer survival.

Conclusions: The trimodality therapy concept with RP demonstrates promising results in terms of long-term survival, morbidity and mortality. We propose that a surgical philosophy of limiting the procedure related morbidity while achieving comparable cytoreductive results allows patients to maintain physiological reserve to be eligible for multimodality treatment options in the long-term. The observed and theoretical benefits of this trimodality treatment approach warrant confirmation in larger RCT.

Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.
Telomerase activity in pleural malignant mesotheliomas. A.Y. Au, T. Hackl, T.R. Yeager, et al. 2011;73(3):283-8. PubMed · Publisher · Free full text

Abstract

New treatments are needed for malignant pleural mesothelioma (MPM), which currently has a poor prognosis. Cellular immortalisation, one of the hallmarks of cancer, depends on the activity of a telomere length maintenance mechanism (TMM) - either telomerase or alternative lengthening of telomeres (ALT). The TMMs are widely regarded as potential targets for cancer therapies and telomerase inhibitors have entered clinical trials. The aim of this study was to determine what proportion of MPMs use ALT and/or telomerase. Forty-three MPMs from 42 patients were examined for telomerase and ALT activity. Telomerase activity was detected by immunoaffinity purification followed by the telomere repeat amplification protocol (TRAP), and ALT activity was determined by the C-circle assay and by assessing telomere lengths using terminal restriction fragment analyses. We found that 43 of 43 MPMs were telomerase-positive[+] and ALT-negative[-]. Therefore, to investigate whether pleural mesothelial cells are unusually susceptible to activation of telomerase, we examined activation of the TMMs in an in vitro model of cellular immortalisation, in which normal pleural mesothelial cells were transduced with simian virus 40 (SV40) oncogenes. We found that normal mesothelial cells were TMM-negative, and that expression of the SV40 oncogenes did not directly activate telomerase or ALT. Immortalisation, which in this experimental system results from additional genetic changes that have not yet been identified, was accompanied by activation of either TMM. Therefore, pleural mesothelial cells are capable of activating either TMM in vitro, and the observation that 100% of MPMs were telomerase[+] suggests that there are factors in vivo that select for telomerase activity during oncogenesis of this tumour type. We conclude that MPM is a tumour that could be considered for anti-telomerase therapy.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
A bibliometric analysis of scientific production in mesothelioma research. D. Ugolini, M. Neri, C. Casilli, et al. 2010;70(2):129-35. PubMed · Publisher

Abstract

This study aims at comparing scientific production in malignant mesothelioma (MM) among countries and evaluating publication trends and impact factor (IF). The PubMed database was searched with a strategy combining keywords listed in the Medical Subject Headings and free-text search. Publications numbers and IF were evaluated both as absolute values and after standardization by population and gross domestic product (GDP). 5240 citations were retrieved from the biennium 1951-1952 (n = 22) to 2005-2006 (n = 535). The 177% increase of MM publications from 1987 to 2006 exceeded by large the corresponding value of total cancer literature (123.5%). In these two decades, 2559 articles with IF were published: 46.4% came from the European Union (EU) (the UK, Italy and France ranking at the top), and 36.2% from the US. The highest mean IF was reported for the US (3.346), followed by Australia (3.318), and EU (2.415, with the UK, Belgium and the Netherlands first). Finland, Sweden and Australia had the best ratio between IF (sum) and resident population or GDP. The number of publications correlated with GDP (p = 0.001) and national MM mortality rates (p = 0.002). An association was found between a country commitment to MM research and the burden of disease (p = 0.04). Asbestos, survival, prognosis, occupational exposure, differential diagnosis, and immunohistochemistry were the most commonly used keywords. This report represents the first effort to explore the geographical and temporal distribution of MM research and its determinants. This is an essential step in understanding science priorities and developing disease control policies.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Adaptation of a commercial fluorescent in situ hybridization test to the diagnosis of malignant cells in effusions. C. Flores-Staino, E. Darai-Ramqvist, K. Dobra, et al. 2010;68(1):39-43. PubMed · Publisher

Abstract

In effusion cytology, adjuvant techniques are often needed for the differentiation of reactive proliferating mesothelial cells and malignant cells. In the case of malignancy the further challenge is to distinguish metastatic tumors from the primary malignant mesothelioma. Fluorescence in situ hybridization (FISH) of cells in interphase is an accurate method to monitor the genetic status of cells, detecting aneuploid signals and gene deletions. Moreover, it has been proposed that a homozygous deletion of the p16(INK4A) gene could more specifically identify malignant mesothelial cells among the exfoliated cells. The first objective of this study was to adapt the commercial FISH-test, UroVysion originally designed for the cytological diagnosis of bladder cancer, to the analysis of cells in effusions. The second objective was to test the clinical utility of the test. Sixty-eight pleural effusions were evaluated. The cytological diagnosis was malignant in 29 cases, inconclusive in 24 cases and benign in 15 cases. The independently verified final diagnoses were mesothelioma in 21 cases, metastatic cancer in 29 and benign in 18 cases. The algorithm for aneuploidy distinguished almost all tested malignant conditions from benign ones, also those with inconclusive cytology. The 9p21 locus, carrying the p16(INK4A) gene, was homozygously deleted in two of the metastatic cancers, while this was seen in 12 of the 21 malignant mesotheliomas. Thus the commercial UroVysion-test can be used to accurately distinguish malignant and reactive cells in effusions, particularly when cytology is inconclusive. The test may also indicate presence of MM.

Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.
Antiproliferative effect of Aurora kinase targeting in mesothelioma. S. Crispi, C. Fagliarone, A. Biroccio, et al. 2010;70(3):271-9. PubMed · Publisher

Abstract

The Aurora proteins are a small family of serine/threonine kinase that function in various stages of mitosis. Current interest in Aurora kinase relates to its role in tumours, and its potential as a therapeutic target. In this work we studied the expression of Aurora kinases A and B and related genes in human mesothelioma tissues and in five mesothelioma cell lines. Moreover, we analyzed the effects of ZM447439 (ZM), an Aurora kinase inhibitor, on cellular growth. Results evidenced an over-expression of Aurora kinase A and related genes in human mesothelioma tissues and an over-expression of Aurora kinases A and B in all cell lines. Moreover, we demonstrated that ZM447439 was able to inhibit cell growth in all cell lines and that this inhibition was due to a specific effect as demonstrated by the reduction in the level of Histone H3 phosphorylation. Our findings support a role of Aurora kinase in mesothelioma and the possibility of using Aurora kinase inhibitors in therapeutic modalities.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Characterization of side population cells in human malignant mesothelioma cell lines. K. Kai, S. D'Costa, B.I. Yoon, et al. 2010;70(2):146-51. PubMed · Publisher

Abstract

Side population (SP) assay composed of Hoechst 33342 staining and subsequent flow cytometric analysis has been widely utilized for characterizing putative cancer stem cells (CSCs) in various human malignancies. The present study was designed to evaluate the SP assay as a research tool for mesothelial CSCs. A distinct fraction of SP cells was identified in various human malignant mesothelioma (HMM) cell lines, ranging from 0.05 to 1.32%. The sorted mesothelial SP cells exhibited enhanced proliferation potentials and higher expression of stem-cell genes, compared to non-SP (NSP) cells. Cisplatin treatment increased percentage of SP cells in the HMM cell lines. However, tumorigenic potential of SP cells in immunodeficient mice was similar to that of the NSP cells. These data indicated that SP assay may not be appropriate for enriching putative CSCs in HMM cell lines, and thus warrants the development of a novel tool for mesothelial CSC study.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Combined FDG-PET/CT in response evaluation of malignant pleural mesothelioma. P. Veit-Haibach, N.G. Schaefer, H.C. Steinert, et al. 2010;67(3):311-7. PubMed · Publisher

Abstract

Purpose: Based on the complex growth pattern of MPM, conventional response evaluation in this cancer entity is challenging. Therefore, there is growing interest in therapy response evaluation with FDG-PET/CT. The aim of the study was to evaluate the value of several FDG-PET/CT-parameters in therapy response evaluation concerning prediction of survival at baseline and after three cycles of therapy.

Patients And Methods: The study was performed in accordance with the regulations of the local ethics committee. Forty-one patients with proven MPM and treated with palliative pemetrexed and platinum-based chemotherapy were included. All patients were evaluated by FDG-PET/CT at baseline and after three cycles of chemotherapy. Responders and non-responders were evaluated based on modified RECIST- and EORTC-criteria. Additional PET-parameters (SUVmean, tumor lesion glycolysis (TLG) and tumor volume (PETvol)) were evaluated. Results were evaluated using the COX regression and the Kaplan-Meier method.

Results: None of the baseline CT-measurements or the initial PET-parameters were predictive for survival. Based on CT, after three cycles of therapy 10 patients were categorized as responders, 30 were classified as stable disease and 1 had progressive disease. Based on PET-evaluation, 14 responders were identified, 23 patients with stable disease and 4 patients were progressive. CT-response after 3 cycles of chemotherapy was significantly related to overall survival (p=0.001). However, neither SUVmax-response (p=0.61) nor SUVmean-response (p=0.68) were related to survival. A decrease of TLG and PETvol, however, was found to be predictive (TLG: p=0.01; PETvol: p=0.002).

Conclusion: Response evaluation based on modified RECIST by CT as well as response evaluation by TLG and PETvol in FDG-PET, but not SUVmax-measurements are predictive for survival in MPM.
COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines. S.L. O'Kane, G.L. Eagle, J. Greenman, et al. 2010;67(2):160-5. PubMed · Publisher

Abstract

Background: Although malignant pleural mesothelioma is a rare tumour, its incidence is increasing. The prognosis remains very poor with an average survival of 10 months from diagnosis. The choice of chemotherapy regimens for mesothelioma patients is limited and new approaches are required. COX-2 inhibition induces apoptosis in a variety of tumour cell lines. The cytotoxic effect of conventional drugs may be enhanced by the addition of a COX-2 inhibitor. In order to identify possible new therapeutic approaches we aimed to determine whether the addition of COX-2 inhibitors would enhance the cytotoxic effect of chemotherapeutic agents in mesothelioma cell lines.

Materials And Methods: Three mesothelioma cell lines MSTO-211H, NCI-H2052 and NCI-H2452 were utilised. Using the COX-2 positive A549 lung cancer cell line as control, all cell lines were assayed using an MTT assay with non-specific COX-2 inhibitors (sulindac and flurbiprofen), specific COX-2 inhibitors (DuP-697 and NS-398), and chemotherapeutic agents (cisplatin, vinorelbine and pemetrexed).

Results: All cell lines exhibited COX-2 expression by western blotting using two antibodies. The addition of either DuP-697 or NS-398 increased the sensitivity to pemetrexed in all cell lines.

Conclusion: These findings suggest that the design of novel pemetrexed-containing combination regimens with increased cytotoxicity may be feasible.

Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
Imaging in pleural mesothelioma: a review of imaging research presented at the 9th International Meeting of the International Mesothelioma Interest Group. A.K. Nowak, S.G. Armato, G.L. Ceresoli, et al. 2010;70(1):1-6. Review PubMed · Publisher

Abstract

Imaging of malignant pleural mesothelioma (MPM) poses many challenges for imaging specialists and clinicians due to the anatomic location and unique growth pattern of this tumor. Nevertheless, imaging in MPM plays a critical role in diagnosis, prognostication, prediction or measurement of response to therapy, and monitoring of disease recurrence after aggressive surgical management. Imaging-based studies presented at the 9th International Conference of the International Mesothelioma Interest Group (IMIG) in October 2008 sought to further define the current practice and future potential of imaging for the mesothelioma patient. The Imaging Session was dominated by presentations that addressed the use of fluorodeoxyglucose positron emission tomography (FDG-PET), a clear indication of the expanding role of this modality. These uses included FDG-PET imaging at the point of diagnosis, in prognostication, and in the assessment of response to chemotherapy. Often FDG-PET studies were combined with computed tomography (CT) scans in an attempt to overcome limitations associated with either imaging modality alone. At diagnosis, FDG-PET parameters had a high sensitivity and specificity for differentiation of benign from malignant pleural disease. The use of FDG-PET to extract quantitative features from metabolically active tumor volume was shown to be a significant factor in the prediction of patient survival. The prognostic value of FDG-PET was not confounded by prior talc pleurodesis, despite the inflammatory response associated with the procedure. Metabolic response based on FDG-PET was found to be significantly correlated with progression-free survival. CT-based assessment of mesothelioma was determined to be inconsistent with spherical-model-based criteria so that changes in tumor area, a presumably more complete assessment of tumor burden, exhibited a 46% concordance rate with changes in linear measurements.

Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Impact of malignant mesothelioma in Taiwan: a 27-year review of population-based cancer registry data. L.J. Lee, Y.Y. Chang, J.D. Wang. 2010;68(1):16-9. PubMed · Publisher

Abstract

Purpose: To describe the epidemiologic characteristics of malignant mesothelioma (MM) in Taiwan; to evaluate the impact of the condition.

Methods: The Taiwan Cancer Registry Database was used to retrieve the cases of MM registered from 1979 to 2005. Only cases of histopathologically verified MM were included. For evaluating the impact of MM, the cancer sites of the pleura and peritoneum (ICD-O codes 163 and 158, respectively) were used for statistical analysis and estimation of the expected years of life lost (EYLL). Their survival was calculated by Kaplan-Meier analysis and extrapolated to obtain the EYLL using the Monte Carlo simulation by borrowing information from gender- and age-matched populations in Taiwan.

Results: A total of 423 cases of MM were included; MM of the pleura and peritoneum accounted for 91% of all cases (387/423). The median survival of pleural and peritoneal MM was 7.6 and 13.5 months for males and females, respectively. The incidence of MM increased during the observation period. A total of 232 males and 155 females diagnosed with MM were used for estimation of EYLL: 14.8 [95% Confidence Interval: 13.1-16.6] life years for males and 13.7 [11.2-16.2] life years for females.

Conclusion: The increasing incidence and significant EYLL for MM were observed for both males and females during 1979-2005 in Taiwan, although under-diagnosis and under-estimation were likely.

Crown Copyright (c) 2009. Published by Elsevier Ireland Ltd. All rights reserved.
Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy. R. Hassan, C. Schweizer, K.F. Lu, et al. 2010;68(3):455-9. PubMed · Publisher · Free full text

Abstract

Background: Mesothelin, a tumor differentiation antigen highly expressed in mesothelioma and ovarian cancer, is the receptor for CA-125 (MUC 16) and this interaction may play a role in tumor metastasis. MORAb-009 is a chimeric anti-mesothelin monoclonal antibody.

Methods: Twenty-four patients with mesothelin expressing cancers were treated on a phase I study of MORAb-009 administered as an intravenous infusion (12.5-400mg/m(2)) weeklyx4 doses with 2 weeks off before the next cycle. This report summarizes the effect of MORAb-009 on serum CA-125 kinetics in the eight patients with mesothelioma who had CA-125 levels measured before and at different time-points following therapy.

Results: MORAb-009 treatment led to a marked increase in serum CA-125 levels in all patients including those without elevated CA-125 levels before therapy. The increase in CA-125 levels was not due to disease progression since CA-125 levels decreased rapidly after stopping MORAb-009 therapy. No patients had signs of peritoneal or pleural inflammation as the possible cause of CA-125 rise. In addition, the elevated CA-125 levels were not due to MORAb-009 interfering with the laboratory assay used to measure CA-125.

Conclusion: The increase in serum CA-125 produced by treatment with MORAb-009 is most likely due to MORAb-009 inhibiting the binding of tumor shed CA-125 to mesothelin present on mesothelial cells lining the pleural and peritoneal cavities. Inhibiting the mesothelin-CA-125 interaction could be a useful strategy to prevent tumor metastasis in mesotheliomas and ovarian cancer.

Published by Elsevier Ireland Ltd.
Is risk of pleural mesothelioma an environmental risk outside Turkey? A study on immigrants to Sweden. S.M. Mousavi, J. Sundquist, K. Hemminki. 2010;68(1):125-6. Letter PubMed · Publisher

Summary

This letter asked whether the high risk of malignant pleural mesothelioma known among people from Cappadocia, Turkey, where villagers are environmentally exposed to erionite and tremolite asbestos, also appears among immigrants from other countries. The authors used the nationwide Swedish Family-Cancer Database (2008 update) to study first-generation immigrants to Sweden from 63 countries or country groups. Follow-up ran from 1958 to the end of 2006. They calculated standardized incidence ratios (SIRs) with 95% confidence intervals, using the native Swedish population as the reference and adjusting for 5-year age group, sex and time period. There were 2128 mesothelioma cases among native Swedes and 188 among immigrants. Compared with native Swedes, risk was significantly increased in Turkish men (SIR 2.82) and Turkish women (SIR 23.76), Danish men (SIR 1.64) and women from Benelux (SIR 8.93). No significant risk difference was found among the large immigrant groups. Among Turkish immigrants the male-to-female ratio was 1.1, and more than two decades on average had passed between immigration and diagnosis. The authors suggested that environmental exposure was similar for both sexes and that early-life exposure may have been responsible, although genetic predisposition could also explain the excess. They considered the borderline Danish and Benelux results possibly due to occupational or passive exposure, or chance. They concluded that high risk was confirmed in Turkish immigrants only and called for study of second-generation immigrants.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets. O.D. Røe, E. Anderssen, H. Sandeck, et al. 2010;67(1):57-68. PubMed · Publisher

Abstract

Malignant pleural mesothelioma is an asbestos-related multi-resistant tumour with increasing incidence worldwide. Well-characterized snap-frozen normal parietal, visceral pleura and mesothelioma samples were analysed with Affymetrix Human Genome U133 Plus 2.0 GeneChip oligoarray of 38500 genes. We discovered a close relation between gene profile and resistance towards topoisomerase poisons, alkylating agents, antitubulines, antifolates, platinum compounds and radiation therapy. Target genes of chemo- (e.g. TOP2A, BIRC5/Survivin and proteasome) and radiotherapy (e.g. BRCA2, FANCA, FANCD2, CCNB1 and RAD50) were significantly overexpressed. The Fanconi anemia/BRCA2 pathway, responsible for homologous recombination DNA repair appears as a key pathway in both chemo- and radio-resistance of mesothelioma. Leukocyte trans-endothelial migration gene down-regulation could partly explain resistance against immunological therapies. Gene expression features found in other resistant cancer types related to DNA repair and replication are shared by mesothelioma and could represent general features of tumour resistance. Targeted suppression of some of those key genes and pathways combined with chemotherapy or radiation could improve the outcome of mesothelioma therapy. We propose CHEK1, RAD21, FANCD2 and RAN as new co-targets for mesothelioma treatment. The pro-angiogenic AGGF1 mRNA and protein was highly overexpressed in all tumours and may serve as a target for anti-angiogenic treatment. Overexpression of NQO1 may render mesothelioma sensitive to the novel compound beta-Lapachone.
p16INK4A inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos. P. Andujar, J. Wang, A. Descatha, et al. 2010;67(1):23-30. PubMed · Publisher

Abstract

Epidemiological studies have shown that asbestos fibers constitute the major occupational risk factor and that asbestos acts synergistically with tobacco smoking to induce lung cancer. Although some somatic gene alterations in lung cancer have been linked to tobacco smoke, few data are available on the role of asbestos fibers. P16/CDKN2A is an important tumor suppressor gene that is frequently altered in lung cancer via promoter 5'-CpG island hypermethylation and homozygous deletion, and rarely via point mutation. Many studies suggest that tobacco smoking produces P16/CDKN2A promoter hypermethylation in lung cancer, but the status of this gene in relation to asbestos exposure has yet to be determined. The purpose of this study was to investigate the mechanism of P16/CDKN2A alterations in lung cancer in asbestos-exposed patients. P16/CDKN2A gene status was studied in 75 human non-small-cell lung cancer (NSCLC) cases with well-defined smoking habits, and detailed assessment of asbestos exposure, based on occupational questionnaire and determination of asbestos bodies in lung tissue. The results of this study confirm published data on the effect of tobacco smoke on P16/CDKN2A gene alterations, characterized by significantly higher P16/CDKN2A promoter hypermethylation in heavy smokers (more than 40 pack-years (P-Y)) than in smokers of less than 40 P-Y. These results also demonstrate a higher incidence of loss of heterozygosity and homozygous deletion in asbestos-exposed cases, after adjustment for age and cumulative tobacco consumption, than in unexposed cases (P=0.0062). This study suggests that P16/CDKN2A gene inactivation in asbestos-exposed NSCLC cases mainly occurs via deletion, a feature also found in malignant mesothelioma, a tumor independent of tobacco smoking but associated with asbestos exposure, suggesting a possible relationship with an effect of asbestos fibers.
Tissue and serum EGFR as prognostic factors in malignant pleural mesothelioma. R. Gaafar, A. Bahnassy, I. Abdelsalam, et al. 2010;70(1):43-50. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is an asbestos related aggressive tumor. Asbestos causes genetic modifications and cell signaling events that favor resistance to chemotherapy. A variety of receptor tyrosine kinases have been identified to play a central role in various aspects of tumorigenesis. Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignancies including lung cancer in which EGFR aberrations not only predict response to EGFR tyrosine kinase inhibitors but also indicate tumor progression. However in MPM, the role of EGFR is less clear. This study was designed to identify serum and tissue EGFR levels in patients with MPM and to evaluate the relationship between serum and tissue EGFR levels and clinicao-pathological prognostic factors and survival.

Methods: We investigated 71 cases of MPM for EGFR expression in tissue. Serum EGFR was assessed in 40 out of those 71 cases and 20 healthy subjects as a control. Pre-treatment serum EGFR levels were measured using quantitative enzyme-linked immunosorbent assay. Tissue EGFR protein overexpression was assessed by immunohistochemistry and gene amplification was assessed by the chromogen in situ hybridization (CISH) technique. Results were correlated with the clinical-pathological factors of the patients and overall survival (OS).

Results: Out of the 71 patients included in the study, 19 had undergone extrapleural pneumonectomy. As for the rest of the patients, 46 received chemotherapy while 6 had only best supportive care. EGFR immuno-reactivity was detected in 74.6% of the cases, 37 (52.1%) cases were positive for EGFR gene amplification by CISH, 31 of them revealed moderate to high (++, +++) EGFR immuno-reactivity. Elevated serum EGFR >2.5 ng/ml (the median concentration of EGFR in MPM) was reported in 45% of the cases. The overall response rate (RR) for the 46 treated patients who received chemotherapy was 24.1%. After a median follow up of 29 months, the median overall survival (OS) was 10 months. Elevated serum and tissue EGFR is significantly associated with advanced disease stage. However neither EGFR overexpression in tissues nor high serum levels were associated with survival rates.

