British Journal of Cancer

About the journal

Publisher: Nature Publishing Group on behalf of Cancer Research UK
Published: 1947 to the present, England
Language: English
ISSN: 0007-0920 (print), 1532-1827 (electronic)
Its record in the NLM Catalog

2020s

Genomic sequencing of multicystic mesothelioma finds cohesin complex mutations associated with disease recurrence in patients referred for cytoreductive surgery and HIPEC. J. Gibson, N.J. Carr, S. Stanford, et al. 2026;134(9):1352-1359. PubMed · Publisher · Free full text

Abstract

Background: Multicystic mesothelioma (MCM) is a rare disease and there is debate about it's neoplastic nature with a spectrum of disease behaviour and little known about the genomic profile. In contrast, the genomic profile of malignant peritoneal mesothelioma (MPeM) is characterised.

Methods: We characterized 24 MCM and 18 MPeM cases across a panel of cancer related regions and expanded to whole-exome sequencing for 11 MCMs. Validation by amplicon sequencing and functional assessment by molecular dynamic simulation were carried out. Kaplan-Meier analysis was carried out to assess recurrence-free survival.

Results: Few mutations were identified in MCMs across the panel. Exome sequencing revealed 28 genes mutated in >1 MCM case. We saw significant overrepresentation of mutations in the cohesin complex in SMC3, SMC1A, and STAG3. Multiple mutations in SMC3 at codon p.E1144 indicated a mutational hotspot. Molecular dynamics simulations showed mutation at this site impacts the protein function. Amplicon sequencing confirmed hotspot mutations in further MCMs. We observed a significant association (p = 0.0302) of mutation in SMC3 or SMC1A with disease recurrence.

Conclusions: We see recurrent somatic mutations in MCMs particularly at a novel mutational hotspot in SMC3, consistent with a neoplastic process. Mutations in cohesin complex genes are associated with disease recurrence.

© 2026. The Author(s).
Multiplexed single-cell and spatial profiling reveal B cells and tertiary lymphoid structures as prognostic indicators in pleural mesothelioma. A. Rigutto, N.G. Núñez, J.C. Kienzler, et al. 2026;135(2):214-222. PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma (PM) is an orphan disease with poor prognosis. While T cell dynamics in the tumor microenvironment (TME) have been extensively studied, the role of B cells remains poorly characterized. Tumor-infiltrating B cells, particularly when organized into tertiary lymphoid structures (TLS), have been associated with improved outcomes of patients with cancer.

Methods: In this study, high-dimensional flow cytometry (HDCyto) and high-plex imaging were applied to analyze fresh-frozen and formalin-fixed paraffin-embedded (FFPE) PM tumor samples, enabling a comprehensive immune profiling of the TME.

Results: We identified 15 distinct immune cell subsets and stratified tumors into three subgroups with significantly different survival outcomes. Longer survival correlated with increased T and B cell infiltration, with B cells and CD4+ T cells forming TLS in specific cases.

Conclusions: These findings underscore the heterogeneity of PM tumors and highlight the critical role of B cells and TLS in shaping anti-tumor immunity and influencing patient prognosis.

© 2026. The Author(s).
Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma. K. Schelch, N. Maach, M. Hashim, et al. 2025;133(9):1391-1400. PubMed · Publisher · Free full text

Abstract

Background: The cold-shock domain protein YB-1 is overexpressed in pleural mesothelioma (PM) and was shown to contribute to increased cell migration and platinum resistance.

Methods: Phosphorylation of YB-1 at position serine 102 was analysed by immunohistochemistry, immunofluorescence and immunoblotting in PM tissue specimens and cell lines. Intracellular localisation experiments involved immunoblotting, transfection of fluorescent protein-tagged YB-1 and confocal imaging. YB-1 phosphorylation was inhibited with the RSK inhibitors BI-D1870 and LJH685. Effects of inhibition alone and in combination with radiation or cisplatin treatment were analysed by cell viability assays, clonogenic assays and videomicroscopy-based migration and cell fate map analyses.

Results: YB-1 phosphorylated at serine 102 is present in PM cell lines and tissue. Inhibition of phosphorylation with BI-D1870 reduced YB-1 localisation in the cell nucleus and led to reduced cell viability, clonogenicity, migration and disrupted cell division. Moreover, exposure to BI-D1870 increased the effect of radiation and cisplatin treatment with additive to synergistic effects in PM cell lines and primary cultures.

Conclusions: The serine 102 phosphorylated form of YB-1 contributes to the malignant phenotype of PM. Inhibition of YB-1 phosphorylation warrants further exploration as part of treatment strategies for this devastating disease.

© 2025. The Author(s).
Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma. N. Landman, D. Hulsman, J. Badhai, et al. 2024;130(11):1855-1865. PubMed · Publisher · Free full text

Abstract

Background: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time.

Methods: A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed.

Results: Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1.

Conclusions: We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.

© 2024. The Author(s).
Genomic landscape of pleural and peritoneal mesothelioma tumours. S. Hiltbrunner, Z. Fleischmann, E.S. Sokol, et al. 2022;127(11):1997-2005. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural and peritoneal mesotheliomas are rare malignancies with unacceptable poor prognoses and limited treatment options. The genomic landscape is mainly characterised by the loss of tumour suppressor genes and mutations in DNA repair genes. Currently, data from next-generation sequencing (NGS) of mesothelioma tumours is restricted to a limited number of cases; moreover, data comparing molecular features of mesothelioma from the pleural and peritoneal origin with NGS are lacking.

Methods: We analysed 1113 pleural mesothelioma and 355 peritoneal mesothelioma samples. All tumours were sequenced with the FoundationOne® or FoundationOne®CDx assay for detection of substitutions, insertion-deletions, copy-number alterations and selected rearrangements in at least 324 cancer genes.

Results: This analysis revealed alterations in 19 genes with an overall prevalence of at least 2%. Alterations in BAP1, CDKN2A, CDKN2B, NF2, MTAP, TP53 and SETD2 occurred with a prevalence of at least 10%. Peritoneal, compared to pleural mesothelioma, was characterised by a lower prevalence of alterations in CDKN2A, CDKN2B and MTAP. Moreover, we could define four distinct subgroups according to alterations in BAP1 and CDKN2A/B. Alterations in Hedgehog pathway-related genes (PTCH1/2 and SUFU) and Hippo pathway-related gene (NF2) as well as KRAS, EGFR, PDGFRA/B, ERBB2 and FGFR3 were detected in both cohorts.

Conclusion: Here, we report the molecular aberrations from the largest cohort of patients with mesothelioma. This analysis identified a proportion of patients with targetable alterations and suggests that molecular profiling can identify new treatment options for patients with mesothelioma.

© 2022. The Author(s).
Biological basis for novel mesothelioma therapies. J. Obacz, H. Yung, M. Shamseddin, et al. 2021;125(8):1039-1055. Review PubMed · Publisher · Free full text

Abstract

Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.

© 2021. The Author(s).
Comment on "Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy". H. Yang, S.R.R. Hall, B. Sun, et al. 2021;124(6):1177-1178. Letter · Comment PubMed · Publisher · Free full text
Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM). M. Lapidot, A.E. Case, E.L. Weisberg, et al. 2021;125(4):582-592. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM.

Methods: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways.

Results: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth.

Conclusions: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.

© 2021. The Author(s).
Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy. M.G. White, J.J. Schulte, L. Xue, et al. 2021;124(3):564-566. PubMed · Publisher · Free full text

Abstract

Programmed death-ligand 1 (PD-L1) expression has been described in patients with malignant peritoneal mesothelioma (MPM), but treatment strategies utilising immune checkpoint inhibition are yet to be defined. Here, we examine levels of PD-L1 expression in MPM patients treated with systemic and/or intraperitoneal chemotherapy using tissue from patient tumour biopsies or resections at multiple time points. We found the mean PD-L1 expression was higher in those with a germline mutation and/or those with a higher somatic mutation burden. Moreover, PD-L1 expression was lower in patients who had received prior chemotherapy as compared to the treatment-naive cohort. Twenty patients who received chemotherapy, either systemic and/or peritoneal, between PD-L1 measurements showed marked heterogeneity. Six (30%) patients demonstrated upregulation of PD-L1, while eight (40%) demonstrated downregulation. Heterogeneity in PD-L1 expression in MPM before and after cytotoxic therapies may present an additional consideration when initiating immune checkpoint inhibition in this rare and challenging disease.
Response to Comment on "Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy". M.G. White, O.S. Eng. 2021;124(6):1179-1180. Letter · Comment PubMed · Publisher · Free full text

Summary

In this letter, the authors of a study on heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma treated with systemic or intraperitoneal chemotherapy replied to a letter from Dr. Yang and colleagues commenting on that study. They explained that leaving out the sarcomatoid subtype was not intentional. It reflected the fact that patients with this subtype had not been treated surgically during the study period. They noted that this subtype is known to be more aggressive and to be a poor prognostic factor even with cytoreductive surgery. They agreed that T-cell infiltrates are of interest as a possible marker of responsiveness. They said their group planned future work on B-cells and tertiary lymphoid structures in mesothelioma, which have been linked to better responses to immunotherapy in melanoma, sarcoma and renal cell carcinoma. They welcomed Yang and colleagues' suggestion to use tumour suppressor gene inactivation and tumour microenvironment differences to select patients most likely to respond to immune checkpoint blockade. They described selection by histology augmented by molecular profiling as a hopeful future direction. However, they cautioned that those observations were made in pleural rather than peritoneal mesothelioma, and that the immune microenvironment of the peritoneum remains poorly understood. They concluded that, because mesothelioma is rare, improving care often requires multi-institutional and international collaboration.

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.
Tumour treating fields therapy for glioblastoma: current advances and future directions. O. Rominiyi, A. Vanderlinden, S.J. Clenton, et al. 2021;124(4):697-709. Review PubMed · Publisher · Free full text

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and continues to portend poor survival, despite multimodal treatment using surgery and chemoradiotherapy. The addition of tumour-treating fields (TTFields)-an approach in which alternating electrical fields exert biophysical force on charged and polarisable molecules known as dipoles-to standard therapy, has been shown to extend survival for patients with newly diagnosed GBM, recurrent GBM and mesothelioma, leading to the clinical approval of this approach by the FDA. TTFields represent a non-invasive anticancer modality consisting of low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz), alternating electric fields delivered via cutaneous transducer arrays configured to provide optimal tumour-site coverage. Although TTFields were initially demonstrated to inhibit cancer cell proliferation by interfering with mitotic apparatus, it is becoming increasingly clear that TTFields show a broad mechanism of action by disrupting a multitude of biological processes, including DNA repair, cell permeability and immunological responses, to elicit therapeutic effects. This review describes advances in our current understanding of the mechanisms by which TTFields mediate anticancer effects. Additionally, we summarise the landscape of TTFields clinical trials across various cancers and consider how emerging preclinical data might inform future clinical applications for TTFields.
Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds. G. Li Petri, B. El Hassouni, R. Sciarrillo, et al. 2020;123(4):644-656. PubMed · Publisher · Free full text

Abstract

Background: Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation.

Methods: Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients.

Results: Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine.

Conclusions: This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors.
Metabolic rewiring and redox alterations in malignant pleural mesothelioma. L. Urso, I. Cavallari, E. Sharova, et al. 2020;122(1):52-61. Review PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in 18F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.
Standards of care in mesothelioma treatment. S.V. Harden, L. Darlison, P. Beckett, et al. 2020;123(11):1588-1589. PubMed · Publisher · Free full text

Abstract

The UK has the highest incidence of mesothelioma in the world, but services vary across the country partly due to uneven geographical distribution of cases. The Mesothelioma UK-funded national organisational audit has highlighted challenges in accessing diagnostic procedures such as thoracoscopy, as well as identifying examples of best practice, including access to clinical trials and specialist therapeutic procedures. To ensure equitable and optimal patient care, cancer alliances should have established referral pathways to specialist multidisciplinary team (MDT) services for discussion of all mesothelioma patients.

2010s

A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours. G. Mak, J.C. Soria, S.P. Blagden, et al. 2019;120(10):975-981. PubMed · Publisher · Free full text

Abstract

Background: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy.

Methods: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed.

Results: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks).

Conclusions: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.
Family history of cancer and risk of paediatric and young adult's testicular cancer: A Norwegian cohort study. R. Del Risco Kollerud, E. Ruud, H.S. Haugnes, et al. 2019;120(10):1007-1014. PubMed · Publisher · Free full text

Abstract

Background: The aim of this study was to examine the association of a family history of cancer with the risk of testicular cancer in young adults.

Methods: This is a prospective cohort study including 1,974,287 males born 1951-2015, of whom 2686 were diagnosed with TC before the age of 30.

Results: A history of TC in male relatives was significantly associated with a diagnosis of TC among children and young adults, including brothers (6.3-fold), sons (4.7-fold), fathers (4.4-fold), paternal uncles (2.0-fold) and maternal uncles (1.9-fold). Individuals with a father diagnosed with a carcinoma or sarcoma showed an elevated risk (1.1-fold and 1.8-fold, respectively). A family history of mesothelioma was positively associated with a risk of TC [(father (2.8-fold), mother (4.6-fold) and maternal uncles and aunt (4.4-fold)]. Elevated risks were also observed when siblings were diagnosed with malignant melanoma (1.4-fold). The risk of TC was also increased when fathers (11.1-fold), paternal (4.9-fold) and maternal uncles and aunts (4.6-fold) were diagnosed with malignant neuroepithelial-tumours.

Conclusion: We found an increased risk of TC among children and young adults with a family history of TC, carcinoma, mesothelioma, sarcoma, malignant melanoma and malignant neuroepithelial tumours. Hereditary cancer syndromes might underlie some of the associations reported in this study.
Ingested asbestos in filtered beer, in addition to occupational exposure, as a causative factor in oesophageal adenocarcinoma. R.C. Fitzgerald, J.M. Rhodes. 2019;120(12):1099-1104. Review PubMed · Publisher · Free full text

Abstract

Oesophageal adenocarcinoma has become much more common over the past 50 years, particularly in Britain, with an unexplained male to female ratio of > 4:1. Given the use of asbestos filtration in commercial brewing and reports of its unregulated use in British public houses in the 1970's to clear draught beer "slops", we have assessed the hypothesis that ingested asbestos could be a causative factor for this increased incidence. Importantly, occupational asbestos exposure increases the risk of adenocarcinoma but not squamous cell carcinoma of the oesophagus. The presence of asbestos fibres was consistently reported in filtered beverages including beers in the 1970s and asbestos bodies have been found in gastrointestinal tissue, particularly oesophageal tissue, at autopsy. There is no reported association between the intake of alcohol and oesophageal adenocarcinoma but studies would mostly have missed exposure from draught beer before 1980. Oesophageal adenocarcinoma has some molecular similarities to pleural mesothelioma, a condition that is largely due to inhalation of asbestos fibres, including predominant loss of tumour suppressor genes rather than an increase of classical oncogenic drivers. Trends in incidence of oesophageal adenocarcinoma and mesothelioma are similar, rising rapidly over the past 50 years but now plateauing. Asbestos ingestion, either from beer consumed before around 1980, or from occupational exposure, seems a plausible causative factor for oesophageal adenocarcinoma. If this is indeed the case, its incidence should fall back to a low baseline by around 2050.
MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial. E. Maille, S. Brosseau, V. Hanoux, et al. 2019;120(4):387-397. Randomized trial PubMed · Publisher · Free full text

Abstract

Background: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.

Methods: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.

Results: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.

Conclusions: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.
An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma. A. Linton, Y.Y. Cheng, K. Griggs, et al. 2018;118(6):e13. PubMed · Publisher · Free full text

Abstract

This corrects the article doi:10.1038/bjc.2017.85.
Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma. D. Xu, S.Q. Liang, H. Yang, et al. 2018;119(1):65-75. PubMed · Publisher · Free full text

Abstract

Background: Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; however, this is confronted by drug resistance. Proteotoxic stress in the endoplasmic reticulum (ER) is a hallmark of cancer and some rely on this stress signalling in response to cytotoxic chemotherapeutics. We hypothesise that ER stress and the adaptive unfolded protein response (UPR) play a role in chemotherapy resistance of MPM.

Methods: In vitro three-dimensional (3D) and ex vivo organotypic culture were used to enrich a chemotherapy-resistant population and recapitulate an in vivo MPM microenvironment, respectively. Markers of ER stress, the UPR and apoptosis were assessed at mRNA and protein levels. Cell viability was determined based on acid phosphatase activity.

Results: MPM cells with de novo and/or acquired chemotherapy resistance displayed low ER stress, which rendered the cells hypersensitive to agents that induce ER stress and alter the UPR. Bortezomib, an FDA-approved proteasome inhibitor, selectively impairs chemotherapy-resistant MPM cells by activating the PERK/eIF2α/ATF4-mediated UPR and augmenting apoptosis.

Conclusions: We provide the first evidence for ER stress and the adaptive UPR signalling in chemotherapy resistance of MPM, which suggests that perturbation of the UPR by altering ER stress is a novel strategy to treat chemotherapy-refractory MPM.
Comparison of outcomes following a cytological or histological diagnosis of malignant mesothelioma. S. Muruganandan, H. Alfonso, P. Franklin, et al. 2017;116(6):703-708. PubMed · Publisher · Free full text

Abstract

Background: Survival with the epithelioid subtype of malignant mesothelioma (MM) is longer than the biphasic or sarcomatoid subtypes. There is concern that cytology-diagnosed epithelioid MM may underdiagnose the biphasic subtype. This study examines survival differences between patients with epithelioid MM diagnosed by cytology only and other subtypes diagnosed by histology.

Methods: Demographics, diagnosis method, MM subtype and survival were extracted from the Western Australia (WA) Mesothelioma Registry, which records details of all MM cases occurring in WA.

Results: A total of 2024 MM cases were identified over 42 years. One thousand seven hundred forty-four (86.2%) were male, median (IQR) age was 68.6 (60.4-77.0) years. A total of 1212 (59.9%) cases were identified as epithelioid subtype of which 499 (41.2%) were diagnosed using fluid cytology only. Those with a cytology-only diagnosis were older than the histology group (median 70.2 vs 67.6 years, P<0.001), but median survival was similar (cytology 10.6 (5.5-19.2) vs histology 11.1 (4.8-19.8) months, P=0.727) and Cox regression modelling adjusting for age, sex, site and time since first exposure showed no difference in survival between the different diagnostic approaches.

Conclusions: Survival of cytologically and histologically diagnosed epithelioid MM cases does not differ. A diagnostic tap should be considered adequate to diagnose epithelioid MM without need for further invasive testing.
Evaluating the effect of immune cells on the outcome of patients with mesothelioma. S.J. Chee, M. Lopez, T. Mellows, et al. 2017;117(9):1341-1348. PubMed · Publisher · Free full text

Abstract

Background: We systematically assessed the prognostic and predictive value of infiltrating adaptive and innate immune cells in a large cohort of patients with advanced mesothelioma.