Conclusions: EGFR expression is a common feature in MPM patients. High pre-treatment levels of serum EGFR are associated with advanced stage but not with reduced OS. Detailed mutational analysis of EGFR on a larger number of patients is still needed to clarify the exact role of EGFR in MPM patients.

Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Well-differentiated papillary mesothelioma with invasion to the chest wall. I. Torii, M. Hashimoto, T. Terada, et al. 2010;67(2):244-7. Case report PubMed · Publisher

Abstract

Well-differentiated papillary mesothelioma (WDPM) is an uncommon tumor with a papillary architecture, bland cytologic features, a tendency toward superficial spread without invasion, and good prognosis with prolonged survival. WDPM occurs primarily in the peritoneum of women, but also rarely in the pleura. We here report a case of 48-year-old woman who developed WDPM in the pleura with no history of asbestos exposure. Tumors were multifocal and widespread with a velvety appearance on the surface of parietal and visceral pleurae resected by extrapleural pneumonectomy (EPP). Tumors showed papillary structures with fibrovascular cores and lined by epithelioid cells. Immunohistochemically, these epithelioid tumor cells were positive for epithelial membrane antigen (EMA), a marker of malignant mesothelioma, with more than 50% positive for p53. Tumor cells microinvaded into subpleural parenchyma of the lung and minimally spread to adipose tissues of the mediastinal lesion. In addition, tumor cells invaded into the chest wall with a trabecular or glandular architecture. Based on these findings, this case is pathologically considered as WDPM of the pleura with malignant potential.

Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

2000s

Decitabine, differently from DNMT1 silencing, exerts its antiproliferative activity through p21 upregulation in malignant pleural mesothelioma (MPM) cells. S. Amatori, F. Papalini, R. Lazzarini, et al. 2009;66(2):184-90. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a locally aggressive neoplasm, principally linked to asbestos fibres exposure. Strong evidences associate this pollutant with induction of DNA breaks, aberrant chromosomes segregation and important chromosomal rearrangements, considered crucial events in malignant transformation. A considerable contribution to cellular transformation in MPM is also given by the presence of high genomic instability, as well as by the increased DNA methylation, and consequent decreased expression, of tumor-suppressor genes. In this study we first demonstrated that MPM cells are characterized by a decreased methylation level of pericentromeric DNA sequences which can justify, at least in part, the genomic instability observed in this neoplasia. Concomitantly, we found a paradoxical increased expression of DNMT1, the most expressed DNA methyltransferases in MPM cells, DNMT3a and all five isoforms of DNMT3b. Thus, we compared two experimental strategies, DNMT1 silencing and usage of a demethylating agent (5-aza-2'-deoxycytidine or Decitabine), both theoretically able to revert the locally hypermethylated phenotype and considered potential future therapeutic approaches for MPM. Interestingly, both strategies substantially decrease cell survival of MPM cells but the antitumor activity of Decitabine, differently from DNMT1 silencing, is mediated, at least in part, by a p53-independent p21 upregulation, and is characterized by the arrest of MPM cells at the G2/M phase of the cell cycle. These results indicate that the two approaches act probably through different mechanisms and, thus, that DNMT1 silencing can be considered an effective alternative to Decitabine for cancer treatment.
Functional inactivation of NF2/merlin in human mesothelioma. C. Thurneysen, I. Opitz, S. Kurtz, et al. 2009;64(2):140-7. PubMed · Publisher

Abstract

The tumor suppressor merlin is encoded by the neurofibromatosis type 2 gene (NF2) which is located on chromosome 22q12 and mutations in this gene have been found in 40% of mesothelioma. Mutations including deletions and insertions lead to truncated and inactivated merlin. Experimental animal models indicate that disruption of the NF2 signalling pathway, together with a deficiency in ink4a, is essential for mesothelioma development. Our hypothesis was that in human mesothelioma without detectable NF2 mutations, regulators of NF2/merlin activity such as CPI-17 would be altered. CPI-17 is an oncogene inhibiting the NF2/merlin phosphatase which is necessary to maintain NF2/merlin activity. Samples obtained from 44 mesothelioma, 3 asbestosis patients and 6 normal pleura from non-asbestos related disease patients were analyzed. Truncated NF2 transcripts or presence of isoform II only were observed in 11 mesothelioma samples. In all other mesothelioma samples only NF2 isoform I or isoforms I and II were detected. 18 mesothelioma and 1 normal pleura samples also expressed splicing variant delE2/3. Unexpected variants in addition to wild-type were identified in 24 mesothelioma samples. NF2 protein was either truncated or phosphorylated on Ser 518 in primary cultures derived from 25 tumors. CPI-17 expression was significantly increased in tumor samples without deleted NF2 compared to normal pleura and tumor expressing truncated NF2. Our results support the hypothesis that the disruption of NF2 signalling is essential for the development of human mesothelioma. In tumors where no NF2 truncation can be detected, NF2 is rendered inactive by phosphorylation of Ser 518 and this can be explained at least in part by an increased expression of CPI-17.
MET as a target for treatment of chest tumors. N.A. Cipriani, O.O. Abidoye, E. Vokes, et al. 2009;63(2):169-79. Review PubMed · Publisher · Free full text

Abstract

The receptor tyrosine kinase MET has been studied of a large variety of human cancers, including lung and mesothelioma. The MET receptor and its ligand HGF (hepatocyte growth factor) play important roles in cell growth, survival and migration, and dysregulation of the HGF-MET pathway leads to oncogenic changes including tumor proliferation, angiogenesis and metastasis. In small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and malignant pleural mesothelioma (MPM), MET is dysregulated via overexpression, constitutive activation, gene amplification, ligand-dependent activation, mutation or epigenetic mechanisms. New drugs targeted against MET and HGF are currently being investigated in vitro and in vivo, with promising results. These drugs function at a variety of steps within the HGF-MET pathway, including MET expression at the RNA or protein level, the ligand-receptor interaction, and tyrosine kinase function. This paper will review the structure, function, mechanisms of tumorigenesis, and potential for therapeutic inhibition of the MET receptor in lung cancer and mesothelioma.
Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin. K. Iwahori, T. Osaki, S. Serada, et al. 2008;62(1):45-54. PubMed · Publisher

Abstract

Purpose: An early and reliable blood test is one deficiency in diagnosis of malignant pleural mesothelioma (MPM). Megakaryocyte potentiating factor (MPF) and mesothelin variants (MSLN), members of the mesothelin gene family, have been studied as candidate serum markers for MPM. We developed a novel enzyme-linked immunosorbent assay (ELISA) system to compare the diagnostic efficacy of MPF and MSLN in MPM and control groups.

Experimental Design: MPF and MSLN were assayed with ELISA in 27 consecutive MPM patients and 129 controls including patients with lung cancer and asymptomatic asbestos-exposed subjects.

Results: Statistically significant elevation of serum MPF and MSLN levels was noted in MPM patients in comparison with every control group. The area under the receiver operating characteristic curve (AUC) was calculated for differentiation of MPM and lung cancer, healthy asbestos-exposed subjects, and healthy adults. While the AUC for serum MPF was 0.879, cut-off=19.1ng/ml (sensitivity=74.1%, specificity=90.4%), the AUC for serum MSLN was 0.713, cut-off=93.5ng/ml (sensitivity=59.3%, specificity=86.2%). Comparison between AUC for MPF and MSLN values shows that MPF is significantly superior to MSLN (p=0.025). Finally, there was a significant correlation between MPF and MSLN values for MPM (Pearson's correlation coefficient=0.77; p<0.001).

Conclusions: These findings suggest that diagnostic value of MPF for MPM was better than that of MSLN although both markers showed almost equal specificity for MPM.
Mesothelin-related predictive and prognostic factors in malignant mesothelioma: a nested case-control study. O.D. Roe, J. Creaney, S. Lundgren, et al. 2008;61(2):235-43. PubMed · Publisher

Abstract

Soluble mesothelin-related protein (SMRP) in serum is potentially a sensitive marker of malignant mesothelioma (MM) diagnosis and progression, and may be useful as screening marker. Mesothelin expression in tumors is regarded as a sensitive marker for diagnosis and disease progression, and is a candidate prognostic marker. Levels of SMRP, CA125 and CYFRA 21-1 in pre-diagnostic (1-30 years) serum samples from 47 mesothelioma cases and 141 matched controls were analysed. Mesothelin expression in tumors was assessed. The association between biomarker level and mesothelioma risk and survival was analysed, adjusting for asbestos exposure. Survival related to tumor mesothelin expression, age, sex, histological type, location, asbestos exposure and pre-clinical SMRP was analysed. There was no significant association between biomarker levels and mesothelioma risk when analysed as continuous variables or as tertiles. Biomarker levels <10, 10-19 and >or=20 years before diagnosis were not significantly associated to mesothelioma risk. Mesothelin expressed in >50% of tumor cells was seen in 36 of 47 (77%) tumors. Mesothelin expression in <50% of tumor cells was a significant negative prognostic marker in all cases of malignant mesothelioma (median survival=6 months vs. 12 months, hazard ratio (HR)=2.49, 95%CI 1.17-5.27), and also when only epithelial mesothelioma was analysed (median=6 months vs. 14 months, HR=2.36, 95%CI 1.07-5.22). When adjusted for age and gender, the prognosis was still dismal, but non-significant (HR=1.85, 95%CI 0.85-4.05). High age (>65 years) was an independent negative prognostic factor that was related to both mesothelin expression and asbestos exposure. Mesothelioma of the epithelial type of the peritoneum had a significantly longer survival than epithelial type in pleura and was also related to mesothelin expression.
Biphasic malignant mesothelioma cases with osseous differentiation and long survival: a review of the literature. F. Demirag, E. Unsal, I. Tastepe. 2007;57(2):233-6. Case report · Review PubMed · Publisher

Abstract

This report describes two cases of diffuse biphasic malignant mesothelioma with osseous differentiation and long survival. Two male patients aged 66 and 54 years presented with chest pain, bloody pleural effusions, and diffuse and nodular pleural thickening. They both had a history of prolonged asbestos exposure. Sarcomatoid and epithelioid areas were identified on histopathological examination. In addition, there were foci of ossification. Epithelioid tumor cells as well as benign osteoclasts within the ossification reacted positively for cytokeratin 5/6, whereas sarcomatoid areas were negative. Both patients survived 39 and 69 months, respectively. To our knowledge, these two cases with biphasic malignant mesothelioma and osseous differentiation with long survival are the first to be described from Central Anatolia.
DNA methylation profile of 28 potential marker loci in malignant mesothelioma. J.A. Tsou, J.S. Galler, A. Wali, et al. 2007;58(2):220-30. PubMed · Publisher · Free full text

Abstract

Patients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of non-invasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/DNA, we also examined the methylation of these markers in lung samples (age- or environmentally induced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM versus non-tumor lung samples was found for estrogen receptor 1 (ESR1; p = 0.0002), solute carrier family 6 member 20 (SLC6A20; p = 0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival.
Low-dose CT: a useful and accessible tool for the early diagnosis of lung cancer in selected populations. L. Callol, F. Roig, A. Cuevas, et al. 2007;56(2):217-21. PubMed · Publisher

Abstract

Objective: An evaluation is made of the effectiveness of low-dose computed tomography (LDCT) in diagnosing early stage lung cancer in the Autonomous Community of Madrid (Spain).

Methods: The study comprised subjects over 50 years of age who were active smokers (or who had stopped smoking up to 6 months previously) who smoked more than 30 cigarettes daily for at least 15 years, or 20 cigarettes daily for 20 years, or more than 10packs/year and in contact with asbestos at work. The study group was evaluated using LDCT. For all participants in whom LDCT showed no pathological findings, or in those cases classified as benign, a new LDCT scan was performed 2 years after the first. In case of doubt regarding the benign nature of the findings, an assessment algorithm was applied.

Results: Among the initial 482 candidates in the study group, 466 LDCT scans were performed at baseline, revealing 9 extrapulmonary lesions and 114 pulmonary lesions in 98 subjects. The latter raised diagnostic doubts in 32 cases; of these, 15 were confirmed as benign by high resolution computed tomography (HRCT). In the remaining 17 cases, stage IAp adenocarcinoma was diagnosed at baseline (0.2%). With LDCT after 2 years, an additional four adenocarcinomas were diagnosed-all in stage IAp (0.98%). The complete study, including prevalence cut-off and incidence calculation after 2 years, resulted in the diagnosis of five cancers (1.1%) and two false positive cases (28%).

Conclusions: The use of low-dose computed tomography in risk groups is valid for the early diagnosis of bronchogenic cancer. Nevertheless, significant problems remain, particularly those associated with false positive interpretations. The results of randomized studies on lung cancer mortality such as the US NLST trial and the Dutch-Belgian NELSON trial have to be awaited before any conclusion regarding the effectiveness of LDCT screening can be drawn.
Malignant mesothelioma following thoracic radiotherapy for lung cancer. S.M. Witherby, K.J. Butnor, S.M. Grunberg. 2007;57(3):410-3. Case report · Review PubMed · Publisher

Abstract

As the number of long-term cancer survivors increases, secondary malignancies are becoming a greater clinical issue. Although some of these malignancies may be related to common environmental exposures, a significant number are considered to be therapy-related. Pleural malignant mesothelioma is a neoplasm that may be related to asbestos exposure or radiation exposure. Previous reports of pleural mesothelioma as a second malignancy have tended to follow radiotherapy for extra-thoracic malignancies such as Hodgkin's disease, breast cancer and Wilms' tumor. We report the case of a 66-year-old woman with no prior asbestos exposure who developed pleural mesothelioma 17 years after pneumonectomy and adjuvant radiation therapy for non-small cell lung cancer. Opacification of the lung field from prior therapy made determination of the diagnosis more challenging. Secondary malignancies such as mesothelioma should be considered in patients who develop unexplained symptoms even long after treatment of a primary tumor.
Malignant pleural mesothelioma: two cases in first degree relatives. A. Wilkins, S. Popat, S. Hughes, et al. 2007;57(3):407-9. PubMed · Publisher

Abstract

We report two cases of malignant pleural mesothelioma in first degree relatives arising within weeks of each other. The patients had a shared exposure to asbestos and age difference of over 20 years at time of presentation. In both cases, the anatomical pattern was similar and unusual for mesothelioma and initial histology was reported for both as non-small cell lung cancer. Both patients were treated with platinum-based combination chemotherapy.
Copy number gains on 5p15, 6p11-q11, 7p12, and 8q24 are rare in sputum cells of individuals at high risk of lung cancer. E. Kettunen, K. Salmenkivi, K. Vuopala, et al. 2006;54(2):169-76. PubMed · Publisher

Abstract

Unlabelled: Lung cancer specimens display recurrent copy number aberrations in distinguished chromosomal regions as compared with normal lung cells. Such alterations have been utilized in design of fluorescence in situ hybridization (FISH) probe sets in attempts to improve the cytological diagnosis of lung cancer. One of such probe sets, LAVysion, detects copy number changes in the centromeric region of chromosome 6 (CEP6), and regions 5p15, 8q24, and 7p12, often gained in lung cancer.

Methods: We evaluated the feasibility of the LAVysion multi-color probe set in detection of individuals at high risk of lung cancer by applying the FISH probe set on smears prepared of induced sputa obtained from 20 lung cancer patients, 43 asbestos-exposed workers, 21 heavy tobacco smokers, and 15 healthy never-smokers. The hybridized sputum smears were examined using fluorescence microscopy and the number of signals in epithelial cells was examined throughout the hybridized area. Additionally, we review here the previous studies using LAVysion probe set.

Results: The FISH probe set was slightly more sensitive than cytology alone in detecting lung cancer. No significant differences in copy number gain were found between high-risk individuals and healthy never-smokers. The proportions of individuals with copy number gains in sputa among the lung cancer patients, asbestos-exposed workers, tobacco smokers, and never-smokers were 50, 20, 12, and 27%, respectively, when three or more cells with a copy number gain detected by at least two different probes was used as the cut-off point. In comparison, the sensitivity of cytology in detecting lung cancer was 44%. In the lung cancer patients the number of abnormal cells by FISH correlated well with the cytologic atypia class (Spearman rank correlation coefficient 0.77, p<0.01). Using multivariant variance analysis, gains in CEP6, 5p15, 8q24 and 7p12 were not associated with smoking or asbestos exposure.

Conclusions: FISH did not significantly exceed the sensitivity of sputum cytology in finding lung cancers. Significant differences were not found between sputa of asbestos-exposed individuals, heavy-smokers and never-smokers. More sensitive methods are needed for the follow-up of populations at high risk of contracting lung cancer.
EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma. J.G. Edwards, D.E. Swinson, J.L. Jones, et al. 2006;54(3):399-407. PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a fatal tumour of increasing incidence which is related to asbestos exposure. This work evaluated expression in MM of Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry in 168 tumour sections and its correlations with clinicopathological and biological factors. The microvessel density (MVD) was derived from CD34 immunostained sections. Hematoxylin and eosin stained sections were examined for intratumoural necrosis. COX-2 protein expression was evaluated with semi-quantitative Western blotting of homogenised tumour supernatants (n=45). EGFR expression was correlated with survival by Kaplan-Meier and log rank analysis. Univariate and multivariate Cox proportional hazards models were used to compare the effects of EGFR with clinicopathological and biological prognostic factors and prognostic scoring systems. EGFR expression was identified in 74 cases (44%) and correlated with epithelioid cell type (p<0.0001), good performance status (p<0.0001), the absence of chest pain (p<0.0001) and the presence of TN (p=0.004), but not MVD or COX-2. EGFR expression was a good prognostic factor in univariate analysis (p=0.01). Independent indicators of poor prognosis in multivariate analysis were non-epithelioid cell type (p=0.0001), weight loss, performance status and WBC>8.3x10(9)L(-1). EGFR status was not an independent prognostic factor. EGFR expression in MM correlates with epithelioid histology and TN. EGFR may be a target for selective therapies in MM.
Malignant pleural mesothelioma: a new standard of care. R.A. Stahel. 2006;54 Suppl 2:S9-S14. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-associated cancer that occurs most commonly in the pleural cavities and generally has a poor prognosis. A rise in the incidence of this fatal disease, which, in the past has been considered to be relatively refractory to therapy, is predicted over the next decade. The realisation that patients can benefit from systemic chemotherapy and more aggressive multimodal approaches, including extrapleural pneumonectomy (EPP), in earlier stages of disease now provides the opportunity to offer more effective treatment for this disease.
Asbestos and mesothelioma: worldwide trends. L. Kazan-Allen. 2005;49 Suppl 1:S3-8. Review PubMed · Publisher

Abstract

A correlation between national asbestos consumption and the incidence of asbestos disease, including mesothelioma, has been observed. Towards the end of the 20th century, governments in many developed countries banned or seriously restricted the use of asbestos. As a result, global asbestos producers have engaged in aggressive marketing campaigns to sell asbestos to developing countries; consumption of white asbestos is increasing in Asia, Latin America and the Commonwealth of Independent States. In most of the countries, there is little, if any, control on hazardous asbestos exposures from occupational, environmental and domestic sources. It is likely that the lethal asbestos harvest which is occurring in the U.S., the UK and Australia will be reproduced in the developing world.
Asbestos problem in India. V. Subramanian, N. Madhavan. 2005;49 Suppl 1:S9-12. PubMed · Publisher

Abstract

Primary exposure to asbestos in India can be encountered in the form of asbestos mining, asbestos cement industries, asbestos processing unit and during renovation and demolition of old asbestos cemented roof or other structures as well as modern electrical as well as mechanical appliances in which asbestos is still found. Ultimately construction workers, electricians, vehicle mechanics and other workers in the building trades who are exposed to asbestos inhale hundreds and thousands of amphiboles, which causes lung damage. It is being mined in India at places such as Andhra Pradesh (Pulivendla), Jharkand (Roro), Rajasthan (Ajmer, Bhilwara, Udaipur, Rajsamand) and the common problem faced by the locals are asbestosis through air and fluorosis through drinking water. The problem continues to be in India as well as other developing countries. Also, India import and re-export asbestos to other countries and workers at shipyard, transport of the hazardous material on road and roadside residents all are vulnerable to this uncommon disease. The signs and symptoms generally found with the workers are shortness of breath, persistent and productive cough due to pulmonary fibrosis can show up many years after the asbestos exposure.
Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung. J.A. Tsou, L.Y. Shen, K.D. Siegmund, et al. 2005;47(2):193-204. PubMed · Publisher

Abstract

DNA methylation markers provide a powerful tool to make diagnoses based on genetic material obtained directly from tumors or from "remote" locations such as sputum, pleural fluid, or serum. In particular when limited cell numbers are available, amplifyable DNA markers can provide a very sensitive tool for cancer detection and classification. Malignant mesothelioma (MM), an aggressive cancer strongly associated with asbestos exposure, can be difficult to distinguish from adenocarcinoma of the lung when limited material is available. In an attempt to identify molecular markers for MM and adenocarcinoma, we examined the DNA methylation status of 14 loci. Analysis of methylation levels in 10 MM and 8 adenocarcinoma cell lines showed that methylation of APC was significantly elevated in adenocarcinoma compared to MM cell lines (P=0.0003), while methylation of CDH1 was higher in MM (P<0.02). Subsequent examination of the methylation status of the 14 loci in 6 MM and 7 adenocarcinoma primary tumors, which yielded similar methylation profiles, supported these observations. Comparison of methylation in MM cell lines and tumors versus non-tumor lung tissue indicated that APC exhibits less methylation in MM (P=0.003) while RASSF1, PGR1, ESR1, and CDH1 show more methylation in MM, the latter two showing the most significant difference between the two tissue types (P< or = 0.0001). Comparison of methylation in adenocarcinoma cell lines and tumors versus non-tumor lung tissue showed methylation of ESR1, PGR1 and RASSF1 to be significantly elevated in adenocarcinoma, with RASSF1 being most significant (P=0.0002). Thus, with the examination of 14 loci, we have identified 5 candidates that show potential for distinguishing between MM, adenocarcinoma and/or non-cancer lung. Our observations support the strong potential of methylation markers as tools for accurate diagnosis of neoplasms in and around the lung.
Epidemic of mesothelioma in Egypt. R.M. Gaafar, N.H. Eldin. 2005;49 Suppl 1:S17-20. PubMed · Publisher