Methods: A tissue microarray from 302 samples was constructed. Markers of adaptive immune response in T-cells (CD8+, FOXP3+, CD4+, CD45RO+, CD3+) and B-cells (CD20+), and of innate immune response; neutrophils (NP57+), natural killer cells (CD56+) and macrophages (CD68+) were evaluated.

Results: We found that in the epithelioid tumours, high CD4+ and CD20+ counts, and low FOXP3+, CD68+ and NP57+ counts linked to better outcome. In the non-epithelioid group low CD8+ and low FOXP3+ counts were beneficial.On multivariate analysis low FOXP3+ remained independently associated with survival in both groups. In the epithelioid group additionally high CD4+, high CD20+, and low NP57+ counts were prognostic.

Conclusions: Our data demonstrate for the first time, in predominately advanced disease, the association of key markers of adaptive and innate immunity with survival and the differential effect of histology. A better understanding of the immunological drivers of the different subtypes of mesothelioma will assist prognostication and disease-specific clinical decision-making.
First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers. E. Angevin, N. Isambert, V. Trillet-Lenoir, et al. 2017;116(9):1126-1134. PubMed · Publisher · Free full text

Abstract

Background: YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects.

Methods: This FIH study was designed to determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) to assess the tolerance, pharmacokinetics (PK) and pharmacodynamics profiles of YS110 and preliminary efficacy. YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours.

Results: Thirty-three patients (22 mesothelioma) received a median of 3 (range 1-30) YS110 infusions across six dose levels (0.1-6 mg kg-1). MTD was not reached and two dose-limiting toxicities (infusion hypersensitivity reactions) led to the institution of a systemic premedication. Low-grade asthenia (30.3%), hypersensitivity (27.3%), nausea (15.2%), flushing (15.2%), chills (12.1%) and pyrexia (12.1%) were reported as ADRs. Pharmacokinetic parameters (AUC and Cmax) increased in proportion with the dose. sCD26/DPPIV assays indicated CD26 modulation. Prolonged stable diseases were observed in 13 out of 26 evaluable patients.

Conclusions: YS110 is well tolerated up to 6 mg kg-1 Q1W, which has been defined as the RP2D, with encouraging prolonged disease stabilisations observed in a number of patients with advanced/refractory mesothelioma.
Prognostication and monitoring of mesothelioma using biomarkers: a systematic review. D.T. Arnold, D. De Fonseka, F.W. Hamilton, et al. 2017;116(6):731-741. Systematic review PubMed · Publisher · Free full text

Abstract

Background: Radiological markers of treatment response and prognostication in malignant pleural mesothelioma have limitations due to the morphology of the disease. Serum or pleural fluid biomarkers that could act as an adjunct to radiological assessment would be of significant value. The aim of this review was to collate and summarise the literature relating to this topic.

Methods: A systematic review was performed on the databases Pubmed and EMBASE to identify relevant studies. Two independent researchers read the abstracts and used the Quality in Prognostic Studies tool to assess the quality of the evidence.

Results: Forty-five studies were identified from the current literature. Twenty studies investigated the role of serum soluble mesothelin with majority suggesting that it has variable utility as a baseline test but when measured serially correlates with treatment response and prognosis. Several studies demonstrated that serum osteopontin correlated with survival at baseline. Other biomarkers have shown prognostic utility in individual studies but are yet to be reproduced in large cohort studies.

Conclusions: From the available literature no serum or pleural fluid biomarker was identified that could be recommended currently for routine clinical practice. However, a falling serum soluble mesothelin might correlate with treatment response and improved survival.
A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma. S.C. Kao, M.B. Kirschner, W.A. Cooper, et al. 2016;114(5):524-31. PubMed · Publisher · Free full text

Abstract

Background: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM).

Methods: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts.

Results: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC.

Conclusions: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.
Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53. W.B. Ou, M. Lu, G. Eilers, et al. 2016;115(10):1253-1263. PubMed · Publisher · Free full text

Abstract

Background: Improved mesothelioma patient survival will require development of novel and more effective pharmacological interventions. TP53 genomic mutations are uncommon in mesothelioma, and recent data indicate that p53 remains functional, and therefore is a potential therapeutic target in these cancers. In addition, the tumour suppressor NF2 is inactivated by genomic mechanisms in more than 80% of mesothelioma, causing upregulation of FAK activity. Because FAK is a negative regulator of p53, NF2 regulation of FAK-p53-MDM2 signalling loops were evaluated.

Methods: Interactions of FAK-p53 or NF2-FAK were evaluated by phosphotyrosine-p53 immunoaffinity purification and tandem mass spectrometry, and p53, FAK, and NF2 immunoprecipitations. Activation and/or expression of FAK, p53, and NF2 were also evaluated in mesotheliomas. Effects of combination MDM2 and FAK inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, expression of cell cycle checkpoints, and cell cycle alterations.

Results: We observed constitutive activation of FAK, a known negative regulator of p53, in each of 10 mesothelioma cell lines and each of nine mesothelioma surgical specimens, and FAK was associated with p53 in five of five mesothelioma cell lines. In four mesotheliomas with wild-type p53, FAK silencing by RNAi induced expression and phosphorylation of p53. However, FAK regulation of mesothelioma proliferation was not restricted to p53-dependent pathways, as demonstrated by immunoblots after FAK knockdown in JMN1B mesothelioma cells, which have mutant/inactivated p53, compared with four mesothelioma cell lines with nonmutant p53. Additive effects were obtained through a coordinated reactivation of p53, by FAK knockdown/inhibition and MDM2 inhibition, as demonstrated by immunoblots, cell viability, and cell-cycle analyses, showing increased p53 expression, apoptosis, anti-proliferative effects, and cell-cycle arrest, as compared with either intervention alone. Our results also indicate that NF2 regulates the interaction of FAK-p53 and MDM2-p53.

Conclusions: These findings highlight novel therapeutic opportunities in mesothelioma.
Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients. C.J. Jennings, B. Murer, A. O'Grady, et al. 2015;113(1):69-75. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence.

Methods: The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression.

Results: A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001).

Conclusions: Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention.
Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis. M.B. Kirschner, E. Pulford, M.A. Hoda, et al. 2015;113(6):963-9. PubMed · Publisher · Free full text

Abstract

Background: Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies.

Methods: ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan-Meier method, respectively.

Results: FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1-76.4) and 56% (95% CI: 41.5-71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14-45.93)).

Conclusions: These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients.
Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study. B. Ghanim, T. Klikovits, M.A. Hoda, et al. 2015;112(5):783-92. PubMed · Publisher · Free full text

Abstract

Background: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM.

Methods: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98).

Results: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048).

Conclusion: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.
MDM2 is an important prognostic and predictive factor for platin-pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53. R.F. Walter, F.D. Mairinger, S. Ting, et al. 2015;112(5):883-90. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed. Until now, predictive and prognostic biomarkers are lacking, making it a non-tailored therapy regimen with unknown outcome. P53 is frequently inactivated in MPM, but mutations are extremely rare. MDM2 and P14/ARF are upstream regulators of P53 that may contribute to P53 inactivation.

Methods: A total of 72 MPM patients were investigated. MDM2 immunoexpression was assessed in 65 patients. MDM2 and P14/ARF mRNA expression was analysed in 48 patients of the overall collective. The expression results were correlated to overall survival (OS) and progression-free survival (PFS).

Results: OS and PFS correlated highly significantly with MDM2 mRNA and protein expression, showing a dismal prognosis for patients with elevated MDM2 expression (for OS: Score (logrank) test: P⩽0.002, and for PFS: Score (logrank) test; P<0.007). MDM2 was identified as robust prognostic and predictive biomarker for MPM on the mRNA and protein level. P14/ARF mRNA expression reached no statistical significance, but Kaplan-Meier curves distinguished patients with low P14/ARF expression and hence shorter survival from patients with higher expression and prolonged survival.

Conclusions: MDM2 is a prognostic and predictive marker for a platin-pemetrexed therapy of patients with MPMs. Downregulation of P14/ARF expression seems to contribute to MDM2-overexpression-mediated P53 inactivation in MPM patients.
Stomach cancer and occupational exposure to asbestos: a meta-analysis of occupational cohort studies. L. Fortunato, L. Rushton. 2015;112(11):1805-15. Meta-analysis PubMed · Publisher · Free full text

Abstract

Background: A recent Monographs Working Group of the International Agency for Research on Cancer concluded that there is limited evidence for a causal association between exposure to asbestos and stomach cancer.

Methods: We performed a meta-analysis to quantitatively evaluate this association. Random effects models were used to summarise the relative risks across studies. Sources of heterogeneity were explored through subgroup analyses and meta-regression.

Results: We identified 40 mortality cohort studies from 37 separate papers, and cancer incidence data were extracted for 15 separate cohorts from 14 papers. The overall meta-SMR for stomach cancer for total cohort was 1.15 (95% confidence interval 1.03-1.27), with heterogeneous results across studies. Statistically significant excesses were observed in North America and Australia but not in Europe, and for generic asbestos workers and insulators. Meta-SMRs were larger for cohorts reporting a SMR for lung cancer above 2 and cohort sizes below 1000.

Conclusions: Our results support the conclusion by IARC that exposure to asbestos is associated with a moderate increased risk of stomach cancer.
The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial. D.T. Arnold, C.E. Hooper, A. Morley, et al. 2015;112(7):1183-9. PubMed · Publisher · Free full text

Abstract

Background: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice.

Method: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13.

Results: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks.

Conclusions: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.
The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication. C.E. Hooper, I.D. Lyburn, J. Searle, et al. 2015;112(7):1175-82. PubMed · Publisher · Free full text

Abstract

Background: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care.

Methods: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months.

Findings: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001).

Interpretation: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.
An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma. A. Linton, Y.Y. Cheng, K. Griggs, et al. 2014;110(2):510-9. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumour originating in the thoracic mesothelium. Prognosis remains poor with 9- to 12-month median survival, and new targets for treatments are desperately needed.

Methods: Utilising an RNA interference (RNAi)-based screen of 40 genes overexpressed in tumours, including genes involved in the control of cell cycle, DNA replication and repair, we investigated potential therapeutic targets for MPM. Following in vitro characterisation of the effects of target silencing on MPM cells, candidates were assessed in tumour samples from 154 patients.

Results: Gene knockdown in MPM cell lines identified growth inhibition following knockdown of NDC80, CDK1 and PLK1. Target knockdown induced cell-cycle arrest and increased apoptosis. Using small-molecule inhibitors specific for these three proteins also led to growth inhibition of MPM cell lines, and Roscovitine (inhibitor of CDK1) sensitised cells to cisplatin. Protein expression was also measured in tumour samples, with markedly variable levels of CDK1 and PLK1 noted. PLK1 expression in over 10% of cells correlated significantly with a poor prognosis.

Conclusion: These results suggest that RNAi-based screening has utility in identifying new targets for MPM, and that inhibition of NDC80, CDK1 and PLK1 may hold promise for treatment of this disease.
Assessing the function of homologous recombination DNA repair in malignant pleural effusion (MPE) samples. M.J. Patterson, R.E. Sutton, I. Forrest, et al. 2014;111(1):94-100. PubMed · Publisher · Free full text

Abstract

Background: Patients with malignant pleural effusions (MPEs) generally have advanced disease with poor survival and few therapeutic options. Cells within MPEs may be used to stratify patients for targeted therapy. Targeted therapy with poly(ADP ribose) polymerase inhibitors (PARPi) depends on identifying homologous recombination DNA repair (HRR)-defective cancer cells. We aimed to determine the feasibility of assaying HRR status in MPE cells.

Methods: A total of 15 MPE samples were collected from consenting patients with non-small-cell lung cancer (NSCLC), mesothelioma and ovarian and breast cancer. Primary cultures were confirmed as epithelial by pancytokeratin, and HRR status was determined by the detection of γH2AX and RAD51 foci following a 24-h exposure to rucaparib, by immunofluorescence microscopy. Massively parallel next-generation sequencing of DNA repair genes was performed on cultured MPE cells.

Results: From 15 MPE samples, 13 cultures were successfully established, with HRR function successfully determined in 12 cultures. Four samples - three NSCLC and one mesothelioma - were HRR defective and eight samples - one NSCLC, one mesothelioma, one sarcomatoid, one breast and four ovarian cancers - were HRR functional. No mutations in DNA repair genes were associated with HRR status, but there was probable loss of heterozygosity of FANCG, RPA1 and PARP1.

Conclusions: HRR function can be successfully detected in MPE cells demonstrating the potential to stratify patients for targeted therapy with PARPi.
CD74: a new prognostic factor for patients with malignant pleural mesothelioma. C. Otterstrom, A. Soltermann, I. Opitz, et al. 2014;110(8):2040-6. PubMed · Publisher · Free full text

Abstract

Background: The pro-inflammatory cytokine migration inhibitory factor (MIF) and its receptor CD74 have been proposed as possible therapeutic targets in several cancers. We studied the expression of MIF and CD74 together with calretinin in specimens of malignant pleural mesothelioma (MPM), correlating their expression levels with clinico-pathologic parameters, in particular overall survival (OS).

Methods: Migration inhibitory factor, CD74, and calretinin immunoreactivity were investigated in a tissue microarray of 352 patients diagnosed with MPM. Protein expression intensities were semiquantitatively scored in the tumour cells and in the peritumoral stroma. Markers were matched with OS, age, gender, and histological subtype.

Results: Clinical data from 135 patients were available. Tumour cell expressions of MIF and CD74 were observed in 95% and 98% of MPM specimens, respectively, with a homogenous distribution between the different histotypes. CD74 (P<0.001) but not MIF overexpression (P=0.231) emerged as an independent prognostic factor for prolonged OS. High expression of tumour cell calretinin correlated with the epithelioid histotype and was also predictive of longer OS (P<0.001). When compared with previously characterised putative epithelial-to-mesenchymal transition markers, CD74 correlated positively with tumoral PTEN and podoplanin expressions, but was inversely related with periostin expression.

Conclusions: High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.
Circulating fibrinogen is a prognostic and predictive biomarker in malignant pleural mesothelioma. B. Ghanim, M.A. Hoda, T. Klikovits, et al. 2014;110(4):984-90. PubMed · Publisher · Free full text

Abstract

Background: To investigate the clinical utility of pretreatment plasma fibrinogen levels in malignant pleural mesothelioma (MPM) patients.

Methods: A retrospective multicenter study was performed in histologically proven MPM patients. All fibrinogen levels were measured at the time of diagnosis and clinical data were retrospectively collected after approval of the corresponding ethics committees.

Results: In total, 176 MPM patients (mean age: 63.5 years ± 10.4 years, 38 females and 138 males) were analysed. Most patients (n=154, 87.5%) had elevated (≥ 390 mg dl(-1)) plasma fibrinogen levels. When patients were grouped by median fibrinogen, patients with low level (≤ 627 mg dl(-1)) had significantly longer overall survival (OS) (19.1 months, confidence interval (CI) 14.5-23.7 months) when compared with those with high level (OS 8.5; CI 6.2-10.7 months). In multivariate survival analyses, fibrinogen was found to be an independent prognostic factor (hazard ratio 1.81, CI 1.23-2.65). Most interestingly, fibrinogen (cutoff 75th percentile per 750 mg dl(-1)) proved to be a predictive biomarker indicating treatment benefit achieved by surgery within multimodality therapy (interaction term: P=0.034). Accordingly, only patients below the 75th percentile benefit from surgery within multimodality therapy (31.3 vs 5.3 months OS).

Conclusions: Fibrinogen is a novel independent prognostic biomarker in MPM. Most importantly, fibrinogen predicted treatment benefit achieved by surgery within multimodality therapy.
Comment on 'Existing prognostic models, but not neutrophil-to-lymphocyte ratio, are prognostic in malignant mesothelioma'. S.C. Kao, N. van Zandwijk, S. Clarke. 2014;111(12):2376. Letter · Comment PubMed · Publisher · Free full text
Comment on 'The latency period of mesothelioma among a cohort of British asbestos workers (1978-2005)'. D. Mirabelli, D. Zugna. 2014;111(8):1675. Letter · Comment PubMed · Publisher · Free full text

Summary

In this letter, the authors commented on a 2013 paper by Frost. That paper analysed mesothelioma mortality among members of the Great Britain Asbestos Survey (GBAS) using accelerated failure time models and concluded that there was not sufficient evidence that greater intensity of asbestos exposure led to shorter latency. The authors were concerned that the analysis may have been inappropriate and its conclusions unwarranted. Citing Frost's data, they noted that of 94,960 workers entering GBAS between 1978 and 2005, 614 died from mesothelioma and 14,009 from other causes. About 85% were alive at follow-up, and mesothelioma decedents contributed only 9280 of more than 1.6 million person-years. They argued that restricting the analysis to workers who died with mesothelioma, in a setting with substantial censoring and competing mortality, would bias estimates of the cause-specific hazard and cumulative incidence. Drawing on a 1965 paper by Pike and Doll on smoking and age at onset of lung cancer, they also argued that differences in latency between exposure groups would depend largely on historical factors rather than on any biological property of the exposure. They pointed to the fixed observation period, left truncation, and the distinct secular trends of the two main comparison groups, asbestos insulators and asbestos removers. They concluded that the analysis did not find consistent deviations of time ratios from unity because there was no chance for such deviations to occur consistently in the GBAS setting.

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Comment on 'The latency period of mesothelioma among a cohort of British asbestos workers (1978-2005)': methodological problems with case-only survival analysis. D. Consonni, F. Barone-Adesi, C. Mensi. 2014;111(8):1674. Letter · Comment PubMed · Publisher · Free full text

Summary

This letter commented on a 2013 article by Frost on mesothelioma latency in the GB Asbestos Survey, a prospective cohort of asbestos workers set up in 1971. Frost defined latency as the time from first occupational exposure to asbestos to death from mesothelioma, studied mesothelioma deaths in 1978–2005, and concluded that there was not sufficient evidence of an inverse relationship between exposure intensity and latency length. The letter's authors argued that the analysis was methodologically flawed. The cohort had 94 960 subjects, but only the 614 mesothelioma deaths were analysed. They explained that when follow-up ends before everyone has the outcome (censoring), the survival times of cases do not represent the whole cohort. They gave a fictitious trial of 40 subjects as an example. With complete follow-up, mean survival was 43 and 24 months and median survival was 33 and 15 months. When follow-up ended at 48 months, the means became 18 and 16 months and the medians 10 and 13 months, which made the groups look more similar than they were. They stated that a regression model would not solve this, and that more than 99% of mesothelioma survival times in Frost's study were not directly observable. They noted that the same problem had affected studies of mesothelioma registry case series. They concluded that Frost's results were not interpretable. They said latency should be analysed using all cohort members, treating those not dying of mesothelioma as censored.