Abstract

Asbestos has been recognized in Egypt since a long time as ancient Egyptians were using it in mummification. Mesothelioma in Egypt is mainly attributed to environmental origin with a high incidence of women and young adults affected. The incidence of mesothelioma is rising in Egypt. Epidemiological data for 635 malignant mesothelioma (MM) patients over 4 years in the third Millennium were collected from the National Cancer Institute (NCI), Cairo University and Abbassia Chest hospital. This number is more than four times the number diagnosed in the previous 11 years at NCI. A clinicopathological study was done for 100 malignant pleural mesothelioma (MPM) patients and showed that asbestos exposure and SV40 positivity were evident in 67% and 60% of cases, respectively. The median survival was 14.3 months and the 1 and 2 year survival rates were 60% and 27%, respectively. Evaluation of p53 and pRb immunohistochemically showed that pRb alteration was related to poor survival. Other biological prognostic factors such as EGFR, HER-2, glutathione S transferase (GST) and MDR were evaluated in 50 cases. Overexpression of EGFR was correlated with lack of clinical benefit and poor survival. GST potentiated the effect of EGFR on survival. The use of EGFR inhibitors may have a role in the treatment of MM. Asbestos in Cairo is a silent killer and measures toward eliminating it entirely or at least strictly controlling human contact with this dangerous carcinogen have to be taken in order to combat the coming epidemic of mesothelioma in Egypt.
Epidemiology of mesothelioma--a South African perspective. R.P. Abratt, N.W. White, D.A. Vorobiof. 2005;49 Suppl 1:S13-5. PubMed · Publisher

Summary

This narrative review described the epidemiology of mesothelioma from a South African perspective. The authors recounted how, in the 1950s, Dr C.A. Sleggs, a tuberculosis physician in the Kimberley district of the Northern Cape, noticed patients with pleural effusions that did not respond to anti-tuberculosis drugs. All came from an area of crocidolite deposits, and many, but not all, had worked in the mines. With a thoracic surgeon and a pathologist, he assembled 33 mesothelioma cases in 4 years, and their 1960 paper led to recognition that asbestos causes mesothelioma. The authors stated that asbestos companies deliberately tried to obscure this link. They reviewed the asbestos fibre types and reported that crocidolite is about ten times more potent than amosite, which is about ten times more potent than chrysotile. They described occupational, bystander, household (for example, laundering work clothes) and environmental exposures. They cited 1993 WHO data showing male mesothelioma mortality of 10–50 per million and female mortality of 5–10 per million in most Western European countries. They described three waves of the epidemic: miners, millers and transport workers; wider industrial use of amphibole asbestos; and exposure to asbestos remaining in buildings or during its removal. The authors noted that South Africa's last asbestos mine had closed and that a settlement for South African claimants had been reached with Cape Asbestos PLC in London.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Identification of intelectin overexpression in malignant pleural mesothelioma by serial analysis of gene expression (SAGE). A. Wali, P.J. Morin, C.D. Hough, et al. 2005;48(1):19-29. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a fatal neoplasm with no acceptable curative approaches. We used serial analysis of gene expression (SAGE) to compare the gene expression pattern of a surgically resected MPM to the autologous normal mesothelium. Intelectin gene overexpression (>139-fold) was found in the tumor. Online SAGE datasets revealed intelectin to be consistently present in mesothelioma(s), ovarian cancer, and colon cancer. Intelectin mRNA expression was found by RT-PCR in 4 of 5 resected MPM tumors, and Intelectin protein expression was confirmed by immunohistochemistry in 28 of 53 MPM tumors, and in 4 of 4 mesothelioma cell lines studied by Western blot. A marked induction in intelectin gene expression was observed among human primary mesothelial cells as a consequence of crocidolite asbestos exposure and simian virus 40 infection. Intelectin overexpression in mesothelioma could have potential screening, and therapeutic implications.
Mesothelioma, perspective from the industry. U.F. Gruber. 2005;49 Suppl 1:S21-3. PubMed · Publisher
Prognostic significance of Bax and Fas ligand in erionite and asbestos induced Turkish malignant pleural mesothelioma. N. Kokturk, P. Firat, H. Akay, et al. 2005;50(2):189-98. PubMed · Publisher

Abstract

Environmentally exposed erionite is a potent and unique inducer of malignant pleural mesothelioma (MPM) in Central Anatolia in Turkey. Previous studies have shown that erionite induced MPM has different biological behavior than asbestos induced MPM. Although impaired apoptosis has been implicated in tumor biology, the relationship between the type of environmental exposure and apoptosis has not yet been evaluated in MPM. The purpose of this study was to determine the expression of apoptosis regulating proteins and their prognostic significance in erionite and asbestos induced MPM. Thirty-five patients with MPM (16 erionite and 19 asbestos induced), and 17 patients with adenocarcinoma were comparatively evaluated. Expression of Bcl-2, Bax, Fas and Fas Ligand, were assessed by immunohistochemistry. Bcl-2 and Fas did not stain in almost all specimens. The staining extension of Bax was 13.75 +/- 19.27%, 5.89 +/- 14.51% and 7.38 +/- 14.53% for erionite and asbestos induced MPM and adenocarcinoma, respectively (p = 0.566). The staining extension of Fas Ligand was 26.87 +/- 31.87%, 46.10 +/- 37.30% and 26.47 +/- 23.23% for erionite and asbestos induced MPM, and adenocarcinoma, respectively (p = 0.123). Bax negative patients in erionite group had longer survival than Bax positive patients (18 months versus 14 months) (p = 0.06). Fas Ligand positive patients showed statistically better survival than Fas Ligand negative patients in all MPM group (15 months versus 12 months) (p = 0.05). Although all proteins expressed in similar extension in all samples, Bax staining displayed an inverse relation with survival in erionite group. This may implicate a difference in Bax functioning in erionite induced MPM. However, Fas Ligand may be functionally intact to reduce tumor survival.
Soluble mesothelin-related protein--a blood test for mesothelioma. B.W. Robinson, J. Creaney, R. Lake, et al. 2005;49 Suppl 1:S109-11. PubMed · Publisher

Abstract

Identification of tumor marker for mesothelioma (MM) might prove useful in diagnosis as well as for monitoring tumor in response to therapy and for screening at-risk individuals. We tested the hypothesis that soluble mesothelin-related protein (SMRP), a mesothelin family member, in the serum would be such a marker. Our data show that determination of SMRP in serum is a marker of MM with a sensitivity of sensitivity 83% and specificity 95% in the first 48 MM patients tested. Changes in serum SMRP levels parallel clinical course/tumor size and SMRP is elevated in 75% of patients at diagnosis. SMRP should also be useful for monitoring disease progression, and importantly, may prove useful for screening asbestos-exposed individuals for early MM.
Transcriptional profiling of mesothelioma using microarrays. G.J. Gordon. 2005;49 Suppl 1:S99-S103. Review PubMed · Publisher

Abstract

Mesothelioma is an asbestos-related neoplasm of the thoracic pleura about which little is known and for which effective therapy is lacking. Large-scale transcriptional profiling using microarrays is frequently a part of studies to explore gene expression patterns in cancer and other diseases. In general, microarray based experiments can facilitate the identification of tumor molecular markers, provide clues relating to mechanisms carcinogenesis, as well as aid in the discovery of candidate targets for therapy. Relatively few studies of this sort have been attempted for mesothelioma, likely due to its relatively rare incidence and by extension the difficulty in acquiring suitable tissues for analysis. Microarray analysis of mesothelioma will likely lead to a better understanding of a highly lethal malignancy and result in the identification of potential therapeutic targets to ultimately affect better treatment options and patient clinical outcome. This mini-review will address general issues pertaining to all expression profiling experiments (e.g., data interpretation) and summarize similar studies that have been attempted for mesothelioma.
Asbestos and mesothelioma in South Africa. R.P. Abratt, D.A. Vorobiof, N. White. 2004;45 Suppl 1:S3-6. Review PubMed · Publisher

Abstract

Asbestos has been used by man since 4000 before the Christian era (BCE) in many different parts of the world and for a wide range of functions. Blue asbestos (crocidolite) was first discovered in South Africa in 1805 and within a few years was being mined there extensively. Mining reached its peak in 1977 with >380,000 tons being exported and 20,000 miners employed in the industry. South Africa also has large deposits of white asbestos (chrysotile) and brown asbestos (amosite) both of which have been mined extensively. At the turn of the 20th century, it was noted that those working with asbestos suffered lung disease and in 1960, the link between asbestosis and mesothelioma was established in the Kimberley area of South Africa. Further studies in the 1970s and 1980s showed an alarming incidence of mesothelioma based on pathology reports. The majority of the reported mesothelioma cases result from exposure to asbestos in its many uses in secondary industry although incidence of the condition among miners is also significant. A high proportion of mesothelioma in patients in South Africa is attributed to environmental origin with a high incidence of women and children affected.
Asbestos: a clear and present danger--a UK perspective. A. Budgen. 2004;45 Suppl 1:S77-9. Historical article PubMed · Publisher

Abstract

The hazardous nature of asbestos has been recognised for over a hundred years yet, despite legislation to protect and compensate workers, the battle for adequate compensation continues.
Epidemiology of malignant mesothelioma in Australia. A.W. Musk, N.H. de Klerk. 2004;45 Suppl 1:S21-3. Review PubMed · Publisher

Abstract

In Australia, consumption of asbestos peaked in about 1975 at around 70,000t per year--the majority being used for asbestos cement manufacture. Chrysotile, amphibole and crocidolite have all been mined in Australia and employment records from the single company which mined most of the crocidolite deposits at Wittenoom have formed the basis of an ongoing cohort mortality study of the workforce.
Epidemiology of pleural mesothelioma in Italy. R. Filiberti, F. Montanaro. 2004;45 Suppl 1:S25-7. Review PubMed · Publisher

Abstract

The incidence of malignant mesothelioma (MM) in Italy is increasing and is assumed to be a consequence of high levels of asbestos exposure. Establishment of the National Mesothelioma Registry (ReNaM) and the co-operation of five regional centers has allowed the estimation of the incidence of malignant mesothelioma in major parts of Italy and the definition of exposure to asbestos.
Impact of low-dose CT on lung cancer screening. S. Diederich, D. Wormanns. 2004;45 Suppl 2:S13-9. Review PubMed · Publisher

Abstract

Despite advances in therapy, the prognosis of lung cancer remains dismal due to the fact that most cases of lung cancer are diagnosed at advanced stages, when the chance of cure is poor. In cases detected at early stages prognosis is better. Unfortunately, early lung cancer usually causes no symptoms and is, consequently, rarely diagnosed. Therefore, screening for early asymptomatic lung cancer with diagnostic procedures appears promising particularly as risk factors for lung cancer are well known (cigarette smoking, occupational asbestos exposure and others) and screening could, therefore, focus on these risk groups. In the past, screening trials using analysis of sputum cytology and to some extent chest radiography have failed to demonstrate a reduction in lung-cancer mortality with screening, probably due to insufficient sensitivity of these tests for early lung cancer. During the last decade the introduction of spiral computed tomography (CT) has provided a technique with a much higher sensitivity for small lung cancers. Feasibility studies using low-radiation-dose CT demonstrated a high proportion of non-small-cell lung cancer at the initial examination (prevalence) with decreasing numbers of detected cancers at follow-up (incidence). The proportion of early-stage tumors was high both at prevalence and incidence examinations. The rate of invasive procedures for benign lesions was low; most indeterminate lesions could be classified with non-invasive diagnostic approaches. The proportion of interval cancers (cancers diagnosed by symptoms between two screening CT scans) was low. As, however, these one-arm feasibility trials are not appropriate to assess a potential mortality reduction through CT screening, prospective randomised multicenter trials were recently initiated in several countries to analyse the effect of CT screening on lung-cancer mortality.
Malignant pleural mesothelioma in Turkey, 2000-2002. S. Emri, A.U. Demir. 2004;45 Suppl 1:S17-20. Review PubMed · Publisher

Abstract

Both asbestos and erionite related malignant pleural mesothelioma (MPM) is a serious health problem in Turkey. Erionite has a higher potency in the lung than asbestos and familial clustering of malignant mesothelioma suggests a genetic predisposition to this cancer among affected individuals. Neither Simian virus 40 (SV40) nor human herpes virus 8 (HHV-8) are co-factors in the pathenogenesis of environmentally induced mesothelioma. A survival advantage has been demonstrated in patients with asbestos-induced mesothelioma compared with erionite-induced mesothelioma. This together with the proliferation index (PI) can be used as an independent prognostic factor for patients with malignant pleural mesothelioma. It is envisaged that the application of these prognostic approaches together with the new TNM staging system will allow investigations to be more precisely carried out and evaluated.
Pathological anatomy and molecular pathology. M. Krismann, K.M. Müller, M. Jaworska, et al. 2004;45 Suppl 1:S29-33. Review PubMed · Publisher

Abstract

The incidence of malignant mesotheliomas in Germany has increased since about the mid 1980s, and a further increase is expected until about 2020 due to the peak in asbestos processing in Germany between 1965 and 1980. About 90% of the mesotheliomas recorded in the files of the German Mesothelioma Registry in Bochum are asbestos-related and therefore possibly due to an occupational exposure. In 2003, 717 mesotheliomas were newly diagnosed at the German Mesothelioma Registry. Mesotheliomas are very heterogeneous in terms of histological appearances and of prognosis. At present, the diagnostic gold standard is conventional histology in combination with additional immunohistochemical analysis. We were not able to confirm a promising report that described telomerase reverse transcriptase catalytic subunit (TERT) for the differentiation between reactive and neoplastic mesothelial lesions, which can be extremely difficult. DNA cytometric analysis may also help differentiate between reactive and neoplastic mesothelial lesions. There are some characteristic patterns of chromosomal imbalances as detectable by comparative genomic hybridization (CGH), but at present, specific chromosomal or genetic defects that give rise to a mesothelioma are not known. A reliable pathological diagnosis is the basis for therapeutic, prognostic, and medicolegal consequences. In general, it can be achieved by thoracoscopic inspection with specifically directed biopsy. Furthermore, a description of the peculiarities of each mesothelioma by the pathologist might be the key to a more individual therapy in the future.
Positron emission tomography in the diagnosis of mesothelioma. U. Haberkorn. 2004;45 Suppl 1:S73-6. Review PubMed · Publisher

Abstract

The increasing incidence of malignant pleural mesothelioma has led to the development of new treatment strategies and a need for new diagnostic techniques to identify the extent of the disease at an early stage and to evaluate treatment. Computed tomography (CT) and magnetic resonance imaging (MRI) are helpful in identifying the location and extent of the involved areas but cannot always differentiate between benign and malignant processes. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, which in oncology, is based on changes in metabolic pathways of glucose, has been shown in a number of studies to differentiate malign and benign lesions in patients with asbestos exposure. FDG-PET images were also found to provide excellent delineation of the active tumour sites. Further evaluations of this technique included a combined experimental/clinical study to investigate the difference in rates of FDG uptake between malignant and inflammatory cells and processes.
The epidemiology of asbestos-related diseases. J. Niklinski, W. Niklinska, E. Chyczewska, et al. 2004;45 Suppl 1:S7-S15. Review PubMed · Publisher

Abstract

Asbestos has been recognised as a potential health hazard since the 1940s. Of the two major species of asbestos; white asbestos (chrysotile) and blue asbestos (crocidolite), both of which are hazardous. The workers at extraction facilities are at the greatest risk of exposure to asbestos and, therefore, the development of asbestos-related diseases, commonly mesothelioma. However, other individuals at a high risk of exposure include asbestos-cement workers, insulation workers and ship-yard workers. Environmental exposure to asbestos can occur as a result of living in areas either characterised by natural outcrops of asbestos or asbestos-related materials, or those close to asbestos-producing or -using plants. Unfortunately, man-made fibre alternatives to asbestos, such as rock and slag-wool and glass wool, have also been shown to have a detrimental effect on human health. A characteristic of mesothelioma is that there is a long latency period (20-30 years) before the signs and symptoms of the disease become apparent. In addition, diagnosis of the disease can be difficult. The use of biological markers, such as tissue polypeptide antigen, may play a useful role in the early detection of the disease in individuals at risk.
The use of magnetic resonance imaging in malignant mesothelioma. J. Entwisle. 2004;45 Suppl 1:S69-71. Review PubMed · Publisher

Abstract

Magnetic resonance imaging (MRI) is not routinely used in investigations for patients with suspected malignant pleural mesothelioma but it can be a useful tool in some instances--particularly predicting malignancy in patients with asbestos exposure; differentiating between metastatic pleural disease and malignant pleural mesothelioma (MPM); assessing patients for radical surgery and post treatment evaluation of patients.
Smoking status, occupational asbestos exposure and bronchial location of lung cancer. C. Paris, J. Benichou, F. Saunier, et al. 2003;40(1):17-24. PubMed · Publisher

Abstract

The objective of this study was to determine the factors associated with central airway versus peripheral bronchial location of lung cancer. All patients diagnosed with lung cancer from 1997 through 2000 in the Respiratory Disease Department of Rouen University Hospital were prospectively interviewed about their smoking and occupational history using a standardized questionnaire. All patients underwent white-light bronchial endoscopy using a 4.5 mm flexible endoscope. Tumors were classified as central when they were accessible and visible using this technique. Out of 217 cases of lung cancer included in this study, 155 (71%) were central. Histological type of lung cancer was strongly associated with bronchial location as central location was observed in 48, 82 and 92% of Adenocarcinoma (AC), Squamous Cell (SqC), and Small Cell Carcinoma (SCC), respectively (P<0.0001). Among non asbestos-exposed patients, location varied little with smoking status, with central location frequency ranging from 74 to 80%. In contrast, lung cancer was recorded central in 41% of long-term (> or =10 years) ex-smokers, 67% of short-term (<10 years) ex-smokers and 75% of current smokers (P=0.04) among patients exposed to asbestos, suggesting an interaction between duration of smoking cessation and occupational asbestos exposure with respect to lung cancer location. These findings were confirmed after adjustment for sex, age and histologic type in multivariate analysis. These results suggest that individually-tailored multimodality screening strategies relying on various combinations of low-dose CT scan, sputum analysis and fluorescence endoscopy according to each patient's profile may be more effective than standard strategies based on a single approach for all patients.
Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis. T. Berghmans, M. Paesmans, Y. Lalami, et al. 2002;38(2):111-21. Meta-analysis · Systematic review PubMed · Publisher

Abstract

The role of chemotherapy for unresectable malignant mesothelioma is unclear. The aims of the present study were to evaluate the methodological quality of published papers relative to chemotherapy or immunotherapy in malignant mesothelioma and to aggregate, for trials having a similar methodology, the response rates in order to identify the most active chemotherapeutic drugs and regimens. The literature relative to this topic, published between 1965 and June 2001 was reviewed. A methodological qualitative evaluation was performed according to the European Lung Cancer Working Party scale, specifically designed for phase II trials. A study was considered as potentially positive if the upper limit of the 95% confidence interval (CI) of the response rate was greater than 20% and positive if the lower limit of the 95% CI was > 20%. Eighty-three studies (88 treatment arms) were eligible for the systematic review. Fifty-three arms were considered as positive or potentially positive. No statistically significant difference in the methodological quality was observed between negative and positive studies. Studies were aggregated in four groups according to the presence of cisplatin and/or doxorubicin in the treatment regimen. The combination of cisplatin and doxorubicin had the highest response rate (28.5%; P < 0.001). Cisplatin was the most active single-agent regimen. Our systematic qualitative and quantitative overview of the literature suggests that the most active chemotherapeutic regimen, in term of objective response rate, is the combination of cisplatin and doxorubicin and the best single-agent is cisplatin. The combination of these two drugs can be recommended as control arm for future randomised phase III trials.

Copyright 2002 Elsevier Science Ireland Ltd.
Computed tomography screening for lung cancer in asbestos-exposed workers. M. Tiitola, L. Kivisaari, M.S. Huuskonen, et al. 2002;35(1):17-22. Case report PubMed · Publisher

Abstract

We conducted a computed tomography (CT) screening for lung cancer in a high-risk population. Six hundred and two workers (38-81 years, 97% smokers) with asbestos-related occupational disease were screened using spiral CT and chest radiography. The national cancer registry was checked for possible false negative cases. The screening detected 111 patients with non-calcified nodules >0.5 cm in diameter and 66 of them were referred for further hospital examination. We found five lung cancers (106 false positive cases) with a histological spectrum similar to the national, natural occurrence of the disease (two adeno, one squamous cell, one anaplastic and one metastatic carcinoma) and one peritoneal mesothelioma. Three cases were potentially operable (stage I-II). Unfortunately there was one false negative fine-needle aspiration biopsy (FNAB) with misinterpretation of the follow-up CT scan and another patient who refused further investigations after an inadequate FNAB. In the end only one patient with adenocarcinoma underwent surgery. After 3 years of follow-up two new lung cancers were reported to the cancer registry with no evidence of tumour in the retrospective analysis of the screening CT scan. The sensitivity of CT screening was 100%. CT was capable of detecting early lung cancer in asbestos-exposed patients with a lot of confusing pulmonary and pleural pathology. Due to the high number of positive findings attention should be paid to patient compliance and the follow-up protocols and patient selection in future screening programmes.
Intrapleural interleukin-2 induces nitric oxide production in pleural effusions from malignant mesothelioma: a possible mechanism of interleukin-2-mediated cytotoxicity?. C. Porta, V. Rizzo, M. Zimatore, et al. 2002;38(2):159-62. PubMed · Publisher

Abstract

Due to the frequent use of intrapleural interleukin-2 (IL-2) to treat pleural effusions from malignant mesothelioma (MMe), we measured nitric oxide (NO) end product nitrite (NO(2)(-)) in pleural effusions of 12 MMe patients with chronic or chronic-relapsing pleurisy. Through high performance liquid chromatography analysis, NO(2)(-) was found in the initial pleural fluid sample of all patients (156.25 pmol ml(-1)), and increased significantly following IL-2 intrapleural instillation, both at 24 (589.91 pmol ml(-1), P < or = 0.0005) and 48 h (756 pmol ml(-1), P< or = 0.0005). Even though it is difficult to argue if the large amounts of NO end product NO(2)(-) we observed is produced by IL-2-stimulated and recruited immune cells, by MMe cells themselves, or by both, it is possible that NO could contribute to the complex antitumor activity of IL-2.