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Comment on 'The latency period of mesothelioma among a cohort of British asbestos workers (1978-2005)': the effect of left censoring. A. Farioli, S. Mattioli, S. Curti, et al. 2014;111(11):2197-8. Comment PubMed · Publisher · Free full text

Summary

This letter to the editor responded to Frost's 2013 study of mesothelioma latency among a cohort of British asbestos workers, which used a follow-up window of 1978–2005. Frost had reported a median latency of 48 years for deaths among workers first exposed before 1940 and 11 years for those first exposed from 1980 onwards. The authors argued that this pattern could reflect left censoring, because deaths before 1978 were excluded, and right censoring, because deaths after 2005 were not observed. To show the possible effect, they ran a simulation. It assumed a true latency that was the same for every period of first exposure, following a gamma distribution with a median of 32 years. The simulation used six first-exposure categories with 300 mesothelioma deaths each. With complete follow-up, time ratios ranged from 0.97 to 1.02. With left and right censoring applied, median latency fell from 47.8 to 18.8 years and time ratios fell from 1.00 to 0.37, a spurious association. Results from 10,000 repetitions were reported as highly consistent. The authors suggested that this bias could also affect Frost's estimates for duration of exposure and occupation. They asked for a reanalysis restricted to cases first exposed in 1950–1969, using the full 1972–2005 follow-up and without adjusting for year of first exposure.

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Factors associated with survival in a large series of patients with malignant pleural mesothelioma in New South Wales. A. Linton, N. Pavlakis, R. O'Connell, et al. 2014;111(9):1860-9. PubMed · Publisher · Free full text

Abstract

Background: Although the prognosis of most patients presenting with malignant pleural mesothelioma (MPM) is poor, a small proportion survives long term. We investigated factors associated with survival in a large patient series.

Methods: All patients registered with the NSW Dust Diseases Board (2002-2009) were included in an analysis of prognostic factors using Kaplan-Meier and Cox regression analysis. On the basis of these analyses, we developed a risk score (Prognostic Index (PI)).

Results: We identified 910 patients: 90% male; histology (epithelioid 60%; biphasic 13%; sarcomatoid 17%); stage (Tx-I-II 48%; III-IV 52%); and calretinin expression (91%).

Treatment: chemotherapy(CT) 44%, and extrapleural-pneumonectomy (EPP) 6%. Median overall survival (OS) was 10.0 months. Longer OS was associated with: age <70 (13.5 vs 8.5 months; P<0.001); female gender (12.0 vs 9.9 months; P<0.001); epithelioid subtype (13.3 vs 6.2 months; P<0.001); ECOG status 0 (27.4 vs 9.7 months; P=0.015), calretinin expression (10.9 vs 5.5 months; P<0.001); neutrophil-lymphocyte ratio (NLR) <5 (11.9 vs 7.5 months; P<0.001); platelet count <400 (11.5 vs 7.2 months; P<0.001); and normal haemoglobin (16.4 vs 8.8 months; P<0.001). On time-dependent analysis, patients receiving pemetrexed-based chemotherapy (HR=0.83; P=0.048) or EPP (HR=0.41; P<0.001) had improved survival. Age, gender, histology, calretinin and haematological factors remained significant on multivariate analysis. In all, 24% of patients survived >20 months: 16% of these receiving EPP, and 66% CT. The PI offered improved prognostic discrimination over one of the existing prognostic models (EORTC).

Conclusions: We identified calretinin expression, age, gender, histological subtype, platelet count and haemoglobin level as independent prognostic factors. Patients undergoing EPP or pemetrexed-based chemotherapy demonstrated better survival, but 84% and 34% of long survivors, respectively, did not receive radical surgery or chemotherapy.
Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. S. Zhou, L. Liu, H. Li, et al. 2014;110(10):2479-88. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis.

Methods: Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations.

Results: We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation.

Conclusions: These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.
Prognostic factors in elderly patients with malignant pleural mesothelioma: results of a multicenter survey. G.L. Ceresoli, F. Grosso, P.A. Zucali, et al. 2014;111(2):220-6. PubMed · Publisher · Free full text

Abstract

Background: The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. There are no specific guidelines for their management.

Methods: The clinical records of elderly patients (⩾70 years old) with MPM referred from January 2005 to November 2011 to six Italian Centres were reviewed. Age, gender, histology, International Mesothelioma Interest Group (IMIG) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were analysed and correlated to overall survival (OS).

Results: In total, 241 patients were identified. Charlson Comorbidity Index was ⩾1 in 92 patients (38%). Treatment was multimodality therapy including surgery in 18, chemotherapy alone in 180 (75%) and best supportive care in 43 cases (18%). Chemotherapy was mainly pemetrexed based. Median OS was 11.4 months. Non-epithelioid histology (HR 2.32; 95% CI 1.66-3.23, P<0.001), age ⩾75 years (HR 1.44; 95% CI 1.08-1.93, P=0.014), advanced (III-IV) stage (HR 1.47; 95% CI 1.09-1.98, P=0.011) and CCI⩾1 (HR 1.38; 95% CI 1.02-1.85, P=0.034) were associated to a shorter OS. Treatment with pemetrexed was associated with improved OS (HR 0.40; 95% CI 0.28-0.56, P<0.001).

Conclusions: Non-epithelioid histology, age ⩾75 years, advanced IMIG stage and presence of comorbidities according to CCI were significant prognostic factors in elderly patients with MPM. Treatment with pemetrexed-based chemotherapy was feasible in this setting. Prospective dedicated trials in MPM elderly patients selected according to prognostic factors including comorbidity scales are warranted.
Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma. J. Yamamoto, K. Ohnuma, R. Hatano, et al. 2014;110(9):2232-45. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo.

Methods: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression.

Results: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens.

Conclusions: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.
Response to comment on 'Existing prognostic models, but not neutrophil-to-lymphocyte ratio, are prognostic in malignant mesothelioma'. T.M. Meniawy, J. Creaney, R.A. Lake, et al. 2014;111(12):2377. Letter · Comment PubMed · Publisher · Free full text
Response to comment on 'The latency period of mesothelioma among a cohort of British asbestos workers (1978-2005)'. G. Frost. 2014;111(11):2198-9. Comment PubMed · Publisher · Free full text
Comment on 'estimating the asbestos-related lung cancer burden from mesothelioma mortality' - IARC and chrysotile risks. R.A. Lemen, A.L. Frank, C.L. Soskolne, et al. 2013;109(3):823-5. Letter · Comment PubMed · Publisher · Free full text

Summary

In this letter, five authors responded to a 2012 British Journal of Cancer article by McCormack et al. that estimated the asbestos-related lung cancer burden from mesothelioma mortality. They argued that the article's estimates and conclusions were erroneous because it omitted newer data, relied on incomplete or outdated data, omitted critiques of data it used, and drew conclusions from heterogeneous data sets not adequately controlled for latency or exposure. On chrysotile, they stated that the article cited a 1990 study of the Balangero, Italy, mining cohort, which reported two mesothelioma cases in miners. It did not cite a 2008 update that found 27 mesothelioma cases associated with the site, including white-collar and environmental cases. They also stated that the article relied on a 1987 IARC evaluation rather than the 2012 IARC monograph, and on Hodgson and Darnton's 2000 potency estimates rather than their later revised estimates. They disputed the conclusion that mesotheliomas in chrysotile-exposed cohorts were due to other asbestos types. In support they cited animal studies, findings of chrysotile in the pleura, and a 1984 Ontario Royal Commission report. They also noted published criticisms of industry-sponsored Quebec research. They concluded that the article minimised chrysotile's risks and that its suggestion of 'strict regulation' conflicted with the World Health Organization's recommendation to stop all asbestos use. They also called its recommendation of smoking cessation only for formerly exposed workers inconsistent.

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Existing models, but not neutrophil-to-lymphocyte ratio, are prognostic in malignant mesothelioma. T.M. Meniawy, J. Creaney, R.A. Lake, et al. 2013;109(7):1813-20. PubMed · Publisher · Free full text

Abstract

Background: Recent studies proposed neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker in malignant pleural mesothelioma (MPM). We examined baseline prognostic variables including NLR and the EORTC and CALGB models as predictors of overall survival (OS) in MPM.

Methods: In this retrospective study, 274 consecutive eligible, newly presenting patients with MPM were included. Of these, 159 received chemotherapy, 10 had tri-modality therapy, 2 underwent surgery only and 103 received supportive care alone. Univariate analyses and multivariate Cox models were calculated for OS.

Results: In univariate analysis, poor prognostic factors were: age ≥65 years, nonepithelioid histology, stage III-IV, poor performance status (PS), weight loss, chest pain, low haemoglobin and high platelet count. A baseline NLR≥ 5 did not predict worse OS (hazard ratio (HR) 1.25; P=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain and platelet count remained significant. The EORTC and CALGB prognostic groups were validated as predictive for OS (HR 1.62; P<0.001 and HR 1.65; P<0.001, respectively).

Conclusion: Our findings validate standard prognostic variables and the existing EORTC and CALGB models, but not NLR, at initial diagnosis of MPM. In guiding patient management at diagnosis, it is important to consider multiple baseline variables that jointly predict survival.
Mutation analysis of the EGFR gene and downstream signalling pathway in histologic samples of malignant pleural mesothelioma. R. Mezzapelle, U. Miglio, O. Rena, et al. 2013;108(8):1743-9. PubMed · Publisher · Free full text

Abstract

Background: As epidermal growth factor receptor (EGFR) is involved in the pathogenesis of malignant pleural mesotheliomas (MPMs), the anti-EGFR drugs may be effective in treating MPM patients. Mutations of the EGFR gene or its downstream effectors may cause constitutive activation leading to cell proliferation, and the inhibition of apoptosis and metastases. Consequently, molecular profiling is essential for select patients with MPM who may respond to anti-EGFR therapies.

Methods: After manual macrodissection, genomic DNA was extracted from 77 histological samples of MPM: 59 epithelioid, 10 biphasic, and 8 sarcomatoid. Epidermal growth factor receptor gene mutations were sought by means of real-time polymerase chain reaction (PCR) and direct sequencing, KRAS gene mutations by mutant-enriched PCR, and PIK3CA and BRAF gene mutations by direct sequencing.

Results: Gene mutations were identified in nine cases (12%): five KRAS, three BRAF, and one PI3KCA mutation; no EGFR gene mutations were detected. There was no difference in disease-specific survival between the patients with or without gene mutations (P=0.552).

Conclusions: Mutations in EGFR downstream pathways are not rare in MPM. Although none of those found in this study seemed to be prognostically significant, they may support a more specific selection of patients for future trials.
Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. G.L. Ceresoli, P.A. Zucali, M. Mencoboni, et al. 2013;109(3):552-8. PubMed · Publisher · Free full text

Abstract

Background: The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).

Methods: Eligible patients received pemetrexed 500 mg m(-2), carboplatin area under the plasma concentration-time curve (AUC) 5 mg ml(-1) per minute and bevacizumab 15 mg kg(-1), administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.

Results: Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7-46.0%). Forty-four (57.9%, 95% CI 46.0-69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3-4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.

Conclusion: The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.
Reply: comment on 'estimating the asbestos-related lung cancer burden from mesothelioma mortality'. V. McCormack, J. Peto, G. Byrnes, et al. 2013;109(3):825-6. Letter · Comment PubMed · Publisher · Free full text
The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma. L.E. Dalton, H.J. Clarke, J. Knight, et al. 2013;108(6):1340-7. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer.

Method: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters.

Results: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas.

Conclusion: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology.
The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma. D.J. Pinato, F.A. Mauri, T. Lloyd, et al. 2013;108(3):621-8. PubMed · Publisher · Free full text

Abstract

Background: Recent preclinical studies identified Axl, a tyrosine kinase receptor implicated in tumour progression and epithelial-to-mesenchymal transition, as a putative therapeutic target in malignant pleural mesothelioma (MPM), an invariably fatal malignancy with limited treatment options. Here, we studied the expression of Axl and its ligand Gas-6 (growth arrest signal-6) in primary specimens of MPM, correlating their expression levels with tumour phenotype and clinical outcomes.

Methods: Two independent cohorts of consecutive patients diagnosed with MPM were studied: a derivation cohort composed of 63 cases and a validation set of 35 cases. Clinical variables including patients' demographics, tumour stage, histotype, performance status (PS), Axl and Gas-6 staining were tested for predicting overall survival (OS) using univariate and multivariate analyses.

Results: In the derivation cohort, Axl (P=0.001) but not Gas-6 overexpression (P=0.35) emerged as a univariate prognostic factor for OS, together with stage (P=0.05), PS (P<0.001) hypoalbuminaemia (P<0.001) and anaemia (P<0.001). Multivariate analyses confirmed Axl overexpression (P=0.01), PS (P=0.01), hypoalbuminaemia (P<0.001) and anaemia (P=0.04) as independent predictors of OS. The prognostic role of Axl overexpression was externally validated in an independent cohort (P=0.03).

Conclusion: Overexpression of Axl is found in the majority of MPM specimens and influences patient's survival independently from other established prognostic factors. Such information may support patient selection for future trials.
The latency period of mesothelioma among a cohort of British asbestos workers (1978-2005). G. Frost. 2013;109(7):1965-73. PubMed · Publisher · Free full text

Abstract

Background: The Great Britain (GB) Asbestos Survey is a prospective cohort of asbestos workers in GB. The objective of this study was to investigate determinants of mesothelioma latency, paying particular attention to indicators of intensity of asbestos exposure such as occupation, sex, and presence of asbestosis.

Methods: The analysis included members of the cohort who died with mesothelioma between 1978 and 2005. The primary outcome was the latency period defined as the time from first occupational exposure to asbestos to death with mesothelioma. Generalised gamma accelerated failure-time models were used to estimate time ratios (TRs).

Results: After excluding missing data, there were 614 workers who died with mesothelioma between 1978 and 2005. Total follow-up time was 9280 person-years, with a median latency of 22.8 years (95% confidence interval (CI) 16.0-27.2 years). In the fully adjusted model, latency was around 29% longer for females compared with males (TR=1.29, 95% CI=1.18-1.42), and 5% shorter for those who died with asbestosis compared with those who did not (TR=0.95, 95% CI=0.91-0.99). There was no evidence of an association between latency and occupation.

Conclusion: This study did not find sufficient evidence that greater intensity asbestos exposures would lead to shorter mesothelioma latencies.
Estimating the asbestos-related lung cancer burden from mesothelioma mortality. V. McCormack, J. Peto, G. Byrnes, et al. 2012;106(3):575-84. PubMed · Publisher · Free full text

Abstract

Background: Quantifying the asbestos-related lung cancer burden is difficult in the presence of this disease's multiple causes. We explore two methods to estimate this burden using mesothelioma deaths as a proxy for asbestos exposure.

Methods: From the follow-up of 55 asbestos cohorts, we estimated ratios of (i) absolute number of asbestos-related lung cancers to mesothelioma deaths; (ii) excess lung cancer relative risk (%) to mesothelioma mortality per 1000 non-asbestos-related deaths.

Results: Ratios varied by asbestos type; there were a mean 0.7 (95% confidence interval 0.5, 1.0) asbestos-related lung cancers per mesothelioma death in crocidolite cohorts (n=6 estimates), 6.1 (3.6, 10.5) in chrysotile (n=16), 4.0 (2.8, 5.9) in amosite (n=4) and 1.9 (1.4, 2.6) in mixed asbestos fibre cohorts (n=31). In a population with 2 mesothelioma deaths per 1000 deaths at ages 40-84 years (e.g., US men), the estimated lung cancer population attributable fraction due to mixed asbestos was estimated to be 4.0%.

Conclusion: All types of asbestos fibres kill at least twice as many people through lung cancer than through mesothelioma, except for crocidolite. For chrysotile, widely consumed today, asbestos-related lung cancers cannot be robustly estimated from few mesothelioma deaths and the latter cannot be used to infer no excess risk of lung or other cancers.
First-line chemotherapy with liposomal doxorubicin plus cisplatin for patients with advanced malignant pleural mesothelioma: phase II trial. Ó. Arrieta, L.A. Medina, E. Estrada-Lobato, et al. 2012;106(6):1027-32. PubMed · Publisher · Free full text

Abstract

Background: Chemotherapy based on platinum is the standard treatment for unresectable malignant pleural mesothelioma (MPM). Liposomal doxorubicin (LD) consists of pegylated phospholipid vesicles that encapsulate doxorubicin-enhancing liposome deposition in the tumour. We evaluated the toxicity profile and anti-tumour activity of cisplatin plus LD in untreated patients with MPM, as well as (99m)Tc-LD distribution in MPM lesions after chemotherapy administration.

Methods: A total of 38 patients with non-resectable MPM received LD 40 mg m(-2) and cisplatin 60 mg m(-2) every 21 days. Gamma camera images of (99m)Tc-LD were acquired to evaluate LD accumulation in measurable tumour tissue. The study was registered in Clinical Trials (NCT00886028).

Results: In all, 72% of patients were stage III and 28% were stage IV. Eighty four percent and 16% have high and low risk acording EORTC respectively. The median time to progression was 4.6 months (95% confidence interval (95% CI: 3.4-5.9 months), and median overall survival (OS) was 19.6 months (15.2-37.2 months). Patients that responded to chemotherapy treatment had better survival than patients who did not. Functional physical scales, dysnea, cough, and chest/arm pain demonstrated improvement. The accumulation ratio of LD in tumour and soft tissues vs liver was 0.78±0.16 and 0.29±0.09, respectively. After 1 h of administration, LD uptake in tumour tissue was higher than in soft tissue (P< 0.001).

Conclusion: The combination of LD and cisplatin results in an active therapeutic regimen for unresectable MPM, with an acceptable toxicity profile and improvement in quality of life. (99m)Tc-LD showed higher levels of tumour uptake as compared with surrounding tissues.
Ionising radiation and occupational cancer in Britain. C.R. Muirhead, R. Haylock. 2012;107(9):1660-1; author reply 1662. Letter · Comment PubMed · Publisher · Free full text
Malignant mesotheliomas in former miners and millers of crocidolite at Wittenoom (Western Australia) after more than 50 years follow-up. G. Berry, A. Reid, P. Aboagye-Sarfo, et al. 2012;106(5):1016-20. PubMed · Publisher · Free full text

Abstract

Background: To report the number of malignant pleural and peritoneal mesotheliomas that have occurred in former Wittenoom crocidolite workers to the end of 2008, to compare this with earlier predictions, and to relate the mesothelioma rate to amount of exposure.

Methods: A group of 6489 men and 419 women who had worked for the company operating the former Wittenoom crocidolite mine and mill at some time between 1943 and 1966 have been followed up throughout Australia and Italy to the end of 2008.

Results: The cumulative number of mesotheliomas up to 2008 was 316 in men (268 pleural, 48 peritoneal) and 13 (all pleural) in women. There had been 302 deaths with mesothelioma in men and 13 in women, which was almost 10% of all known deaths. Mesothelioma rate, both pleural and peritoneal, increased with time since first exposure and appeared to reach a plateau after about 40 to 50 years. The mesothelioma rate increased with amount of exposure and the peritoneal mesotheliomas occurred preferentially in the highest exposure group, 37% compared with 15% overall.