Copyright 2002 Elsevier Science Ireland Ltd.
Pleural small cell carcinoma in pre-existent asbestos related pleural disease. H.F. van der Heijden, Y.F. Heijdra, J. Bulten, et al. 2002;35(1):91-4. Case report PubMed · Publisher

Abstract

Extrapulmonary small cell carcinoma (SCC) is a very rare disease, and a primary pleural manifestation is extremely rare. A case of SCC of the pleura in a 66-year-old man with pre-existent asbestos-related pleural plaques is presented. This is the first case of pleural SCC in a patient with asbestos-induced pleural disease and the third reported case of a pleural SCC. The SCC developed in an area with pre-existent pleural thickening, underlining the need for careful analysis of alterations in the manifestation of pleural disease in patients with asbestos exposition.
A left pleural effusion with a calcified tumoral mass and left hemithoracic uptake on bone scan. E. Quoix, M.P. Chenard, B. Orion, et al. 2001;32(2):203-5. Case report PubMed · Publisher

Abstract

Diffuse malignant pleural mesothelioma is a rare primary tumor of the pleura with three principal histological types, epithelial; mesenchymal and mixed epithelial and mesenchymal. We report here a case of a mesenchymal mesothelioma with foci of osteosarcomatous degeneration revealed by dense calcifications associated with the pleural effusion on the computed tomography (CT) of the thorax. The bone scan revealed extraosseous uptake corresponding to the left pleura.
A phase II study of combined intravenous and subcutaneous interleukin-2 in malignant pleural mesothelioma. C.W. Mulatero, R.T. Penson, D. Papamichael, et al. 2001;31(1):67-72. PubMed · Publisher

Abstract

A total of 29 previously untreated patients with histologically proven malignant pleural mesothelioma, with an ECOG score of < or = 2 and UICC stage I-II disease, were enrolled between May 1994 and October 1996. On days 1 and 2, 18 x 10(6) IU/day of rIL-2 was administered by continuous intravenous infusion, and 6 x 10(6) IU/day of rIL-2 by subcutaneous injection on days 5--20 inclusive of a 42-day cycle. Further treatment was administered if no radiological disease progression was demonstrated. A total of 29 patients were assessable for toxicity and 25 for response, and 49 cycles of IL-2 were administered with a median of one per patient (range, < 1-4). Toxicity included mild fever, nausea and vomiting, and skin rashes, < grade II. Three patients failed to complete one cycle of treatment because of toxicity and one died of disease before response evaluation. Two patients achieved a partial response (8%, 95% CI 1-26%) surviving 18.1 and 18.7 months from diagnosis. A total of 11 patients (44%, 95% CI 24-65%) with stable disease had a median survival of 13.6 months (range 6.5-33.8). The median survival was 8.6 months (range 3.7-34.5) for the 12 patients with progressive disease (48%, 95% CI 28-69%). This regimen of rIL-2 is well tolerated and shows limited activity in mesothelioma.
Asbestos fiber burdens in lung tissues of Hong Kong Chinese with and without lung cancer. Y. Liu, P. Zhang, F. Yi. 2001;32(2):113-6. PubMed · Publisher

Abstract

To investigate the asbestos exposure level in non-occupational population and its relation to lung cancer, pulmonary asbestos fiber counts were observed with a modified alkali digestion method, in lung tissues from 65 random surgically treated lung cancer patients (42 males and 23 females) and that obtained from 107 random autopsy cases who died of either accidental death or acute myocardial infarction (44 males and 63 females) during 1987-1988. The patients and cases were all Hong Kong Chinese with no definite history of occupational exposure to asbestos. The non-lung cancer cases (NLCC) were divided into three groups based on different age ranges: 10 approximately, 40 approximately and 70 approximately years. The results showed that the medians of uncoated fiber counts (0, 32 and 52 fibers per mg dry tissue [f/mgDT] in the different age groups, respectively) increased in an age-dependent manner (P<0.01). However, the medians of coated fiber (asbestos body) counts were all 0 f/mgDT, with no statistically significant difference among the groups, showing a very low level of asbestos body burden in NLCC. In each age group, no difference in those counts between males and females was observed (P>0.05). Moreover, those counts in male lung cancer cases (medians of 62.5 and 17.5 f/mgDT, respectively) were greater than that in the control (32.5 and 0 f/mgDT, respectively) (P<0.01, P<0.05, respectively), however, regarding the female groups there was no statistically significant difference from the control. The results suggest that there is an environmental exposure to asbestos in Hong Kong Chinese, the level of which is, however, generally not sufficient to induce asbestos body. Environmental asbestos exposure in Hong Kong males may be one of the carcinogenic factors leading to lung cancer.
High-dose doxorubicin, dexrazoxane, and GM-CSF in malignant mesothelioma: a phase II study-Cancer and Leukemia Group B 9631. M.P. Kosty, J.E. Herndon, N.J. Vogelzang, et al. 2001;34(2):289-95. PubMed · Publisher

Abstract

Doxorubicin is the most widely studied agent for the treatment of malignant mesothelioma. In conventional doses, the response rate is approximately 17%. Higher dose doxorubicin has been successfully employed in other tumor types. Dexrazoxane has been demonstrated to reduce the cardiac toxicity associated with long term, chronic use of doxorubicin. Based upon phase I data generated by the Cancer and Leukemia Group B (CALGB) indicating that doxorubicin at a dose of 120 mg/m(2) when combined with dexrazoxane and GM-CSF could be safely administered, the CALGB undertook a phase II study of high-dose doxorubicin in patients with malignant mesothelioma. Toxicity was excessive, necessitating protocol modification and ultimately protocol termination. There were no objective responses observed. We conclude that high-dose doxorubicin administered with dexrazoxane is unacceptably toxic in this patient population.
Localised spontaneous regression in mesothelioma -- possible immunological mechanism. B.W. Robinson, C. Robinson, R.A. Lake. 2001;32(2):197-201. Case report PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an aggressive tumor usually associated with asbestos exposure. Although it can remain stable for prolonged periods, it has not been described to spontaneously regress. MM tumors are thought to be immunogenic based both on animal studies and on the good responses in some humans treated with immunotherapy. Here we present a case of pleural MM in which a transient spontaneous regression was associated with tumor tissue infiltration with mononuclear cells and serological evidence of anti-MM reactivity. The patient's tumor eventually progressed and with this progression there was evidence of loss of serological reactivity to some, but not all, of her MM antigens. The patient survived for 20 months and, in contrast to her initial biopsy, no significant lymphoid infiltrate was detected in her MM tissue at post mortem examination.
Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients. B. Castagneto, S. Zai, L. Mutti, et al. 2001;31(2-3):303-10. PubMed · Publisher

Abstract

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.
Prognostic significance of flow cytometric DNA analysis in patients with malignant pleural mesothelioma. S. Emri, H. Akbulut, F. Zorlu, et al. 2001;33(2-3):109-14. PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) due to environmental exposure to asbestos and erionite is a relatively common cancer in Turkey. In this study, we investigated the value of flow cytometric (FCM) DNA analysis and other prognostic factors such as age and etiologic factor in the patients with MPM, treated with surgery+/-combination chemotherapy+/-radiotherapy. A total of 40 patients with a median age of 50 (range 30-68) were included in the study. Twenty-nine patients had asbestos exposure in etiology, while 11 had fibrous zeolite (erionite). Paraffin-embedded tumor specimens were studied by FCM for DNA analysis. Twelve patients (30%) had aneuploid tumors and 28 (70%) had diploid ones. Mean S-phase fraction (SPF; %) was 9.1+/-1.1 and proliferation index (PI, SPF+G2/M phase; %) was 11.3+/-0.9. While the median overall survival (OS) was 10+/-2 months (6-14; 95% CI), 1-year survival rate was 45.2%. Only PI was found to be statistically significant for OS in univariate analysis (P=0.013). PI was also found to be an independent prognostic factor for all patients (P=0.035). Aneuploidy was significantly higher in erionite group compared with asbestos group. Male predominance and poor survival were also prominent in erionite group, though not statistically significant. In conclusion, PI is an independent prognostic factor for patients with MPM and the biologic features of the disease may show differences with respect to different etiologies.
Surgical approach to pleural diffuse mesothelioma in Japan. K. Takagi, R. Tsuchiya, Y. Watanabe. 2001;31(1):57-65. PubMed · Publisher

Abstract

The current status of the surgical treatment of patients with pleural diffuse mesothelioma in Japan was surveyed from the results of a questionnaire sent to members of The Japanese Association for Chest Surgery. Physicians at 57 institutions returned the questionnaire, and a total of 189 surgical cases of diffuse mesothelioma between 1987 and 1996 were analyzed. The age of the patients ranged between 18 and 80 years. They consisted of 154 males and 33 females (the gender of two patients was not indicated). By histological type, 104 cases had the epithelial type, 29 cases had the sarcomatous type, and 46 cases had the mixed type of diffuse mesothelioma (the histology of 10 patients was not indicated). As to the type of surgery, pleuropneumonectomy was performed in 116 cases (61%), and limited resection [including decortication (5 cases) and tumorectomy (68 cases)] was performed in 73 cases (39%). The goal of pleuropneumonectomy is radical resection of the tumor, which often requires combined resection of adjacent structures. The tumor was completely removed macroscopically in 84 (72%) of the 116 cases who underwent pleuropneumonectomy; however, among those with an epithelial-type tumor that was completely removed by pleuropneumonectomy, the tumor recurred postoperatively in 43% of these patients. Perioperative adjuvant therapy was performed in 83 of the 116 patients who underwent pleuropneumonectomy. The 2-year and 5-year survival rates of those who had undergone pleuropneumonectomy were 29.7 and 9.1%, respectively, and the perioperative mortality rate of this procedure was 6%. Limited resection, on the other hand, did not involve radical resection of the tumor. The 2-year and 5-year survival rates of the patients who had undergone limited resection were 26.1 and 9.5%, respectively, and the perioperative mortality rate was 6%. The survival rates and perioperative mortality rate of the patients who had undergone pleuropneumonectomy or limited resection did not significantly differ. The prognostic factors for survival included gender (P=0.0019) and adjuvant therapy (P=0.0034) by Cox's Regression Analysis. The goals of surgical treatment of pleural diffuse mesothelioma are relief of symptoms and prolongation of survival time. Selecting the appropriate surgical procedure and more effective adjuvant therapy for each particular case is necessary under a new, accurate staging system for diffuse mesothelioma.
Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma. G.L. Ceresoli, L.D. Locati, A.J. Ferreri, et al. 2001;34(2):279-87. PubMed · Publisher

Abstract

One-hundred and twenty-one cases of malignant pleural mesothelioma (MPM) seen between 1986 and 1999 at the authors' Institution were reviewed. Histotype was epithelial in 88 patients (73%), sarcomatous in 21 (17%) and mixed in 12 (10%). Ninety-one patients received a treatment (38 palliative pleurectomy and no further therapy, 16 palliative pleurectomy followed by chemotherapy, 37 chemotherapy alone), while 30 were referred to supportive care only. Median survival of the whole population was 10.5 months. The 1-, 2- and 3-year survival were 40, 17 and 8%, respectively. Univariate analysis of subgroups showed that poor performance status (PS), non-epithelial histotype, Butchart stage>I and International Mesothelioma Interest Group (IMIG) stage>I were individually associated with lower survival. Patients receiving any therapy survived longer than patients treated with supportive care only (P=0.0004). Treatment modality had an independent prognostic value (P=0.00005), with a survival advantage for patients receiving surgery and adjuvant chemotherapy. Multivariate analysis confirmed the independent prognostic value of PS (P=0.001; HR=2.48) and treatment modality (P=0.003; HR=1.38). The prognostic role of PS (P=0.02) and treatment modality (P=0.01) was confirmed in the subset of patients with epithelial histology. On the contrary, therapy had no impact on survival in patients with sarcomatoid MPM (P=0.74). Despite the predicted bias of a retrospective non-randomized evaluation of treatment-related factors, patients with good PS and epithelial histology seemed to have a survival benefit from surgery or multimodality therapy, as opposite to patients with poor PS or non-epithelial histotype. However, these results must be confirmed in a larger prospective trial with uniform treatment.