Conclusion: By the end of 2008, the number of mesothelioma deaths had reached 4.7% for all the male workers and 3.1% for the females. Over the past 8 years the numbers were higher than expected. It is predicted that about another 60 to 70 deaths with mesothelioma may occur in men by 2020.
Occupational cancer burden in Great Britain. L. Rushton, S.J. Hutchings, L. Fortunato, et al. 2012;107 Suppl 1(Suppl 1):S3-7. PubMed · Publisher · Free full text

Abstract

A sound knowledge base is required to target resources to reduce workplace exposure to carcinogens. This project aimed to provide an objective estimate of the burden of cancer in Britain due to occupation. This volume presents extensive analyses for all carcinogens and occupational circumstances defined as definite or probable human occupational carcinogens by the International Agency for Research on Cancer. This article outlines the structure of the supplement - two methodological papers (statistical approach and exposure assessment), eight papers presenting the cancer-specific results grouped by broad anatomical site, a paper giving industry sector results and one discussing work-related cancer-prevention strategies. A brief summary of the methods and an overview of the updated overall results are given in this introductory paper. A general discussion of the overall strengths and limitations of the study is also presented. Overall, 8010 (5.3%) total cancer deaths in Britain and 13,598 cancer registrations were attributable to occupation in 2005 and 2004, respectively. The importance of cancer sites such as mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma and stomach cancers are highlighted, as are carcinogens such as asbestos, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists, as well as occupational circumstances such as shift work and occupation as a painter or welder. The methods developed for this project are being adapted by other countries and extended to include social and economic impact evaluation.
Occupational cancer in Britain. Respiratory cancer sites: larynx, lung and mesothelioma. T. Brown, A. Darnton, L. Fortunato, et al. 2012;107 Suppl 1(Suppl 1):S56-70. PubMed · Publisher · Free full text
Occupational risk factors have to be considered in the definition of high-risk lung cancer populations. P. Wild, M. Gonzalez, E. Bourgkard, et al. 2012;106(7):1346-52. PubMed · Publisher · Free full text

Abstract

Background: The aim of this study was to compute attributable fractions (AF) to occupational factors in an area in North-Eastern France with high lung cancer rates and a past of mining and steel industry.

Methods: A population-based case-control study among males aged 40-79 was conducted, including confirmed primary lung cancer cases from all hospitals of the study region. Controls were stratified by broad age-classes, district and socioeconomic classes. Detailed occupational and personal risk factors were obtained in face-to-face interviews. Cumulative occupational exposure indices were obtained from the questionnaires. Attributable fractions were computed from multiple unconditional logistic regression models.

Results: A total of 246 cases and 531 controls were included. The odds ratios (ORs) adjusted on cumulative smoking and family history of lung cancer increased significantly with the cumulative exposure indices to asbestos, polycyclic aromatic hydrocarbons and crystalline silica, and with exposure to diesel motor exhaust. The AF for occupational factors exceeded 50%, the most important contributor being crystalline silica and asbestos.

Conclusion: These AFs are higher than most published figures. This can be because of the highly industrialised area or methods for exposure assessments. Occupational factors are important risk factors and should not be forgotten when defining high-risk lung cancer populations.
Post-chemotherapy T-cell recovery is a marker of improved survival in patients with advanced thoracic malignancies. M.J. McCoy, R.A. Lake, R.G. van der Most, et al. 2012;107(7):1107-15. PubMed · Publisher · Free full text

Abstract

Background: There is increasing interest in combining chemotherapy with immunotherapy. However, the effects of chemotherapy on the human immune system are largely unknown.

Methods: Longitudinal changes in peripheral T-cell subsets in 40 patients with malignant mesothelioma (MM) or advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy were assessed by flow cytometry and evaluated for associations with clinical outcome.

Results: Proliferating T cells of all subsets were almost entirely depleted at day 8 following chemotherapy, but rapidly recovered above baseline levels. Regulatory T cells (Treg) were most profoundly depleted at this time point. A greater increase in CD8(+) T-cell proliferation following one treatment cycle was associated with improved overall survival in univariate (hazard ratio (HR)=0.40; P<0.05) and multivariate (HR=0.17; P<0.01) analyses. A greater increase in the ratio of CD8(+) T cell to Treg proliferation was also predictive of better prognosis.

Conclusion: Chemotherapy potentially provides a favourable environment for the development of anti-tumour immunity through transient Treg depletion and regeneration of the T-cell pool. Change in CD8(+) T-cell proliferation after one cycle of chemotherapy may represent a useful prognostic indicator in patients with MM and NSCLC.
Prognosis and prognostic factors of patients with mesothelioma: a population-based study. S. van der Bij, H. Koffijberg, J.A. Burgers, et al. 2012;107(1):161-4. PubMed · Publisher · Free full text

Abstract

Background: It is important to regularly update survival estimates of patients with malignant mesothelioma as prognosis may vary according to epidemiologic factors and diagnostic and therapeutic management.

Methods: We assessed overall (baseline) survival as well as related prognostic variables in a large cohort of 1353 patients with a confirmed diagnosis of malignant mesothelioma between 2005 and 2008.

Results: About 50% of the patients were 70 years or older at diagnosis and the median latency time since start of asbestos exposure was 49 years. One year after diagnosis, 47% of the patients were alive, 20% after 2 years and 15% after 3 years. Prognostic variables independently associated with worse survival were: older age (HR=1.04 per year 95% CI (1.03-1.06)), sarcomatoid subtype (HR=2.45 95% CI (2.06-2.90)) and non-pleural localisation (HR=1.67 95% CI (1.26-2.22)).

Conclusion: Survival of patients with malignant mesothelioma is still limited and depends highly on patient age, mesothelioma subtype and localisation. In addition, a substantial part of the patients had a long latency time between asbestos exposure and diagnosis.
Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells. M.A. Hoda, J. Münzker, B. Ghanim, et al. 2012;107(12):1978-86. PubMed · Publisher · Free full text

Abstract

Background: Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM).

Methods: The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed.

Results: Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression.

Conclusion: Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.
Markers for the non-invasive diagnosis of mesothelioma: a systematic review. S. van der Bij, E. Schaake, H. Koffijberg, et al. 2011;104(8):1325-33. Systematic review PubMed · Publisher · Free full text

Abstract

Background: Numerous markers have been evaluated to facilitate the non-invasive diagnostic work-up of mesothelioma. The purpose of this study was to conduct a structured review of the diagnostic performance of non-invasive marker tests for the detection of mesothelioma in patients with suspected mesothelioma.

Methods: Studies on the diagnostic accuracy of serum and cytological markers published till 31 December 2009, available in either PUBMED or Embase, to detect or exclude the presence of mesothelioma were extracted. Study quality was assessed with use of the Quadas criteria.

Results: In total, 82 articles were included in this systemic review. Overall, quality of the incorporated studies to address our objective was poor. The most frequently studied immunohistochemical markers for cytological analysis were EMA, Ber-Ep4, CEA, and calretinin. The most frequently investigated serum marker was soluble mesothelin-related protein (SMRP). The markers CEA, Ber-EP4, and calretinin were most valuable in discriminating mesothelioma from other malignant diseases. Markers EMA and SMRP were most valuable in discriminating mesothelioma from non-malignant diseases. No marker performed well in discriminating between mesothelioma and all other diseases.

Conclusion: Currently, there is only limited evidence to properly assess the value of non-invasive marker tests in the diagnosis of mesothelioma. Studies were of limited value to address our objective and results showed considerable unexplained study heterogeneity.
Occupational exposure to dusts and risk of renal cell carcinoma. S. Karami, P. Boffetta, P.S. Stewart, et al. 2011;104(11):1797-803. PubMed · Publisher · Free full text

Abstract

Background: Occupational exposures to dusts have generally been examined in relation to cancers of the respiratory system and have rarely been examined in relation to other cancers, such as renal cell carcinoma (RCC). Although previous epidemiological studies, though few, have shown certain dusts, such as asbestos, to increase renal cancer risk, the potential for other occupational dust exposures to cause kidney damage and/or cancer may exist. We investigated whether asbestos, as well as 20 other occupational dust exposures, were associated with RCC risk in a large European, multi-center, hospital-based renal case-control study.

Methods: General occupational histories and job-specific questionnaires were reviewed by occupational hygienists for subject-specific information. Odds ratios (ORs) and 95% confidence intervals (95% CIs) between RCC risk and exposures were calculated using unconditional logistic regression.

Results: Among participants ever exposed to dusts, significant associations were observed for glass fibres (OR: 2.1; 95% CI: 1.1-3.9), mineral wool fibres (OR: 2.5; 95% CI: 1.2-5.1), and brick dust (OR: 1.5; 95% CI: 1.0-2.4). Significant trends were also observed with exposure duration and cumulative exposure. No association between RCC risk and asbestos exposure was observed.

Conclusion: Results suggest that increased RCC risk may be associated with occupational exposure to specific types of dusts. Additional studies are needed to replicate and extend findings.
Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin. E. Giovannetti, P.A. Zucali, Y.G. Assaraf, et al. 2011;105(10):1542-53. PubMed · Publisher · Free full text

Abstract

Background: Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin-pemetrexed in human MPM cell lines.

Methods: We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation.

Results: Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib-pemetrexed-carboplatin combination.

Conclusion: Vandetanib markedly enhances pemetrexed-carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation.

2011 Cancer Research UK
Cisplatin-induced expression of Gb3 enables verotoxin-1 treatment of cisplatin resistance in malignant pleural mesothelioma cells. D. Johansson, C. Andersson, J. Moharer, et al. 2010;102(2):383-91. PubMed · Publisher · Free full text

Abstract

Background: A major problem with cisplatin treatment is the development of acquired-drug resistance of the tumour cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the membrane glycolipid globotriasosylceramide (Gb3), a molecule associated with drug resistance. Cisplatin- and VT-1-induced apoptosis involves mitogen-activated protein kinase (MAPK) activation, and deactivation of MAPKs is associated with cisplatin resistance. This study aimed to investigate whether a sub-toxic concentration of VT-1 could enhance cisplatin-induced apoptosis and overcome acquired-cisplatin resistance in cultured cancer cell lines.

Method: P31 and H1299 cells with corresponding cisplatin-resistant sub-lines (P31res/H1299res) were incubated with VT-1 and/or cisplatin followed by determination of Gb3 expression, cell viability, apoptosis, and signalling pathways.

Results: Cells from the resistant sub-lines had elevated Gb3 expression compared with the parental cell lines, and cisplatin further increased Gb3 expression, whereas VT-1 reduced the percentage of Gb3-expressing cells. Combination of cisplatin and sub-toxic concentrations of VT-1 led to a super-additive increase of cytotoxicity and TUNEL staining, especially in the cisplatin-resistant sub-lines. Blockade of Gb3 synthesis by a Gb3 synthesis inhibitor not only led to eradicated TUNEL staining of P31 cells, but also sensitised P31res cells to the induction of apoptosis by cisplatin alone. Cisplatin- and VT-1-induced apoptosis involved the MAPK pathways with increased C-Jun N-terminal kinase and MAPK kinase-3 and -6 phosphorylation.

Conclusions: We show the presence of Gb3 in acquired-cisplatin resistance in P31res and H1299res cells. Cisplatin up-regulated Gb3 expression in all cells and thus sensitised the cells to VT-1-induced cytotoxicity. A strong super-additive effect of combined cisplatin and a sub-toxic concentration of VT-1 in cisplatin-resistant malignant pleural mesothelioma cells were observed, indicating a new potential clinical-treatment approach.
Occupation and cancer in Britain. L. Rushton, S. Bagga, R. Bevan, et al. 2010;102(9):1428-37. PubMed · Publisher · Free full text

Abstract

Background: Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens.

Methods: We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed.

Results: 5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer).

Conclusion: This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring.
Projection of mesothelioma mortality in Britain using Bayesian methods. E. Tan, N. Warren, A.J. Darnton, et al. 2010;103(3):430-6. PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma mortality has increased more than ten-fold over the past 40 years in Great Britain, with >1700 male deaths recorded in the British mesothelioma register in 2006. Annual mesothelioma deaths now account for >1% of all cancer deaths. A Poisson regression model based on a previous work by Hodgson et al has been fitted, which has allowed informed statistical inferences about model parameters and predictions of future mesothelioma mortality to be made.

Methods: In the Poisson regression model, the mesothelioma risk of an individual depends on the average collective asbestos dose for the individual in a given year and an age-specific exposure potential. The model has been fitted to the data within a Bayesian framework using the Metropolis-Hastings algorithm, a Markov Chain Monte Carlo technique, providing credible intervals for model parameters as well as prediction intervals for the number of future cases of mortality.

Results: Males were most likely to have been exposed to asbestos between the ages of 30 and 49 years, with the peak year of asbestos exposure estimated to be 1963. The estimated number of background cases was 1.08 cases per million population.

Conclusion: Mortality among males is predicted to peak at approximately 2040 deaths in the year 2016, with a rapid decline thereafter. Approximately 91,000 deaths are predicted to occur from 1968 to 2050 with around 61,000 of these occurring from 2007 onwards.
Secretion of intelectin-1 from malignant pleural mesothelioma into pleural effusion. S. Tsuji, Y. Tsuura, T. Morohoshi, et al. 2010;103(4):517-23. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare but fatal tumour. Although most MPM patients show pleural effusion at even the early stage, it is hard to diagnose as MPM at the early stage because a sensitive and reliable diagnostic marker for MPM has not been found in plasma or pleural effusion.

Methods: In this study, we investigated whether intelectin-1 was specifically contained in MPM cells and the pleural effusion of MPM patient by immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay.

Results: Malignant pleural mesothelioma cell lines, but not lung adenocarcinoma cell lines, secreted intelectin-1. In immunohistochemistry, epithelioid-type MPMs, but neither pleura-invading lung adenocarcinomas nor reactive mesothelial cells near the lung adenocarcinomas, were stained with anti-intelectin antibodies. Pleural effusion of MPM patients contained a higher concentration of intelectin-1 than that of lung cancer patients.

Conclusion: These results suggest that detection of intelectin-1 may be useful for a differential diagnosis of epithelioid-type MPM in immunohistochemistry and that a high concentration of intelectin-1 in pleural effusion can be used as a new marker for clinical diagnosis of MPM.
SV40 associated miRNAs are not detectable in mesotheliomas. G.V. Gee, M.L. Stanifer, B.C. Christensen, et al. 2010;103(6):885-8. PubMed · Publisher · Free full text

Abstract

Background: Simian virus-40 (SV40) is a DNA tumour virus that was introduced into the human population with contaminated poliovirus vaccine, and its role in mesothelioma is widely debated. PCR based testing has been called into question, as false positives can be because of cross-reactivity with related viruses, or to laboratory contamination. The Institute of Medicine has recommended the development of more sensitive and specific tests to resolve this controversy.

Methods: We have characterized highly sensitive RT-PCR based assays that are specific for SV40-encoded microRNAs (miRNAs), as an alternative to current testing methods.

Results: Using this sensitive and specific detection method, we were unable to identify SV40 miRNA expression in human malignant pleural mesothelioma (MM) samples.

Conclusion: Our work indicates that SV40 miRNAs are not likely to contribute to mesothelioma tumourogenesis, but highlights the value of this approach when compared with the relatively unspecific current testing methods.
The role of folate receptor alpha (FRalpha) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy. J.E. Nutt, A.R. Razak, K. O'Toole, et al. 2010;102(3):553-60. PubMed · Publisher · Free full text

Abstract

Background: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRalpha).

Methods: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI(50)). FRalpha expression was determined by western blotting and that of FRalpha, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT-PCR. Immunohistochemistry for FRalpha was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed.

Results: A wide range of GI(50) values was obtained for the cell lines, H2452 cells being the most sensitive (GI(50) 22 nM) and RS5 cells having a GI(50) value greater than 10 microM. No FRalpha protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FRalpha was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FRalpha and the outcome of pemetrexed treatment, and no significant difference between histological subtypes.

Conclusion: Response to treatment with pemetrexed does not depend on the presence of FRalpha.
Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. J.D. Veltman, M.E. Lambers, M. van Nimwegen, et al. 2010;103(5):629-41. PubMed · Publisher · Free full text

Abstract

Background: Suppressive immune cells present in tumour microenvironments are known to augment tumour growth and hamper efficacy of antitumour therapies. The amino-bisphosphonate Zoledronic acid (ZA) is considered as an antitumour agent, as recent studies showed that ZA prolongs disease-free survival in cancer patients. The exact mechanism is a topic of debate; it has been suggested that ZA targets tumour-associated macrophages (TAMs).

Methods: We investigate the role of ZA on the myeloid differentiation to TAMs in murine mesothelioma in vivo and in vitro. Mice were intraperitoneally inoculated with a lethal dose of mesothelioma tumour cells and treated with ZA to determine the effects on myeloid differentiation and survival.

Results: We show that ZA impaired myeloid differentiation. Inhibition of myeloid differentiation led to a reduction in TAMs, but the number of immature myeloid cells with myeloid-derived suppressor cell (MDSC) characteristics was increased. In addition, ZA affects the phenotype of macrophages leading to reduced level of TAM-associated cytokines in the tumour microenvironment. No improvement of survival was observed.

Conclusion: We conclude that ZA leads to a reduction in macrophages and impairs polarisation towards an M2 phenotype, but this was associated with an increase in the number of immature myeloid cells, which might diminish the effects of ZA on survival.

2000s

Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma. B.A. Jacobson, A. De, M.G. Kratzke, et al. 2009;101(3):424-31. PubMed · Publisher · Free full text

Abstract

Background: Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation.

Methods: The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1.

Results: In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4G/eIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4G/eIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1(A37/A46)) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1(A37/A46) repressor protein showed abrogated tumourigenicity compared with control tumours.

Conclusion: IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3K/Akt/mTOR signalling.
Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity. B.J. Stish, S. Oh, H. Chen, et al. 2009;101(7):1114-23. PubMed · Publisher · Free full text

Abstract

Background: Potency, immunogenicity, and toxicity are three problems that limit the use of targeted toxins in solid tumour therapy.

Methods: To address potency, we used genetic engineering to develop a novel bispecific ligand-directed toxin (BLT) called EGF4KDEL, a novel recombinant anti-mesothelioma agent created by linking human epidermal growth factor (EGF) and interleukin-4 (IL-4) to truncated pseudomonas exotoxin (PE38) on the same single-chain molecule. Immunogenicity was reduced by mutating seven immunodominant B-cell epitopes on the PE38 molecule to create a new agent, EGF4KDEL 7Mut.

Results: In vitro, bispecific EGF4KDEL showed superior anti-mesothelioma activity compared with its monospecific counterparts. Toxicity in mice was diminished by having both ligands on the same molecule, allowing administration of a 10-fold greater dose of BLT than a mixture of monomeric IL4KDEL and EGFKDEL. EGF4KDEL 7Mut, retained all of its functional activity and induced about 87% fewer anti-toxin antibodies than mice given the parental, non-mutated form. In vivo, intraperitoneal (IP) injection of the BLT showed significant (P<0.01) and impressive effects against two aggressive, malignant IP mesothelioma models when treatment was begun 14-16 days post tumour innoculation.

Conclusion: These data show that EGF4KDEL 7Mut is a promising new anti-mesothelioma agent that was developed to specifically address the obstacles facing clinical utility of targeted toxins.
DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure. E. Kettunen, M. Aavikko, P. Nymark, et al. 2009;100(8):1336-42. PubMed · Publisher · Free full text

Abstract

Five to seven percent of lung tumours are estimated to occur because of occupational asbestos exposure. Using cDNA microarrays, we have earlier detected asbestos exposure-related genomic regions in lung cancer. The region at 2p was one of those that differed most between asbestos-exposed and non-exposed patients. Now, we evaluated genomic alterations at 2p22.1-p16.1 as a possible marker for asbestos exposure. Lung tumours from 205 patients with pulmonary asbestos fibre counts from 0 to 570 million fibres per gram of dry lung, were studied by fluorescence in situ hybridisation (FISH) for DNA copy number alterations (CNA). The prevalence of loss at 2p16, shown by three different FISH probes, was significantly increased in lung tumours of asbestos-exposed patients compared with non-exposed (P=0.05). In addition, a low copy number loss at 2p16 associated significantly with high-level asbestos exposure (P=0.02). Furthermore, 27 of the tumours were studied for allelic imbalances (AI) at 2p22.1-p16.1 using 14 microsatellite markers and also AI at 2p16 was related to asbestos exposure (P=0.003). Our results suggest that alterations at 2p16 combined with other markers could be useful in diagnosing asbestos-related lung cancer.
Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. C. Rake, C. Gilham, J. Hatch, et al. 2009;100(7):1175-83. PubMed · Publisher · Free full text

Abstract

We obtained lifetime occupational and residential histories by telephone interview with 622 mesothelioma patients (512 men, 110 women) and 1420 population controls. Odds ratios (ORs) were converted to lifetime risk (LR) estimates for Britons born in the 1940s. Male ORs (95% confidence interval (CI)) relative to low-risk occupations for >10 years of exposure before the age of 30 years were 50.0 (25.8-96.8) for carpenters (LR 1 in 17), 17.1 (10.3-28.3) for plumbers, electricians and painters, 7.0 (3.2-15.2) for other construction workers, 15.3 (9.0-26.2) for other recognised high-risk occupations and 5.2 (3.1-8.5) in other industries where asbestos may be encountered. The LR was similar in apparently unexposed men and women (approximately 1 in 1000), and this was approximately doubled in exposed workers' relatives (OR 2.0, 95% CI 1.3-3.2). No other environmental hazards were identified. In all, 14% of male and 62% of female cases were not attributable to occupational or domestic asbestos exposure. Approximately half of the male cases were construction workers, and only four had worked for more than 5 years in asbestos product manufacture.
Treatment with interleukin-2 in malignant pleural mesothelioma: immunological and angiogenetic assessment and prognostic impact. G. Alì, L. Boldrini, M. Lucchi, et al. 2009;101(11):1869-75. PubMed · Publisher · Free full text

Abstract

Background: Administration of interleukin-2 (IL-2) has shown some effects on malignant pleural mesothelioma (MPM) tumour regression. The purpose of this study was to investigate the ability of IL-2 to modify immunological effector cells and angiogenesis in MPM patients and their prognostic value.

Methods: Tumour-infiltrating lymphocytes (CD4, CD8, Foxp3), mast cells (MCs) (tryptase and chymase), microvessel count (MVC) and VEGF were determined by immunohistochemistry in two series of MPM patients: 60 patients treated with intra-pleural preoperative IL-2 and 33 patients untreated.

Results: Tryptase MCs, and CD8 and Foxp3 lymphocytes were significantly increased in the IL-2-treated group, whereas MVC was significantly lower in the same group. Moreover, in the IL-2-treated group, greater tryptase+MCs and greater Foxp3 lymphocytes were associated with improved and poorer clinical outcomes, respectively. Notably, when these two immunological parameters were combined, they predicted outcomes more effectively.

Conclusions: This study showed that IL-2 treatment leads to a significant increase of immunological parameters, concomitantly with a reduction in vasculature, providing new insight into the cancer mechanisms mediated by IL-2. Moreover, these results suggest that tryptase-positive MCs and Foxp3+ lymphocytes predict clinical outcomes in IL-2-treated patients, highlighting the critical role of the inflammatory response in mesothelioma cancer progression.
Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma. J.B. Sørensen, H. Frank, T. Palshof. 2008;99(1):44-50. PubMed · Publisher · Free full text

Abstract

The aim was to evaluate the activity of cisplatin and vinorelbine in previously untreated, inoperable patients having histologically verified malignant pleural mesothelioma (MPM), normal organ function, and performance status 0-2. Treatment was vinorelbine 25 mg m(-2) i.v. weekly and cisplatin 100 mg m(-2) i.v. every 4 weeks with hydration and standard prophylactic antiemetic treatment. Patients gave written informed consent. Characteristics of 54 consecutive patients were: males 85%, epithelial subtype 74%, IMIG stages III and IV 35 and 46%, performance status 0, 1, and 2, 26, 69, and 6%, and median age 63 years (31-78 years). CTC grade 3 or 4 toxicity occurred with respect to leukocytopenia (48% of patients, grade 4 in 13%), nausea (13%), neurotoxicity (11%), nephrotoxicity (4%), and other toxicities (9%). There were no toxic deaths. The median number of cycles was four. The fraction of patients alive at 1-, 2-, and 3-years were 61, 31, and 4%, respectively, and median survival and median time to progression were 16.8 months (0.5 to 46.4 +months) and 7.2 months (1.6 to 40.6 + months). There were two CRs and 14 PRs (response rate 29.6%). Cisplatin and intravenous vinorelbine is a highly active regimen in MPM with a response rate and survival comparable to the most active regimens so far reported.
Magnitude of asbestos-related lung cancer mortality in Italy. A. Marinaccio, A. Scarselli, A. Binazzi, et al. 2008;99(1):173-5. PubMed · Publisher · Free full text

Abstract

An ecological study, based on a data set containing all lung and pleural cancer deaths in each Italian municipality in the period 1980-2001, was performed. The pleural to lung cancer ratio was estimated to be 1 : 1 and 3% (around 700) of all male lung cancer deaths were found to be asbestos-related.
Occupational exposure to asbestos and mortality among asbestos removal workers: a Poisson regression analysis. G. Frost, A.H. Harding, A. Darnton, et al. 2008;99(5):822-9. PubMed · Publisher · Free full text

Abstract

The asbestos industry has shifted from manufacture to stripping/removal work. The aim of this study was to investigate early indications of mortality among removal workers. The study population consisted of 31 302 stripping/removal workers in the Great Britain Asbestos Survey, followed up to December 2005. Relative risks (RR) for causes of death with elevated standardised mortality ratios (SMR) and sufficient deaths were obtained from Poisson regression. Risk factors considered included dust suppression technique, type of respirator used, hours spent stripping, smoking status and exposure length. Deaths were elevated for all causes (SMR 123, 95% CI 119-127, n=985), all cancers including lung cancer, mesothelioma, and circulatory disease. There were no significant differences between suppression techniques and respirator types. Spending more than 40 h per week stripping rather than less than 10, increased mortality risk from all causes (RR 1.4, 95% CI 1.2-1.7), circulatory disease and ischaemic heart disease. Elevated mesothelioma risks were observed for those first exposed at young ages or exposed for more than 30 years. This study is a first step in assessing long-term mortality of asbestos removal workers in relation to working practices and asbestos exposure. Further follow-up will allow the impact of recent regulations to be assessed.
Overexpression and altered glycosylation of MUC1 in malignant mesothelioma. J. Creaney, A. Segal, G. Sterrett, et al. 2008;98(9):1562-9. PubMed · Publisher · Free full text

Abstract

Current interest in the MUC1/EMA mucin relates to its role in malignancy, and its potential as a therapeutic target. MUC1/EMA expression has been observed in the majority of epithelioid mesotheliomas. However, little is known of the characteristics of MUC1/EMA in mesothelioma. Herein, we studied the cell surface and soluble expression of the MUC1/EMA glycoprotein, and determined the mRNA and genomic expression profiles in mesothelioma. We found that the anti-MUC1 antibody, E29, was the most diagnostically useful of seven antibody clones examined with a sensitivity of 84% (16 out of 19 cases) and no false positive results. MUC1 mRNA expression was significantly higher in mesothelioma samples than in benign mesothelial cells. No amplification of the MUC1 gene was observed by FISH. Seven of 9 mesothelioma samples expressed MUC1-secreted mRNA isoform in addition to the archetypal MUC1/transmembrane form. CA15.3 (soluble MUC1) levels were significantly higher in the serum of mesothelioma patients than in healthy controls but were not significantly different to levels in patients with benign asbestos-related disease. CA15-3 in effusions could differentiate malignant from benign effusions but were not specific for mesothelioma. Thus, as in other cancers, alterations in MUC1 biology occur in mesothelioma and these results suggest that specific MUC1 characteristics may be useful for mesothelioma diagnosis and should also be investigated as a potential therapeutic target.
Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials. G.L. Ceresoli, B. Castagneto, P.A. Zucali, et al. 2008;99(1):51-6. PubMed · Publisher · Free full text

Abstract

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m(-2) and carboplatin AUC 5 mg ml(-1) min(-1) intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those >or=70 years old. A total of 178 patients with an ECOG performance status of <or=2 were included. Median age was 65 years (range 38-79), with 48 patients >or=70 years (27%). Grade 3-4 haematological toxicity was slightly worse in >or=70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.
The LLP risk model: an individual risk prediction model for lung cancer. A. Cassidy, J.P. Myles, M. van Tongeren, et al. 2008;98(2):270-6. PubMed · Publisher · Free full text

Abstract

Using a model-based approach, we estimated the probability that an individual, with a specified combination of risk factors, would develop lung cancer within a 5-year period. Data from 579 lung cancer cases and 1157 age- and sex-matched population-based controls were available for this analysis. Significant risk factors were fitted into multivariate conditional logistic regression models. The final multivariate model was combined with age-standardised lung cancer incidence data to calculate absolute risk estimates. Combinations of lifestyle risk factors were modelled to create risk profiles. For example, a 77-year-old male non-smoker, with a family history of lung cancer (early onset) and occupational exposure to asbestos has an absolute risk of 3.17% (95% CI, 1.67-5.95). Choosing a 2.5% cutoff to trigger increased surveillance, gave a sensitivity of 0.62 and specificity of 0.70, while a 6.0% cutoff gave a sensitivity of 0.34 and specificity of 0.90. A 10-fold cross validation produced an AUC statistic of 0.70, indicating good discrimination.If independent validation studies confirm these results, the LLP risk models' application as the first stage in an early detection strategy is a logical evolution in patient care.
First and subsequent asbestos exposures in relation to mesothelioma and lung cancer mortality. E. Pira, C. Pelucchi, P.G. Piolatto, et al. 2007;97(9):1300-4. Meta-analysis PubMed · Publisher · Free full text

Abstract

We analysed data from a cohort of 1966 subjects (889 men and 1,077 women) employed by an Italian asbestos (mainly textile) company in the period 1946-1984, who were followed-up to 2004. A total of 62,025 person-years of observation were recorded. We computed standardised mortality ratios (SMR) for all causes and selected cancer sites using national death rates for each 5-year calendar period and age group. There were 68 deaths from mesothelioma (25 men and 43 women, 39 pleural and 29 peritoneal) vs 1.6 expected (SMR=4,159), and 109 from lung cancer vs 35.1 expected (SMR=310). The SMRs of pleural/peritoneal cancer were 6661 for subjects exposed only before 30 years of age, 8,019 for those first exposed before 30 and still employed at 30-39 years of age and 5,786 for those first exposed before 30 and still employed at 40 or more years of age. The corresponding SMRs for lung cancer were 227, 446 and 562. The SMR of mesothelioma was strongly related to time since first exposure. The SMR of lung cancer, but not of mesothelioma, appeared to be related to subsequent exposures.
Factors affecting the mesothelioma detection rate within national and international epidemiological studies: insights from Scottish linked cancer registry-mortality data. D.R. Camidge, D.L. Stockton, M. Bain. 2006;95(5):649-52. PubMed · Publisher · Free full text

Abstract

ICD-9 code 163 (malignant neoplasm of pleura) listed as underlying cause of death detected only 40% of Scottish mesothelioma cases (all body sites) from the cancer registry in 1981-1999. This is lower than both the previously published 55% figure, derived from UK mesothelioma register data 1986-1991, which is based on any mention of mesothelioma on death certificates, cross-referenced to cancer registry data, and the 44% figure derived from Scottish mortality data 1981-1999, which captured any mention of mesothelioma on the death certificate. Detection from cancer registry data increased to 75% under ICD-10 in Scotland, confirming earlier predictions of the benefit of ICD-10's more specific mesothelioma codes. Including the accidental poisoning codes E866.4 (ICD-9) and X49 (ICD-10), covering poisoning by 'unspecified' and 'other' causes, which appear to have been used as coding surrogates for mesothelioma when asbestos exposure was explicitly mentioned in deaths suggestive of a mesothelioma, and which are recorded as the underlying cause of death in 4-7% of mesotheliomas, may improve the mesothelioma detection rate in future epidemiological studies.
Cancer mortality in a cohort of asbestos textile workers. E. Pira, C. Pelucchi, L. Buffoni, et al. 2005;92(3):580-6. PubMed · Publisher · Free full text

Abstract

A cohort of 889 men and 1077 women employed for at least 1 month between 1946 and 1984 by a former Italian leading asbestos (mainly textile) company, characterised by extremely heavy exposures often for short durations, was followed up to 1996, for a total of 53,024 person-years of observation. Employment data were obtained from factory personnel records, while vital status and causes of death were ascertained through municipality registers and local health units. We observed 222 cancer deaths compared with 116.4 expected (standardized mortality ratio, SMR=191). The highest ratios were found for pleural (SMR=4105), peritoneal (SMR=1817) and lung (SMR=282) cancers. We observed direct relationships with duration of employment for lung and peritoneal cancer, and with time since first employment for lung cancer and mesothelioma. Pleural cancer risk was independent from duration (SMR=3428 for employment <1 year, 7659 for 1-4 years, 2979 for 5-9 years and 2130 for > or =10 years). Corresponding SMRs for lung cancer were 139, 251, 233 and 531. Nonsignificantly increased ratios were found for ovarian (SMR=261), laryngeal (SMR=238) and oro-pharyngeal (SMR=226) cancers. This study confirms and further quantifies the central role of latency in pleural mesothelioma and of cumulative exposure in lung cancer.
The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050. J.T. Hodgson, D.M. McElvenny, A.J. Darnton, et al. 2005;92(3):587-93. PubMed · Publisher · Free full text

Abstract

The British mesothelioma register contains all deaths from 1968 to 2001 where mesothelioma was mentioned on the death certificate. These data were used to predict the future burden of mesothelioma mortality in Great Britain. Poisson regression analysis was used to model male mesothelioma deaths from 1968 to 2001 as a function of the rise and fall of asbestos exposure during the 20th century, and hence to predict numbers of male deaths in the years 2002-2050. The annual number of mesothelioma deaths in Great Britain has risen increasingly rapidly from 153 deaths in 1968 to 1848 in 2001 and, using our preferred model, is predicted to peak at around 1950 to 2450 deaths per year between 2011 and 2015. Following this peak, the number of deaths is expected to decline rapidly. The eventual death rate will depend on the background level and any residual asbestos exposure. Between 1968 and 2050, there will have been approximately 90,000 deaths from mesothelioma in Great Britain, 65,000 of which will occur after 2001.
A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma. S. Bydder, M. Phillips, D.J. Joseph, et al. 2004;91(1):9-10. Randomized trial PubMed · Publisher · Free full text

Abstract

A single 9-MeV electron treatment, following invasive thoracic procedures in patients with malignant pleural mesothelioma, was examined. In all, 58 sites were randomised to prophylactic radiotherapy or not. There was no statistically significant difference in tract metastasis. A single 10-Gy treatment with 9-MeV electrons appears ineffective.
Alpha-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells. M. Tomasetti, M.R. Rippo, R. Alleva, et al. 2004;90(8):1644-53. PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of alpha-tocopheryl succinate (alpha-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to alpha-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or alpha-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAIL-induced apoptosis and its augmentation by alpha-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by alpha-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by alpha-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that alpha-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.
Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers?. P.J. Ross, S. Ashley, A. Norton, et al. 2004;90(10):1905-11. PubMed · Publisher · Free full text

Abstract

To examine whether weight loss at presentation influences outcome in patients who received chemotherapy for lung cancer or mesothelioma. Multivariate analysis of prospectively collected data 1994-2001. Data were available for age, gender, performance status, histology, stage, response, toxicity, progression-free and overall survival. The outcomes of patients with or without weight loss treated with chemotherapy for small cell lung cancer (SCLC; n=290), stages III and IV non-small-cell lung cancer (NSCLC; n=418), or mesothelioma (n=72) were compared. Weight loss was reported by 59, 58 and 76% of patients with SCLC, NSCLC and mesothelioma, respectively. Patients with weight loss and NSCLC (P=0.003) or mesothelioma (P=0.05) more frequently failed to complete at least three cycles of chemotherapy. Anaemia as a toxicity occurred significantly more frequently in NSCLC patients with weight loss (P=0.0003). The incidence of other toxicities was not significantly affected by weight loss. NSCLC patients with weight loss had fewer symptomatic responses (P=0.001). Mesothelioma patients with weight loss had fewer symptomatic (P=0.03) and objective responses (P=0.05). Weight loss was an independent predictor of shorter overall survival for patients with SCLC (P=0.003, relative risk (RR)=1.5), NSCLC (P=0.009, RR=1.33) and mesothelioma (P=0.03, RR=1.92) and an independent predictor of progression-free survival in patients with SCLC (P=0.01, RR=1.43). In conclusion, weight loss as a symptom of lung cancer predicts for toxicity from treatment and shorter survival.
The Mesothelioma epidemic in Western Europe: an update. C. Pelucchi, M. Malvezzi, C. La Vecchia, et al. 2004;90(5):1022-4. PubMed · Publisher · Free full text

Abstract

The number of male deaths from pleural cancer in France, Germany and Italy increased from about 8750 in 1990-1994 to 9550 in 1995-1999, suggesting that mesothelioma deaths in males may be levelling off in most of Western Europe.
A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473). P. Beale, I. Judson, A. O'Donnell, et al. 2003;88(7):1128-34. PubMed · Publisher · Free full text

Abstract

AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1-8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m(-2). Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m(-2). Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.
Cell cycle checkpoint status in human malignant mesothelioma cell lines: response to gamma radiation. C. Vivo, C. Lecomte, F. Levy, et al. 2003;88(3):388-95. PubMed · Publisher · Free full text