1990s

Ifosfamide in malignant mesothelioma: a phase II study. M.K. Andersen, A. Krarup-Hansen, G. Mårtensson, et al. 1999;24(1):39-43. PubMed · Publisher

Abstract

Malignant mesothelioma is a rare malignancy with a median survival, ranging from 4 to 18 months in untreated patients. In a phase II study of patients with mesothelioma, the efficacy and toxicity of ifosfamide and mesna was evaluated. Twenty-nine previously untreated patients, with histologically proven and unresectable mesothelioma, entered the study. Three patients were later excluded from the study due to revision of the diagnoses. The patients had to have bidimensionally measurable disease by CT scans and a WHO performance status < or = 3. Eligible patients received ifosfamide 3000 mg/m2 per day for 3 days as a 1-h infusion and mesna 1800 mg/m2 per day for 3 days every third week. Dose modifications were made according to the degree of hematologic, neurologic and renal toxicity. Response to treatment was evaluated in accordance with WHO criteria. The median age of patients was 59 years (range 39-68), 18 patients (69%) had a history of asbestos exposure and the median of treatment cycles was four (range 1-10). No complete responses were observed. One patient obtained a partial response after five cycles with a duration of response of 25 months. Nine patients (35%) had stable disease, while 13 (54%) progressed. The median survival for all patients was 10 months. The toxicity of the treatment was considerable. Thirteen patients (50%) had grade 4 leucopenia, ten patients (38%) had grade 3 or 4 reversible neurotoxicity and ten patients (38%) had grade 3 or 4 nausea and vomiting. Eleven patients (42%) went off the study due to the toxicity of the treatment. In conclusion, ifosfamide did not show any substantial activity of relevance in malignant mesothelioma at the dose level investigated, in spite of considerable toxicity.
Quantitation of asbestos and asbestos-like fibers in human lung tissue by hot and wet ashing, and the significance of their presence for survival of lung carcinoma and mesothelioma patients. K. Kayser, C. Becker, N. Seeberg, et al. 1999;24(2):89-98. PubMed · Publisher

Abstract

Technical standardization on randomly chosen samples of tissue specimen is essential for the validity of interpretations derived from measurements on the presence of asbestos fibers in lung in combination with further features of the patients. Fixed non-tumorous lung tissue (2-3 g) of 150 patients after surgery for various lung diseases were either digested in 45 ml of 13% solution with sodium hypochlorite (NaClO; wet ashing) or heated in an oven at 600 degrees C for 15 min (hot ashing). After tissue disintegration asbestos and asbestos-like fibers were counted by visual inspection, and the fiber concentration in the lung parenchyma was computed. In addition, the patients' survival, and the occupational and social history were analyzed. As a result, the mean concentrations of fibers were found to be 55 f/g (fibers/gram, hot ashing) and 46 f/g (wet ashing). The difference is statistically not significant. Mesotheliomas contributed 49% (73 patients), non-small cell lung carcinomas 32% (59 patients) to the entire cohort. Eighteen patients had a non-malignant lung disease. Analysis of living habits revealed that 73 (49%) patients were heavy smokers, and 99 (66%) patients had a history of occupational asbestos exposure which lasted for 18 years on average. A statistically significant difference of the asbestos fiber concentration between the group with professional exposure and that without detectable asbestos exposure could be obtained in mesothelioma patients and non-malignant lung diseases only, and a tendency for elevated fiber presence was seen in non-small cell lung carcinoma patients. In tissue specimen of patients with non-malignant lung diseases the highest fiber concentration was measured (median 104 f/g) followed by mesothelioma patients (77 f/g), and lung carcinoma patients (62 f/g wet tissue). The difference in the fiber concentration between smokers and ex-smokers versus non-smokers was particularly high in patients with non-malignant lung diseases (103 f/g in smokers versus 33 f/g in non-smokers), still statistically significant in mesothelioma patients (100 f/g smokers versus 61 f/g non smokers), and negligible in lung carcinoma patients (58 f/g smokers versus 62 f/g non-smokers). Only 5/70 mesothelioma patients were not exposed to asbestos at work, and nearly half of the patients (36) were non-smokers. The median survival of mesothelioma patients was significantly shortened for patients with a high intrapulmonal fiber concentration greater than 70 f/g (35 weeks versus 60 weeks). This correlation was also true for lung carcinoma patients (110 weeks versus 230 weeks).
Weekly systemic combination of cisplatin and interferon alpha 2a in diffuse malignant pleural mesothelioma. A. Purohit, L. Moreau, A. Dietemann, et al. 1998;22(2):119-25. PubMed · Publisher

Abstract

The treatment of diffuse malignant pleural mesothelioma (DMPM) remains grim. Neither surgery, radiotherapy nor chemotherapy can be considered as a standard therapy. Immunotherapy with interferon (IFN) in combination with chemotherapy may be an interesting new approach. In 13 consecutive patients with DMPM, we used a weekly combination of cisplatin (CDDP) (60 mg/m2; day 2) and IFN alpha 2a (6 MU/day; days 1-4) in a protocol of two cycles of 4 weeks on/4 weeks off followed by 3 weeks on/3 weeks off. Total treatment duration was thus 25 weeks. In responders, IFN as maintenance monotherapy was continued for a further 6 months. There were nine males and four females with an average age of 65.3 years (range 51-72 years). Eleven had epithelial, one had mixed and one had a sarcomatoid form of DMPM. Five patients were classified as stage II, six as stage III and two as stage IV, as per the International Mesothelioma Interest Group. Thirty-five cycles were administered with a median of three cycles/patient (range 0.75-4). The median total cumulative dose of CDDP was 596 mg/m2 (range 114-861) and that of IFN alpha 2a was 264 MU (range 72-336). Four patients received IFN maintenance therapy, one for 3 months and three for 6 months. One patient had a complete response, four had a partial response, six had a stable disease and the disease progressed in one. One patient was non evaluable for response. All patients were assessable for toxicity. Hematological toxicity was the most frequently observed but was manageable (grade 3 anemia in five patients, grade 3 thrombocytopenia in three patients, grade 3 neutropenia in five patients). Grade 1 renal toxicity was observed in six patients, grade 2-3 asthenia in six patients and an average 5-kg weight loss was noted in nine patients. In conclusion, systemic combination of CDDP and IFN alpha 2a in large doses is effective at the expense of non-negligible toxicity.
A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group. V.W. Rusch. 1996;14(1):1-12. PubMed · Publisher

Abstract

Study Objective: investigation of the behavior and treatment of diffuse malignant pleural mesothelioma (MPM) is hindered by the lack of an accurate universally accepted staging system. To address this problem, the International Mesothelioma Interest Group (IMIG) has developed a new TNM based staging system.

Methods: the staging system was developed at a consensus meeting of IMIG members involved in clinical research in MPM, including the originators of previously proposed staging systems. The new staging system is based on the analysis of emerging information about the impact of T and N status on survival.

Results: in contrast to five previous staging systems, the T descriptors designated as T1, T2, T3 and T4, provide precise anatomic definitions of the local extent of the primary tumour. The N descriptors, designated as N0, N1, N2 and N3, are virtually identical to those used in the International Lung Cancer Staging System. The stage groupings recognize new data about the better prognosis of T1 and N0 tumours and classify those tumours into stages I and II. The adverse impact of nodal metastases on survival noted in some recent surgical series warrants placing node positive tumours in stage III. Locally advanced unresectable (T4) tumours and extrathoracic disease (N3 or M1) are classified as stage IV.

Conclusion: this proposed staging system reconciles and updates several earlier systems, and can provide the framework for analyzing the results of prospective clinical trials aimed at improving the currently dismal prognosis of MPM.
Evaluation and prognostic value of DNA content and of morphometric parameters in malignant mesothelioma using digital image analysis. K. Segers, S.K. Singh, A. Van Daele, et al. 1996;14(2-3):229-37. PubMed · Publisher

Abstract

Fifty-seven cases of malignant mesothelioma were analyzed for nuclear diameter, DNA content and ploidy-related parameters, using Feulgen stained paraffin sections with a digital imaging analysis system. Thirty cases had a mean nuclear diameter > 7 microns and 31 cases were classified as near-diploid. A statistically significant correlation between survival and the mean nuclear diameter (P = 0.0006) and between survival and DNA index (P = 0.007) was obtained. For other DNA content parameters (proliferation index, 5c exceeding rate), only one of the two statistical tests showed a significant correlation with survival while the other test was of borderline significance. In this malignant mesothelioma population, the prognosis for patients with the epithelial type was better than for those with sarcomatous tumours (P = 0.01). In this population of patients, about half of the malignant mesotheliomas were aneuploid. The mean nuclear diameter, DNA index analysis and proliferation index analysis of the tumour cells on Feulgen stained paraffin sections can be used as independent prognostic parameters.
Two dose levels of ifosfamide in malignant mesothelioma. F. Içli, H. Karaoğuz, S. Hastürk, et al. 1996;15(2):207-13. PubMed · Publisher

Abstract

Thirty-one consecutive patients with histologically proven and symptomatic malignant mesothelioma were treated with two dose levels of ifosfamide. The first group of 15 patients were given 2.3 g/m2/day for 5 days (group A) and the following 16 patients were treated with 1.2 g/m2/day for 5 days of ifosfamide (group B). Treatment cycles were repeated every 3 weeks. While the partial response rate (PR) in group A was 38.5%, it was only 6.25% in group B (P > 0.05). The 95% confidence interval for the difference in PR rates was 3.3-61.2% > The overall survival (OAS) of groups A and B were similar (8 months and 9 months, respectively). Higher Grade 3-4 myelotoxicity was observed in group A when compared to group B (30.8% vs. 18.7%; P > 0.05). In conclusion, a favourable response rate could be achieved in malignant mesothelioma with high dose ifosfamide at the cost of increased toxicity.
Clinical features and current treatment of diffuse malignant pleural mesothelioma. V.W. Rusch. 1995;12 Suppl 2:S127-46. Review PubMed · Publisher

Abstract

Malignant pleural mesothelioma is an uncommon cancer for which the major risk factor is prior asbestos exposure. During the past decade, there has been progress in the diagnosis, staging and biology of mesothelioma. Treatment remains controversial and ranges from supportive care alone to aggressive multimodality therapy. Prospective clinical trials in carefully staged patients are needed to determine what approaches to treatment may confer a survival benefit.
Evaluation of the clinical TNM staging system for malignant pleural mesothelioma: an assessment in 88 patients. L. Tammilehto, L. Kivisaari, U.S. Salminen, et al. 1995;12(1-2):25-34. PubMed · Publisher

Abstract

There is no universally-recognised method for staging malignant mesothelioma, although the use of computed tomograph (CT) scanning has improved the staging of non-invasive disease. The International Union against Cancer has recently proposed using the Tumour Node Metastases (TNM) staging system for mesothelioma, but in clinical practice it is difficult to assess tumour and nodal involvement due to the unique plate-like growth pattern of this tumour. In order to evaluate TNM staging we analysed pre-operative CT scans from 88 patients with histologically-confirmed malignant pleural mesothelioma, all from the same institution. The median age of the patients was 56 years (range 38-79). There were 70 men and 18 women, and 33 had tumours with epithelial histology. The median survival time was 10 months (range 0.2-110), from the date of histological confirmation of mesothelioma. The same radiologist analysed all the CT scans according to the TNM staging system. Actuarial survival curves were constructed by the Kaplan-Meier method. Survival curves for the different TNM categories were compared using the log-rank test. Node evaluation could not be completed in eight cases because the tumour had encompassed the hilum and mediastinum. In multivariate analysis, significant differences in prognosis correlated with the different T categories (P < 0.01), and the different TNM stages (P < 0.05), but not the N categories or the M categories. Larger studies are needed to assess the importance of TNM staging in the selection of treatment and as a prognostic factor for malignant mesothelioma.

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