Abstract

Knowledge of the function of the cell cycle checkpoints in tumour cells may be important to develop treatment strategies for human cancers. The protein p53 is an important factor that regulates cell cycle progression and apoptosis in response to drugs. In human malignant mesothelioma, p53 is generally not mutated, but may be inactivated by SV40 early region T antigen (SV40 Tag). However, the function of p53 has not been investigated in mesothelioma cells. Here, we investigated the function of the cell cycle checkpoints in six human mesothelioma cell lines (HMCLs) by studying the cell distribution in the different phases of the cell cycle by flow cytometry, and expression of cell cycle proteins, p53, p21(WAF1/CIP1) and p27(KIP1). In addition, we studied p53 gene mutations and expression of SV40 Tag. After exposure to gamma-radiation, HMCLs were arrested either in one or both phases of the cell cycle, demonstrating a heterogeneity in cell cycle control. G1 arrest was p21(WAF1/CIP1)- and p53-dependent. Lack of arrest in G1 was not related to p53 mutation or binding to SV40 Tag, except in one HMCL presenting a missense mutation at codon 248. These results may help us to understand mesothelioma and develop new treatments.
Chemotherapy for malignant pleural mesothelioma: past results and recent developments. S. Tomek, S. Emri, K. Krejcy, et al. 2003;88(2):167-74. Review PubMed · Publisher · Free full text

Abstract

This review summarises the results of previously conducted clinical trials, and subsequently presents data arising from all phase II-III studies on chemotherapy of malignant pleural mesothelioma (MPM) published since the last relevant overview. While response rates exceeding 30% have barely been achieved with established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the antimetabolites, and in particular to pemetrexed that produced response rates of up to 45% in combination with platinum compounds. Raltitrexed combined with oxaliplatin has also been shown to be effective, and gemcitabine-applied as a single agent or in combination with cisplatin-as well as vinorelbine appear to improve the quality of life in patients presenting with MPM. Data can now be more precisely analysed by increasingly implemented randomised studies, applying a standardised staging system, and distinguishing prognostic groups. While chemotherapy for MPM remains a challenging task, important steps have clearly been made in the past years to combat this aggressive disease. The publication of pemetrexed with cisplatin phase III results in a peer-reviewed journal may soon establish a standard of care.
Foscan uptake and tissue distribution in relation to photodynamic efficacy. P. Cramers, M. Ruevekamp, H. Oppelaar, et al. 2003;88(2):283-90. PubMed · Publisher · Free full text

Abstract

Clinical photodynamic therapy (PDT) schedules are based on the assumption that optimum drug-light intervals are times at which there is a maximum differential between photosensitiser retention in the tumour and surrounding normal tissue. However, vascular-mediated effects contribute to tumour destruction by PDT; therefore, plasma sensitiser levels and endothelial cell drug exposure could also be important determinants of PDT response. The purpose of this study was to investigate the influence of tumour, tissue and plasma concentrations of the photosensitiser Foscan (meta-tetrahydroxyphenylchlorin, mTHPC) on PDT response. Groups of BalbC nude mice, bearing human mesothelioma xenografts (H-MESO1) were injected (i.v.) with a single dose of (14)C-labelled mTHPC, or with two doses, separated by 72 h. Drug levels in plasma, tumour and normal tissues were measured at 5 min to 120 h after drug administration. The PDT tumour and skin responses were evaluated by illuminating separate groups mice at intervals of 5 min to 120 h after injection of Foscan (nonlabelled). Drug levels in both tumour and skin increased during the first 24 h after a single injection, and remained almost constant for at least 120 h. The second injection produced a further, rapid increase in mTHPC levels in tumours and skin, with steady state being maintained from 20 min to 120 h. By contrast, PDT response of both tumours and skin were maximal for illumination at 1-3 h after drug, with very little response when illumination was given 48-120 h after drug. There was no significant correlation between tumour or skin drug level and PDT response. There was, however, a significant correlation between plasma drug levels and tumour or skin response, excluding an initial distribution time of 20 min. These studies demonstrate a pronounced disassociation between tumour drug levels and optimum drug-light intervals for PDT response with Foscan. We suggest that the PDT effect, in both tumours and normal tissues, is largely mediated via vascular damage and that the selectivity of PDT is not based on differential tumour drug uptake.
Long-term results of intrathoracic chemohyperthermia (ITCH) for the treatment of pleural malignancies. O. Monneuse, A.C. Beaujard, B. Guibert, et al. 2003;88(12):1839-43. PubMed · Publisher · Free full text

Abstract

There is no standard treatment for patients with pleural malignancies. The aim of this prospective study was to investigate the toxicity and long-term results of a multimodality treatment consisting of surgery and intrathoracic chemohyperthermia (ITCH) for the treatment of patients with pleural malignancies. From January 1990 to August 2000, 24 patients with mesothelioma (n=17), fibrosarcoma (n=3), pleural adenocarcinoma (n=3) and thymoma (n=1) were included. The mesothelioma stages were T1 or T2 in 10 cases, and T3 or T4 in seven cases. After cytoreductive surgery, ITCH was carried out for over 60 min, at inflow temperatures less than 45 degrees C, either with mitomycin C (n=7) or cisplatin (n=5) or both (n=12). One patient died from major thoracic air leaks after major decortication and pleurectomy. Seven patients had complications, one pleural clotting necessitating reoperation. After a median follow-up of 89 months, the overall 1-year and 5-year survival rates were 74 and 27%, respectively. For T1 and T2 mesothelioma patients, the median survival was 41.3 months, and for T3 and T4 tumours, it was 4.5 months (P=0.001). The fibrosarcoma patients are alive with no evidence of recurrence at 24, 43 and 54 months. In the conclusion, the combination of surgery with ITCH with mitomycin and/or cisplatin is relatively safe. This procedure may offer unexpected long-term survival in a selected group of patients (T1 and T2 mesothelioma patients and fibrosarcoma patients).
Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura. J.G. Edwards, J. McLaren, J.L. Jones, et al. 2003;88(10):1553-9. PubMed · Publisher · Free full text

Abstract

Matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and -9), play a significant role in tumour invasion and angiogenesis. The expression and activities of MMPs have not been characterised in malignant mesothelioma (MM) tumour samples. In a prospective study, gelatinase activity was evaluated in homogenised supernatants of snap frozen MM (n=35), inflamed pleura (IP, n=12) and uninflammed pleura (UP, n=14) tissue specimens by semiquantitative gelatin zymography. Matrix metalloproteinases were correlated with clinicopathological factors and with survival using Kaplan-Meier and Cox proportional hazard models. In MM, pro- and active MMP-2 levels were significantly greater than for MMP-9 (P=0.006, P<0.001). Active MMP-2 was significantly greater in MM than in UP (P=0.04). MMP-2 activity was equivalent between IP and MM, but both pro- and active MMP-9 activities were greater in IP (P=0.02, P=0.009). While there were trends towards poor survival with increasing total and pro-MMP-2 activity (P=0.08) in univariate analysis, they were both independent poor prognostic factors in multivariate analysis in conjunction with weight loss (pro-MMP-2 P=0.03, total MMP-2 P=0.04). Total and pro-MMP-2 also contributed to the Cancer and Leukemia Group B prognostic groups. MMP-9 activities were not prognostic. Matrix metalloproteinases, and in particular MMP-2, the most abundant gelatinase, may play an important role in MM tumour growth and metastasis. Agents that reduce MMP synthesis and/or activity may have a role to play in the management of MM.
A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. A.K. Nowak, M.J. Byrne, R. Williamson, et al. 2002;87(5):491-6. PubMed · Publisher · Free full text

Abstract

Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2-69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m(-2) i.v. day 1 and gemcitabine 1000 mg m(-2) i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20-46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life.
Cancer testis antigens expression in mesothelioma: role of DNA methylation and bioimmunotherapeutic implications. L. Sigalotti, S. Coral, M. Altomonte, et al. 2002;86(6):979-82. PubMed · Publisher · Free full text

Abstract

Recent evidences suggest that malignant mesothelioma may be sensitive to immunotherapy; however, little is known about malignant mesothelioma-associated tumour antigens. Focusing on cancer/testis antigens, the expression of well-characterised immunogenic tumour-associated antigens was investigated in malignant mesothelioma cells. At variance with MAGE-4 and NY-ESO-1, malignant mesothelioma cells frequently expressed MAGE-1, -2 and -3, GAGE 1-2, GAGE 1-6, SSX-2 and SSX 1-5, and distinct malignant mesothelioma cells concomitantly expressed at least four cancer/testis antigens. Additionally, the tumour-associated antigens RAGE-1 was expressed at high levels in both benign and malignant mesothelial cells. Lastly, treatment with the DNA hypomethylating agent 5-aza-2'-deoxycytidine induced and up-regulated the expression of the cancer/testis antigen examined in malignant mesothelioma cells. Overall, these findings strongly suggest that cancer/testis antigens-based immunotherapy may represent a suitable therapeutic approach to malignant mesothelioma, and foresee the clinical use of 5-aza-2'-deoxycytidine to design new chemo-immunotherapeutic strategies in malignant mesothelioma patients.

Copyright 2002 Cancer Research UK
Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy in patients with malignant mesothelioma. R. Mendes, M.E. O'Brien, A. Mitra, et al. 2002;86(3):336-41. PubMed · Publisher · Free full text

Abstract

The objectives of this study were to determine the toxicity of intratumoural/intrapleural SRL172 in addition to intradermal SRL172 and standard chemotherapy (mitomycin-C, vinblastine and cisplatin) in patients with malignant mesothelioma. Patients received chemotherapy (mitomycin-C: 8 mg m(-2), vinblastine: 6 mg m(-2), cisplatin 50 mg m(-2)) on a 3-weekly basis for up to six courses. IP SRL172 injections were given 3-weekly prior to chemotherapy and escalated in groups of three patients from 1 microg to 1 mg bacilli in 10-fold increments. Patients were also given ID SRL172 at a dose of 1 mg bacilli 4-weekly. Patients were assessed for toxicity after each course of chemotherapy and for response by CT imaging. Immuno-haematological parameters were analyzed pre-treatment and 1 month after completion of treatment. There was no dose limiting toxicity with IP SRL172 although there was greater toxicity at the highest dose (n=13). There were six out of 16 partial responses (37.5%). Haemato-immunological parameters, measured in seven patients pre and post-therapy, revealed that response rate correlated with a decrease in platelet count and there was an increase in activation of natural killer cells and a decrease in the percentage of IL-4 producing T cells in all tested patients post-treatment. SRL172 can be given safely into tumour deposits and the pleural cavity in patients with malignant mesothelioma and we have established the dose for phase II testing.

Copyright 2002 The Cancer Research Campaign
Is the ratio of pleural mesothelioma mortality to pleural cancer mortality approximately unity for Italy? Considerations from the oldest regional mesothelioma register in Italy. G. Gorini, E. Merler, E. Chellini, et al. 2002;86(12):1970-1. Comment · Letter PubMed · Publisher · Free full text

Abstract

doi:10.1038/sj.bjc.6600363 www.bjcancer.com © (2002) Cancer Research UK
Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. J.M. van Haarst, P. Baas, C.H. Manegold, et al. 2002;86(3):342-5. PubMed · Publisher · Free full text

Abstract

Unlabelled: Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma.

Method: Gemcitabine 1250 mg m(-2) was administered on day 1 and day 8 and cisplatin 80 mg m(-2) was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1-31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5-7 months) with a median survival from registration of 9.6 months (95% CI 8-12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.

Copyright 2002 The Cancer Research Campaign
Angiogenesis is an independent prognostic factor in malignant mesothelioma. J.G. Edwards, G. Cox, A. Andi, et al. 2001;85(6):863-8. PubMed · Publisher · Free full text

Abstract

Angiogenesis is essential for tumour growth beyond 1 to 2 mm in diameter. The clinical relevance of angiogenesis, as assessed by microvessel density (MVD), is unclear in malignant mesothelioma (MM). Immunohistochemistry was performed on 104 archival, paraffin-embedded, surgically resected MM samples with an anti-CD34 monoclonal antibody, using the Streptavidin-biotin complex immunoperoxidase technique. 93 cases were suitable for microvessel quantification. MVD was obtained from 3 intratumoural hotspots, using a Chalkley eyepiece graticule at x 250 power. MVD was correlated with survival by Kaplan-Meier and log-rank analysis. A stepwise, multivariate Cox model was used to compare MVD with known prognostic factors and the EORTC and CALGB prognostic scoring systems. Overall median survival from the date of diagnosis was 5.0 months. Increasing MVD was a poor prognostic factor in univariate analysis (P = 0.02). Independent indicators of poor prognosis in multivariate analysis were non-epithelial cell type (P = 0.002), performance status > 0 (P = 0.003) and increasing MVD (P = 0.01). In multivariate Cox analysis, MVD contributed independently to the EORTC (P = 0.006), but not to the CALGB (P = 0.1), prognostic groups. Angiogenesis, as assessed by MVD, is a poor prognostic factor in MM, independent of other clinicopathological variables and the EORTC prognostic scoring system. Further work is required to assess the prognostic importance of angiogenic regulatory factors in this disease.

Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.
Hyaluronan production increases the malignant properties of mesothelioma cells. Y. Li, P. Heldin. 2001;85(4):600-7. PubMed · Publisher · Free full text

Abstract

Malignant pleural mesotheliomas is in most cases associated with elevated amounts of hyaluronan. To investigate the importance of hyaluronan for the malignant properties of mesotheliomas, we have expressed murine hyaluronan synthase 2 (HAS2) in the non-hyaluronan producing mesothelioma cell line, Mero-25. We found that upon hyaluronan overproduction the mesothelioma cells changed their epitheloid character to a fibroblastic phenotype and were surrounded by pericellular matrices, the size of which correlated to the amount of synthesized hyaluronan. HAS2-transfected cells with the ability to synthesize about 520 ng hyaluronan/5 x 10(4)cells/24 h exhibited about a 2-fold increase in the expression of the cell surface hyaluronan receptor CD44 and their locomotion increased compared to that of mock-transfected Mero-25 cells. Furthermore, the malignant properties of mesothelioma cell clones as determined by the ability to grow in a soft agar assay correlated to their hyaluronan production. These results provide evidence for an important role of hyaluronan in the aggressive spread of mesotheliomas in adjacent non-cancerous stromal tissues.

Copyright 2001 Cancer Research Campaign.
Malignant mesothelioma. P. Ruffié, M. Lehmann, F. Galateau-Sallé, et al. 2001;84 Suppl 2(Suppl 2):49-50. Guideline PubMed · Publisher · Free full text
Mutations of the beta- and gamma-catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas. M. Ueda, R.M. Gemmill, J. West, et al. 2001;85(1):64-8. PubMed · Publisher · Free full text

Abstract

Beta-catenin forms complexes with Tcf and Lef-1 and functions as a transcriptional activator in the Wnt signalling pathway. Although recent investigations have been focused on the role of the adenomatous polyposis coli (APC)/ beta-catenin/Tcf pathway in human tumorigenesis, there have been very few reports on mutations of the beta-catenin gene in a variety of tumour types. Using PCR and single-strand conformational polymorphism analysis, we examined 93 lung, 9 breast, 6 kidney, 19 cervical and 7 ovarian carcinoma cell lines for mutations in exon 3 of the beta-catenin gene. In addition, we tested these same samples for mutations in the NH2-terminal regulatory region of the gamma-catenin gene. Mutational analysis for the entire coding region of beta-catenin cDNA was also undertaken in 20 lung, 9 breast, 5 kidney and 6 cervical carcinoma cell lines. Deletion of most beta-catenin coding exons was confirmed in line NCI-H28 (lung mesothelioma) and a silent mutation at codon 214 in exon 5 was found in HeLa (cervical adenocarcinoma). A missense mutation at codon 19 and a silent mutation at codon 28 in the NH2-terminal regulatory region of the gamma-catenin gene were found in H1726 (squamous cell lung carcinoma) and H1048 (small cell lung carcinoma), respectively. Neither deletions nor mutations of these genes were detected in the other cell lines examined. These results suggest that beta- and gamma-catenins are infrequent mutational targets during development of human lung, breast, kidney, cervical and ovarian carcinomas.

Copyright 2001 Cancer Research Campaign.
p53 autoantibodies in patients with malignant mesothelioma: stability through disease progression. J. Creaney, B.M. McLaren, S. Stevenson, et al. 2001;84(1):52-6. PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) generally occurs as a pleural tumour, related to the inhalation of asbestos fibres. It is highly aggressive and largely unresponsive to treatment. The incidence of MM is particularly high in Western Australia because of the extensive blue asbestos mining operations that occurred in the north of the state until 1966. MM is unusual in that mutations in the tumour suppressor gene p53 are rarely observed, whilst over-expression of p53 protein is common. As the level of antibodies directed against p53 is thought to be of prognostic value in some cancers and as MM is known to be immunogenic, we studied a cohort of Western Australian patients to determine the prevalence of anti-p53 antibodies and their value as diagnostic markers or prognostic indicators. 6/88 (7%) of patients had high titres (>2 SD above the mean of controls) of anti-p53 antibodies. There was no correlation between antibody titre and survival. Although 3/38 (8%) of sera obtained from patients exposed to asbestos but prior to a diagnosis of MM contained antibodies, the same proportion of sera obtained from patients exposed to asbestos but who remained disease free also contained antibodies (2/40; 8%). Sera collected sequentially demonstrated a profound temporal stability in the titre of anti-p53 antibodies in patients with MM throughout the course of their illness. These results show that anti-p53 antibodies are observed only at a low frequency in the sera of MM patients and where they do occur, their elicitation is an early event that may be unrelated to antigen load. The occurrence of anti-p53 antibodies does not serve as either a useful prognostic or diagnostic indicator in MM.

Copyright 2001 Cancer Research Campaign.
A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small-cell lung cancer and mesothelioma. M.E. O'Brien, A. Saini, I.E. Smith, et al. 2000;83(7):853-7. Randomized trial PubMed · Publisher · Free full text

Abstract

Mycobacterial preparations have been used with limited success against cancer apart from superficial bladder cancer. Recently, a therapeutic vaccine derived from Mycobacterium vaccae has been given to patients with prostate cancer and melanoma indicating a possible beneficial effect on disease activity in such patients. We have recently initiated a series of randomized studies to test the feasibility and toxicity of combining a preparation of heat-killed Mycobacterium vaccae (designated SRL172) with a multidrug chemotherapy regimen to treat patients with inoperable non-small cell lung cancer (NSCLC) and mesothelioma. 28 evaluable patients with previously untreated symptomatic NSCLC and mesothelioma were randomized to receive either 3 weekly intravenous combination chemotherapy alone, or chemotherapy given with monthly intra-dermal injections of SRL172. Safety and tolerability were scored by common toxicity criteria and efficacy was evaluated by survival of patients and by tumour response assessed by CT scanning. The toxicity of chemotherapy was similar in the two groups. SRL172 caused mild inflammation at the injection site. In the group of patients randomized to receive chemotherapy combined with SRL172, there was a trend towards improved response rate (54% vs. 33%) with more patients in the combined arm receiving radical surgery and radiotherapy, improved median survival (9.7 months vs. 7.5 months) and improved 1 year survival (42% vs. 18%). SRL172 appeared to improve sleep (P = 0.08) and improved appetite (P = 0.01). There was no detectable change in serum cytokine levels for gamma-interferon and TNF-alpha before and after treatment. In patients with NSCLC and mesothelioma, there may be a beneficial interaction when chemotherapy is administered in combination with SRL172. Confirmation of this effect and further investigation is underway in a randomized phase III trial and in laboratory models.

Copyright 2000 Cancer Research Campaign.
Expression of inducible nitric oxide synthase in healthy pleura and in malignant mesothelioma. Y. Soini, K. Kahlos, A. Puhakka, et al. 2000;83(7):880-6. PubMed · Publisher · Free full text

Abstract

In this study we investigated the immunohistochemical expression of inducible nitric oxide synthase (iNOS) in a set of normal pleural mesothelial tissues, malignant mesotheliomas, mesothelioma cell lines and metastatic pleural adenocarcinomas. Furthermore, the expression of mRNA was assessed in four malignant mesothelioma cell lines in culture. Apoptosis and vascular density in malignant mesotheliomas was assessed by the TUNEL method and by immunohistochemistry with an antibody against FVIII-related antigen. Immunohistochemically mesothelial cells in non-neoplastic healthy pleural tissues were mostly negative for iNOS. Positivity for iNOS was observed in 28/38 (74%) and 24/25 (96%) of malignant mesotheliomas and metastatic pleural adenocarcinomas, respectively. Epithelial and mixed mesotheliomas expressed more often strong iNOS immunoreactivity compared to the sarcomatoid subtype (P = 0.023). Moreover, metastatic adenocarcinomas expressed more often iNOS positivity than mesotheliomas (P = 0.021). Experiments with the cell lines confirmed that malignant mesothelioma cells are capable of synthesizing iNOS. No significant association was found between iNOS expression and apoptosis or vascular density in malignant mesotheliomas. The higher expression of iNOS in the epithelial subtype of mesothelioma and pleural metastatic adenocarcinoma might be due to an increased sensitivity of these cell types to cytokine-mediated iNOS upregulation. The strong expression of iNOS suggests a putative role for NO in the growth and progression of these tumours.

Copyright 2000 Cancer Research Campaign.
Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases. P. Harvey, I.M. Clark, M.C. Jaurand, et al. 2000;83(9):1147-53. PubMed · Publisher · Free full text

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional factor involved both in development and tissue repair, as well as pathological processes such as cancer and metastasis. It has been identified in vivo in many types of tumours together with its tyrosine kinase receptor, Met. We show here that exogenous HGF/SF acts as a strong chemoattractant for human mesothelioma cell lines. The factor also enhanced cell adhesion to and invasion into Matrigel. The mesothelioma cell lines synthesized a panel of matrix metalloproteinases critical for tumour progression such as MMP-1, 2, 3, 9 and membrane-bound MT1-MMP. HGF/SF stimulated the expression of MMP-1, 9 and MT1-MMP and had a slight effect on expression of the MMP inhibitor TIMP-1 but not TIMP-2. However, there was no simple correlation between the levels of MMPs and TIMPs of the cell lines and their different invasion properties or between HGF/SF stimulatory effects on MMP expression and invasion. In addition, effects of protease inhibitors on invasion suggested that serine proteases were also expressed in human mesothelioma cell lines and were involved in HGF/SF-induced invasion. The results show a predominant role for HGF/SF in mesothelioma cell invasion, stimulating simultaneously adhesion, motility, invasion and regulation of MMP and TIMP levels.

Copyright 2000 Cancer Research Campaign.
Manganese superoxide dismutase as a diagnostic marker for malignant pleural mesothelioma. K. Kahlos, P. Pääkkö, E. Kurttila, et al. 2000;82(5):1022-9. PubMed · Publisher · Free full text

Abstract

Although several immunohistochemical markers are available, differential diagnosis between mesothelioma and metastatic adenocarcinoma of the pleura is difficult. We have found that the immunoreactivity of manganese superoxide dismutase (MnSOD), an important antioxidant enzyme, is high in mesothelioma compared to healthy pleural mesothelium. The aim of the present study was to investigate whether MnSOD can be used in the differential diagnosis of malignant mesothelioma and metastatic adenocarcinoma of the pleura. MnSOD expression was assessed by using immunohistochemistry in biopsies of malignant mesothelioma (n = 35) and metastatic adenocarcinoma of the pleura (n = 21). MnSOD immunoreactivity was assessed semiquantitatively with and without microwave pretreatment. Fifteen of the 35 malignant mesotheliomas showed moderate or strong MnSOD expression without and 23 with microwave pretreatment, the corresponding figures for metastatic adenocarcinoma of the pleura being 1 and 2 out of 21 (P = 0.002 and P < 0.001, respectively by Fisher's exact test). Only mesothelioma biopsies showed strong MnSOD reactivity, and it was never negative in mesothelioma, whereas one-third of the adenocarcinomas showed no MnSOD reactivity. In conclusion, MnSOD immunoreactivity can, combined with other markers, aid the differential diagnosis between malignant mesothelioma and metastatic adenocarcinoma of the pleura.
Multicentric study on malignant pleural mesothelioma and non-occupational exposure to asbestos. C. Magnani, A. Agudo, C.A. González, et al. 2000;83(1):104-11. PubMed · Publisher · Free full text

Abstract

Insufficient evidence exists on the risk of pleural mesothelioma from non-occupational exposure to asbestos. A population-based case-control study was carried out in six areas from Italy, Spain and Switzerland. Information was collected for 215 new histologically confirmed cases and 448 controls. A panel of industrial hygienists assessed asbestos exposure separately for occupational, domestic and environmental sources. Classification of domestic and environmental exposure was based on a complete residential history, presence and use of asbestos at home, asbestos industrial activities in the surrounding area, and their distance from the dwelling. In 53 cases and 232 controls without evidence of occupational exposure to asbestos, moderate or high probability of domestic exposure was associated with an increased risk adjusted by age and sex: odds ratio (OR) 4.81, 95% confidence interval (CI) 1.8-13.1. This corresponds to three situations: cleaning asbestos-contaminated clothes, handling asbestos material and presence of asbestos material susceptible to damage. The estimated OR for high probability of environmental exposure (living within 2000 m of asbestos mines, asbestos cement plants, asbestos textiles, shipyards, or brakes factories) was 11.5 (95% CI 3.5-38.2). Living between 2000 and 5000 m from asbestos industries or within 500 m of industries using asbestos could also be associated with an increased risk. A dose-response pattern appeared with intensity of both sources of exposure. It is suggested that low-dose exposure to asbestos at home or in the general environment carries a measurable risk of malignant pleural mesothelioma.
Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours. S.L. Cheeseman, M. Brannan, A. McGown, et al. 2000;83(12):1599-606. PubMed · Publisher · Free full text

Abstract

CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C(max)and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C(max)and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V(d)and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m(2)because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m(2)daily x 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination.

Copyright 2000 Cancer Research Campaign.

1990s

Biological effects of naturally occurring and man-made fibres: in vitro cytotoxicity and mutagenesis in mammalian cells. R. Okayasu, L. Wu, T.K. Hei. 1999;79(9-10):1319-24. PubMed · Publisher · Free full text

Abstract

Cytotoxicity and mutagenicity of tremolite, erionite and the man-made ceramic (RCF-1) fibre were studied using the human-hamster hybrid A(L) cells. Results from these fibres were compared with those of UICC Rhodesian chrysotile fibres. The A(L) cell mutation assay, based on the S1 gene marker located on human chromosome 11, the only human chromosome contained in the hybrid cell, has been shown to be more sensitive than conventional assays in detecting deletion mutations. Tremolite, erionite and RCF-1 fibres were significantly less cytotoxic to A(L) cells than chrysotile. Mutagenesis studies at the HPRT locus revealed no significant mutant yield with any of these fibres. In contrast, both erionite and tremolite induced dose-dependent S1- mutations in fibre-exposed cells, with the former inducing a significantly higher mutant yield than the latter fibre type. On the other hand, RCF-1 fibres were largely non-mutagenic. At equitoxic doses (cell survival at approximately 0.7), erionite was found to be the most potent mutagen among the three fibres tested and at a level comparable to that of chrysotile fibres. These results indicate that RCF-1 fibres are non-genotoxic under the conditions used in the studies and suggest that the high mesothelioma incidence previously observed in hamster may either be a result of selective sensitivity of hamster pleura to fibre-induced chronic irritation or as a result of prolonged fibre treatment. Furthermore, the relatively high mutagenic potential for erionite is consistent with its documented carcinogenicity.
Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis. A.M. Björkqvist, M. Wolf, S. Nordling, et al. 1999;81(7):1111-5. PubMed · Publisher · Free full text

Abstract

Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations. Here we further verify the frequency and pattern of deletions at 14q in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite markers was performed on 18 primary mesothelioma tumours. Eight of these had previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%). Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour. The highest number of tumours with deletions at a specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma. Furthermore, confirmation of previous CGH results was obtained in all tumours but one. This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH. Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1-q12 and 14q23-q24 were found to be the most involved regions in deletions. These regions provide a good basis for further molecular analyses and may highlight chromosomal locations of tumour suppressor genes that could be important in the tumorigenesis of malignant mesothelioma.
Evaluation of seven tumour markers in pleural fluid for the diagnosis of malignant effusions. M. Miédougé, P. Rouzaud, G. Salama, et al. 1999;81(6):1059-65. PubMed · Publisher · Free full text

Abstract

Carcinoembryonic antigen (CEA), carbohydrate antigens 15-3, 19-9 and 72-4 (CA 15-3, CA 19-9 and CA 72-4), cytokeratin 19 fragments (CYFRA 21-1), neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCC) were evaluated in pleural fluid for the diagnosis of malignant effusions. With a specificity of 99%, determined in a series of 121 benign effusions, the best individual diagnostic sensitivities in the whole series of 215 malignant effusions or in the subgroup of adenocarcinomas were observed with CEA, CA 15-3 and CA 72-4. As expected, a high sensitivity was obtained with SCC in squamous cell carcinomas and with NSE in small-cell lung carcinomas. CYFRA and/or CA 15-3 were frequently increased in mesotheliomas. Discriminant analysis showed that the optimal combination for diagnosis of non-lymphomatous malignant effusions was CEA + CA 15-3 + CYFRA + NSE: sensitivity of 94.4% with an overall specificity of 95%. In malignant effusions with a negative cytology, 83.9% were diagnosed using this association. The association CYFRA + NSE + SCC was able to discriminate adenocarcinomas from small-cell lung cancers. Regarding their sensitivity and their complementarity, CEA, CA 15-3, CYFRA 21-1, NSE and SCC appear to be very useful to improve the diagnosis of malignant pleural effusions.
Generation of reactive oxygen species by human mesothelioma cells. K. Kahlos, S. Pitkänen, I. Hassinen, et al. 1999;80(1-2):25-31. PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma cells contain elevated levels of manganese superoxide dismutase (MnSOD) and are highly resistant to oxidants compared to non-malignant mesothelial cells. Since the level of cellular free radicals may be important for cell survival, we hypothesized that the increase of MnSOD in the mitochondria of mesothelioma cells may alter the free radical levels of these organelles. First, MnSOD activity was compared to the activities of two constitutive mitochondrial enzymes; MnSOD activity was 20 times higher in the mesothelioma cells than in the mesothelial cells, whereas the activities of citrate synthase and cytochrome c oxidase did not differ significantly in the two cell lines. This indicates that the activity of MnSOD per mitochondrion was increased in the mesothelioma cells. Superoxide production was assayed in the isolated mitochondria of these cells using lucigenin chemiluminescence. Mitochondrial superoxide levels were significantly lower (72%) in the mesothelioma cells compared to the mesothelial cells. Oxidant production in intact cells, assayed by fluorimetry using 2',7'-dichlorodihydrofluorescein as a fluorescent probe, did not differ significantly between these cells. We conclude that mitochondrial superoxide levels are lower in mesothelioma cells compared to nonmalignant mesothelial cells, and that this difference may be explained by higher MnSOD activity in the mitochondria of these cells. Oxidant production was not different in these cells, which may be due to the previously observed increase in H2O2-scavenging mechanisms of mesothelioma cells.
High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma. M. Halme, A. Knuuttila, T. Vehmas, et al. 1999;80(11):1781-5. PubMed · Publisher · Free full text

Abstract

Twenty six patients with pleural mesothelioma of UICC stage I-IV excluding M1 disease (46% of whom had stage I disease and 38% stage III disease) were treated intravenously with high dose MTX (3 g) and calcium folinate rescue three times at intervals of 2 weeks and three times at intervals of 3 weeks. Natural interferon (IFN)-alpha (3 MIU days 2-10) and recombinant IFN-gamma1b (50 microg m(-2) on days 2, 6 and 10) were injected subcutaneously after each MTX dose. At the end of MTX treatment the IFNs were continued as maintenance therapy until disease progression. Seven partial responses were observed among 24 patients evaluable for response (response rate 29%, 95% confidence interval 13-51%). Median duration of response was 10 months (range 3-24 months). Median survival was 17 months and 1-year and 2-year survival rates 62% and 31% respectively. The toxicity of the chemo-immunotherapy was acceptable. Treatment was stopped in one patient who developed grade IV neurological toxicity. MTX dose reductions were rare (two patients with grade 1-2 renal toxicity). The combination of high dose MTX and IFN-alpha and IFN-gamma is active against malignant pleural mesothelioma and well-tolerated. The survival rates are encouraging.
p53 protein, EGF receptor, and anti-p53 antibodies in serum from patients with occupationally derived lung cancer. J. Schneider, P. Presek, A. Braun, et al. 1999;80(12):1987-94. PubMed · Publisher · Free full text

Abstract

The oncogene product epidermal growth factor receptor (EGF-R), the tumour suppressor gene product p53 and anti-p53 antibodies are detectable in the serum of certain cancer patients. Increased levels of some of these products were reported in lung cancer patients after occupational asbestos exposure and after exposure to polycyclic aromatic hydrocarbons or vinylchloride. In the first step, this study investigated the possible diagnostic value of serum EGF-R, p53-protein and anti-p53 antibodies, measured by an enzyme-linked immunosorbent assay, in lung tumour patients. In addition to being investigated on a molecular epidemiological basis, these parameters were examined as biomarkers of carcinogenesis, especially with regard to asbestos incorporation effects or of radon-induced lung cancers. Also, a possible effect of cigarette smoking and age dependence were studied. A total of 116 male patients with lung or pleural tumours were examined. The histological classification was four small-cell cancers, six large-cell cancers, 32 adenocarcinomas, 47 squamous carcinomas, 12 mixed lung carcinomas, five diffuse malignant mesotheliomas and ten lung metastasis of extrapulmonary tumours. Twenty-two lung cancers and all mesotheliomas were related to asbestos, 22 lung cancers were related to ionizing radiation and 61 patients had cigarette smoke-related lung cancer. Besides these patients 50 male patients with non-malignant lung or pleural diseases were included; of the latter eight subjects suffered from asbestosis. Controls were 129 male subjects without any lung disease. No significantly elevated or decreased serum values for p53 protein, EGF-R, or anti-p53 antibodies as a function of histological tumour type, age, or degree and type of exposure (asbestos, smoking, ionizing radiation) could be found. The utility of p53-protein, EGF-R and anti-p53 antibodies as routine biomarkers for screening occupationally derived lung cancers is limited.
Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts. H.B. Ris, T. Krueger, A. Giger, et al. 1999;79(7-8):1061-6. PubMed · Publisher · Free full text

Abstract

The photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm2) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1-4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2-4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC. Tissue concentrations of mTHPC and pegylated mTHPC were measured by high-performance liquid chromatography in non-irradiated animals 4 days after administration. There was no significant difference in tumour uptake between the two sensitizers in mesothelioma, adenocarcinoma and squamous cell carcinoma xenografts. Tissue concentration measurements were of limited use for predicting photosensitization in this model.
Pleuro-pulmonary tumours detected by clinical and chest X-ray analyses in rats transplanted with mesothelioma cells. F. Le Pimpec-Barthes, I. Bernard, I. Abd Alsamad, et al. 1999;81(8):1344-50. PubMed · Publisher · Free full text

Abstract

New strategies for cancer therapy must be developed, especially in severe neoplasms such as malignant pleural mesothelioma. Animal models of cancer, as close as possible to the human situation, are needed to investigate novel therapeutical approaches. Orthotopic transplantation of cancer cells is then relevant and efforts should be made to follow up tumour evolution in animals. In the present study, we developed a method for the orthotopic growth of mesothelioma cells in the pleural cavity of Fischer 344 and nude rats, along with a procedure for clinical survey. Two mesothelioma cell lines, of rat and human origin, were inoculated by transthoracic puncture. Body weight determination and chest X-ray analyses permitted the follow-up of tumour evolution by identifying different stages. Autopsies showed that tumours localized on the whole pleural cavity (diaphragm, parietal pleura), mediastinum and pericardium. Tumour morphology and antigenic characteristics were consistent with those of the inoculated cells and were similar in both types of rats inoculated with the same cell type. These results demonstrate that mesothelioma formation in rats can be followed up by clinical and radiographic survey after gentle intrathoracic inoculation of mesothelioma cells, thus allowing the definition of stages of interest for further experimental trials.
The European mesothelioma epidemic. J. Peto, A. Decarli, C. La Vecchia, et al. 1999;79(3-4):666-72. PubMed · Publisher · Free full text

Abstract

Projections for the period 1995-2029 suggest that the number of men dying from mesothelioma in Western Europe each year will almost double over the next 20 years, from 5000 in 1998 to about 9000 around 2018, and then decline, with a total of about a quarter of a million deaths over the next 35 years. The highest risk will be suffered by men born around 1945-50, of whom about 1 in 150 will die of mesothelioma. Asbestos use in Western Europe remained high until 1980, and substantial quantities are still used in several European countries. These projections are based on the fit of a simple age and birth cohort model to male pleural cancer mortality from 1970 to 1989 for six countries (Britain, France, Germany, Italy, The Netherlands and Switzerland) which together account for three-quarters of the population of Western Europe. The model was tested by comparing observed and predicted numbers of deaths for the period 1990-94. The ratio of mesothelioma to recorded pleural cancer mortality has been 1.6:1 in Britain but was assumed to be 1:1 in other countries.
VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Y. Ohta, V. Shridhar, R.K. Bright, et al. 1999;81(1):54-61. PubMed · Publisher · Free full text

Abstract

The vascular endothelial growth factor (VEGF) family is a novel regulator of endothelial cell proliferation. We assessed the mRNA expression of VEGF, VEGF type C (VEGF-C) and their receptors together with the microvessel density (VD) and microlymphatic vessel density (LVD) in pursuit of their connection and prognostic value in malignant pleural mesothelioma (MPM). We used four human MPM cell lines, 54 MPM tumours and five normal pleural tissues. Expression levels for receptors and ligands were assessed by semiquantitative reverse transcriptase polymerase chain reaction analysis. Microvessels were highlighted by immunohistochemical staining for factor VIII. The discrimination of lymphatics was performed by enzyme-histochemistry for 5'-nucleotidase after adequate inhibition of non-specific activity. The expression levels of VEGF, VEGF-C and VEGFRs were high in all MPM cell lines. The percentages of tumours with higher expression compared to the mean values of normal pleural tissues were 31.5% (17/54) for VEGF, 66.7% (36/54) for VEGF-C, 20.4% (11/54) for fms-like tyrosine kinase (flt)-1, 42.6% (23/54) for kinase insert domain-containing recepter (KDR) and 59.3% (32/54) for flt-4. Significant positive correlations were found between VEGF-C and flt-4, VEGF and KDR, VEGF and flt-1 in tumour tissues. The association between LVD and VEGF-C expression level was especially strong (P< 0.0001, r= 0.63). There were also significant correlations between LVD and flt-4, and VD and VEGF. No correlation, however, was found between LVD and nodal metastasis. VD was a negative prognostic indicator in this study. The associations between VEGFNEGF-C and vessel density suggest that these factors play an important role in angiogenesis and lymphangiogenesis in this tumour, and assessment of vascularity may be a useful prognostic indicator for MPM patients.
Cancer mortality in relation to monitoring for radionuclide exposure in three UK nuclear industry workforces. L.M. Carpenter, C.D. Higgins, A.J. Douglas, et al. 1998;78(9):1224-32. PubMed · Publisher · Free full text

Abstract

Cancer mortality in 40,761 employees of three UK nuclear industry facilities who had been monitored for external radiation exposure was examined according to whether they had also been monitored for possible internal exposure to tritium, plutonium or other radionuclides (uranium, polonium, actinium or other unspecified). Death rates from cancer were compared both with national rates and with rates in radiation workers not monitored for exposure to any radionuclides. Among workers monitored for tritium exposure, overall cancer mortality was significantly below national rates [standardized mortality ratio (SMR) = 83, 165 deaths; 2P = 0.02] and none of the cancer-specific death rates was significantly above either the national average or rates in non-monitored workers. Although the overall death rate from cancer in workers monitored for plutonium exposure was also significantly low relative to national rates (SMR = 89, 581 deaths; 2P = 0.005), mortality from pleural cancer was significantly raised (SMR = 357, nine deaths; 2P = 0.002); none of the rates differed significantly from those of non-monitored workers. Workers monitored for radionuclides other than tritium or plutonium also had a death rate from all cancers combined that was below the national average (SMR = 86, 418 deaths; 2P = 0.002) but prostatic cancer mortality was raised both in relation to death rates in the general population (SMR = 153, 37 deaths; 2P = 0.02) and to death rates in radiation workers who had not been monitored for exposure to any radionuclide [rate ratio (RR) = 1.65; 2P = 0.03]. Mortality from cancer of the lung was also significantly increased in workers monitored for other radionuclides compared with those of radiation workers not monitored for exposure to radionuclides (RR = 1.31, 164 deaths; 2P = 0.01). For cancers of the lung, prostate and all cancers combined, death rates in monitored workers were examined according to the timing and duration of monitoring for radionuclide exposure, with rates of radiation workers not monitored for any radionuclide forming the comparison group. In tritium-monitored workers, RRs for prostatic cancer varied significantly according to the number of years in which they were monitored (2P = 0.03). In workers monitored for plutonium exposure, RRs for all cancers combined increased with the number of years in which they were monitored (2P = 0.04) and with the number of years since first monitoring (2P = 0.0003). There was little suggestion of systematic variation in RRs for workers monitored for other radionuclides in relation to the timing or duration of monitoring, nor did it appear that their raised rates of cancer of the lung and prostate were explained by external radiation dose. These analyses of cancer mortality in relation to monitoring for radionuclide exposure reported in a large cohort of nuclear industry workers suggest that certain patterns of monitoring for some radionuclides may be associated with higher death rates from cancers of the lung, pleura, prostate and all cancers combined. Some of these findings may be due to chance. Moreover, because of the paucity of related data and lack of information about other possible exposures, such as whether plutonium workers are more likely to be exposed to asbestos, firm conclusions cannot be drawn at this stage. Further investigations of the relationship between radionuclide exposure and cancer in nuclear industry workers are needed.
Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung. A.M. Björkqvist, L. Tammilehto, S. Nordling, et al. 1998;77(2):260-9. PubMed · Publisher · Free full text

Abstract

The differential diagnosis of mesothelioma, primary adenocarcinomas and pleural metastases frequently causes problems. We have used the comparative genomic hybridization (CGH) technique on 34 malignant mesotheliomas and 30 primary lung carcinomas (adenocarcinoma, including bronchoalveolar carcinoma and large-cell anaplastic carcinoma) to compare their copy number changes and to evaluate the use of CGH to distinguish between these two types of tumour. In mesothelioma, gains of genetic material occurred as frequently as losses, whereas gains predominated over losses in carcinoma. In mesothelioma, the most frequent changes were losses in 4q, 6q and 14q and gains in 15q and 7p, whereas gains in 8q, 1q, 7p, 5p and 6p were the most common changes in carcinoma. Amplification of KRAS2 was detected in two adenocarcinomas by Southern blot analysis. CGH showed gains in 12p in the same tumours. Statistically significant differences between the two types of tumour were detected in chromosomes X, 1, 2p, 4, 8q, 10q, 12p, 14q, 15q and 18q. When comparing the frequency of gains and losses between mesothelioma and lung carcinoma using discriminant analysis, the sensitivity of CGH to differentiate mesotheliomas from lung carcinomas was 81% and the specificity 77%. The differences in DNA copy number changes between the two types of tumour suggest that they are genetically different tumour entities. Although CGH cannot be used as a definitive discriminatory method, we were able to distinguish between mesothelioma and lung carcinoma in a large proportion of the abnormal cases.
Endogenous antioxidant enzymes and glutathione S-transferase in protection of mesothelioma cells against hydrogen peroxide and epirubicin toxicity. K. Kinnula, K. Linnainmaa, K.O. Raivio, et al. 1998;77(7):1097-102. PubMed · Publisher · Free full text

Abstract

We have previously shown that cultured malignant mesothelioma cells contain elevated manganese superoxide dismutase (MnSOD) mRNA levels and activities compared with non-malignant mesothelial cells. As many cytotoxic drugs generate both superoxide and hydrogen peroxide, we assessed the relative significance of catalase and the glutathione redox cycle, as well as glutathione S-transferase (GST), in protecting these cells against hydrogen peroxide and epirubicin toxicity. Mesothelioma cell lines containing high (M38K cells) and low (M14K cells) MnSOD, and non-malignant MeT-5A mesothelial cells were selected for the study. M38K cells were the most resistant of these three cell types to hydrogen peroxide (0.1-0.5 mM, 4 h) and epirubicin (0.1-0.5 microg ml(-1), 48 h) as judged by lactate dehydrogenase (LDH) release and by high-energy nucleotide (ATP, ADP, AMP) depletion. Total glutathione was higher in M38K cells (63.8 +/- 20.3 nnmol mg(-1) protein) than in M14K (25.2 +/- 8.2 nmol mg[-1]) or MeT-5A cells (23.5 +/- 4.5 nmol mg[-1]). Furthermore, GST specific activity was higher in M38K cells (111.3 +/- 15.8 U mg[-1]) than in M14K cells (77.4 +/- 6.6 U mg[-1]) or in MeT-5A cells (68.8 +/- 7.6 U mg[-1]). Western blotting indicated the presence of GST-pi in all these cells, the reactivity again being highest in M38K cells. Depletion of glutathione by buthionine sulphoximine and inhibition of catalase by aminotriazole enhanced hydrogen peroxide toxicity in all cell types, while only the depletion of glutathione increased epirubicin toxicity. We conclude that simultaneous induction of multiple antioxidant enzymes can occur in human mesothelioma cells. In addition to the high MnSOD activity, hydrogen peroxide scavenging antioxidant enzymes, glutathione and GST can partly explain the high hydrogen peroxide and epirubicin resistance of these cells in vitro.
Evaluation of pleural CYFRA 21-1 and carcinoembryonic antigen in the diagnosis of malignant pleural effusions. G. Salama, M. Miédougé, P. Rouzaud, et al. 1998;77(3):472-6. PubMed · Publisher · Free full text

Abstract

CYFRA 21-1 assay, measuring cytokeratin 19 fragments, was compared with carcinoembryonic antigen (CEA) assay, as an addition to cytological analysis for the diagnosis of malignant effusions. Both markers were determined with commercial enzyme immunoassays in pleural fluid from 196 patients. Cytological analysis and/or pleural biopsy confirmed the malignant origin of the effusion in 99 patients (76 carcinomas, nine pleural mesotheliomas and 14 non-epithelial malignancies). Effusions were confirmed as benign in 97 patients (33 cardiac failures, 39 infectious diseases--including 12 tuberculosis-- and 25 miscellaneous effusions). Both markers were significantly higher in malignant than in benign effusions. All the patients with non-epithelial malignancies presented CYFRA and CEA values lower than the 95% diagnostic specificity thresholds (100 and 6 ng ml(-1) respectively). The diagnostic sensitivity in the group of carcinomas and mesotheliomas was similar for CYFRA (58.8%) and CEA (64.7%). However, CEA had a significantly higher sensitivity in carcinomas (72.4% vs 55.3%), while CYFRA had a clearly higher sensitivity in mesotheliomas (89.9% vs 0%). Interestingly, 12 out of the 16 malignant effusions with a negative cytology were CEA and/or CYFRA positive. Regarding their high diagnostic sensitivity and their complementarity, CEA and CYFRA appear to be very useful for the diagnosis of malignant pleural effusions when cytology is negative.
Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology. P. Harvey, A. Warn, S. Dobbin, et al. 1998;77(7):1052-9. PubMed · Publisher · Free full text

Abstract

The expression of hepatocyte growth factor/scatter factor (HGF/SF) was studied in 12 mesothelioma cell lines characterized by either an epithelioid or a fibroblast-like phenotype. Conditioned media from these lines were analysed by bioassay and ELISA, and HGF/SF was detected in three cell lines, all with a fibroblast-like or mixed morphology. None of eight epithelioid cell lines expressed the factor. Thus, for these cell lines, the ability to secrete HGF/SF correlated with the cell phenotype. Following on from these observations, two cell lines, BR and BT, with a fibroblast-like and an epithelioid phenotype, respectively, were further investigated. Both cell lines expressed the Met receptor but only BR secreted HGF/SF. Both cell lines responded to exogenous HGF/SF treatment by a change of morphology but in different ways: BR became more elongated and bipolar, while BT formed more spread-out cell colonies. HGF/SF acted as a paracrine effector on the epithelioid BT cells and stimulated both cell-spreading and proliferation. Interestingly, BT cells spread but did not scatter in response to exogenous HGF/SF. In contrast BR cells showed only some stimulation of cell motility with HGF/SF and no increase in cell proliferation was observed. Because HGF/SF was previously found in the pleural effusion fluids of patients with malignant mesothelioma and in paraffin-embedded tumour tissues, it is concluded that HGF/SF may well stimulate the growth and spread of malignant mesothelioma in vivo by paracrine and/or autocrine mechanisms.
Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma. T. Nakano, A.P. Chahinian, M. Shinjo, et al. 1998;77(6):907-12. PubMed · Publisher · Free full text

Abstract

The relationship between interleukin 6 (IL-6) levels and clinical parameters was studied in 25 patients with malignant pleural mesothelioma. The serum levels of IL-6, C-reactive protein, alpha1-acid glycoprotein and fibrinogen were significantly higher in mesothelioma than in lung adenocarcinoma with cytology-positive pleural effusion. Serum IL-6 levels correlated with the levels of the acute-phase proteins. We demonstrated a high incidence of thrombocytosis (48%) and a significant correlation between platelet count and the serum IL-6 level. The level of IL-6 in the pleural fluid of patients with mesothelioma was significantly higher than in the pleural fluid of patients with adenocarcinoma, and was about 60-1400 times higher than in the serum. However, even higher levels of IL-6 in the pleural fluid and of thrombocytosis were found in patients with tuberculous pleurisy. These results indicate that large amounts of IL-6 from the pleural fluid of patients with mesothelioma leak into the systemic circulation and induce clinical inflammatory reactions. These profiles are not specific to mesothelioma as similar profiles are found in patients with tuberculous pleurisy. However, the detection of a markedly increased level of IL-6 in pleural fluid argues against a diagnosis of adenocarcinoma.
Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies. P. Baas, L. Murrer, F.A. Zoetmulder, et al. 1997;76(6):819-26. PubMed · Publisher · Free full text

Abstract

Five patients with a pleural malignancy (four malignant mesotheliomas and one localized low grade carcinoid) were treated with maximal surgical resection of the tumour followed by intraoperative adjuvant photodynamic therapy (PDT). The additional photodynamic treatment was performed with light of 652 nm from a high power diode laser, and meta-tetrahydroxy phenylchlorin as the photosensitizer. The light delivery to the thoracic cavity was monitored by in situ isotropic light detectors. The position of the light delivery fibre was adjusted to achieve optimal light distribution, taking account of reflected and scattered light in this hollow cavity. There was no 30-day post-operative mortality and only one patient suffered from a major complication (diaphragmatic rupture and haematopericardium). The operation time was increased by a maximum of 1 h to illuminate the total hemithoracic surface with 10 J cm(-2) (incident and scattered light). The effect of the adjuvant PDT was monitored by examination of biopsies taken 24 h after surgery under thoracoscopic guidance. Significant damage, including necrosis, was observed in the marker lesions with remaining malignancy compared with normal tissue samples, which showed only an infiltration with PMN cells and oedema of the striated muscles cells. Of the five patients treated, four are alive with no signs of recurrent tumour with a follow-up of 9-11 months. One patient was diagnosed as having a tumour dissemination in the skin around the thoracoscopy scar and died of abdominal tumour spread. Light delivery to large surfaces for adjuvant PDT is feasible in a relatively short period of time (< 1 h). In situ dosimetry ensures optimal light distribution and allows total doses (incident plus scattered light) to be monitored at different positions within the cavity. This combination of light delivery and dosimetry is well suited for adjuvant treatment with PDT in malignant pleural tumours.
Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma. A.M. Björkqvist, L. Tammilehto, S. Anttila, et al. 1997;75(4):523-7. PubMed · Publisher · Free full text

Abstract

Comparative genomic hybridization (CGH) analyses were performed on 27 human pleural mesothelioma tumour specimens, consisting of 18 frozen tumours and nine paraffin-embedded tumours, to screen for gains and losses of DNA sequences. Copy number changes were detected in 15 of the 27 specimens with a range from one to eight per specimen. On average, more losses than gains of genetic material were observed. The loss of DNA sequences occurred most commonly in the short arm of chromosome 9 (p21-pter), in 60% of the abnormal specimens. Other losses among the abnormal specimens were frequently detected in the long arms of chromosomes 4 (q31.1-qter, 20%), 6 (q22-q24, 33%), 13 (33%),14 (q24-qter, 33%) and 22 (q13, 20%). A gain in DNA sequences was found in the long arm of chromosome 1 (cen-qter) in 33% of the abnormal specimens. Our analysis is the first genome-wide screening for gains and losses of DNA sequences using comparative genomic hybridization in malignant pleural mesothelioma tumours. The recurrent DNA sequence changes detected in this study suggest that the corresponding chromosomal areas most probably contain genes important for the initiation and progression of mesothelioma.
Cancer in electrical workers: an analysis of cancer registrations in England, 1981-87. N.T. Fear, E. Roman, L.M. Carpenter, et al. 1996;73(7):935-9. PubMed · Publisher · Free full text

Abstract

Associations between work in the electrical and electronic industry and cancer incidence were assessed using data for 371 890 cancers registered in England between 1981 and 1987, of which 7981 were in electrical workers. Proportional registration ratios (PRRs) were calculated, both with and without the commonest cancers, with adjustment for age, social class, cancer registry of origin and sex. Of four cancers previously linked with work in the electrical and electronic industry (leukaemia, brain, breast and melanoma), only two were significantly raised: leukaemia (PRR=124, 95% CI=109-142, based on 217 cases) and malignant brain cancer (PRR=118, 95% CI=103-136, based on 204 cases). A significantly increased risk was also observed for pleural cancer (PRR=201, 95% CI=167-241, based on 115 cases). The histology of almost 90% of pleural cancers was coded as mesothelioma, confirming the previously observed association between pleural cancer and exposure to asbestos in electrical workers. The extent to which workplace exposures to extremely low frequency electromagnetic fields explains the excesses seen here for leukaemia and brain cancer requires further study.
Case-control study of risk factors for prostate cancer. M. Ilić, H. Vlajinac, J. Marinković. 1996;74(10):1682-6. PubMed · Publisher · Free full text

Abstract

One hundred and one patients with histologically confirmed prostate cancer and 202 hospital controls individually matched by age (+/- 2 years), hospital admittance and place of residence, were interviewed during the period 1990-94 in two towns in central Serbia (Yugoslavia). In an analysis using multivariate logistic regression, the followng factors were significantly related to prostate cancer: (1) occupational physical activity during the year preceding the disease [odds ratio (OR)=3.87, 95% confidence interval (95% CI)=2.09-7.16]; (2) occupational exposure to asbestos, steel, dyes and lacquers, bitumen, pitch, iron, nickel, lead, fertilizer and certain other agents (OR=2.13, 95% CI=1.05-4.32); (3) nephrolithiasis (OR=4.52, 95% CI=1.34-15.30); (4) 'other' diseases in medical history such as chronic bronchitis, chronic rheumatic diseases, hypertension, cardiomyopathy, diabetes mellitus, renal diseases, eye diseases and tuberculosis (OR=3.14, 95% CI=1.56-6.33); (5) a greater number (> or = 3) of brothers (OR=2.08, 95% CI=1.35-3.22); and (6) greater numbers (> or = 8) of sexual partners (OR=2.24, 95% CI=1.13-4.44). Marital status, age at first marriage, educational level, age at first sexual intercourse, frequency of sexual intercourse, venereal diseases, tonsillectomy, appendectomy, hernia inguinale and hydrocele, anthropometric characteristics, smoking history, sport and recreational activities and family history of prostatic neoplasms were not found to be independently related to prostate cancer.
Dietary intake and the risk of malignant mesothelioma. J.E. Muscat, M. Huncharek. 1996;73(9):1122-5. PubMed · Publisher · Free full text

Abstract

A high consumption of fruit and vegetables reduces the risk of several types of cancer. There is little information on the association between dietary intake and mesothelioma. A hospital-based case-control study of 94 men and women with malignant mesothelioma and 64 control patients without cancer was conducted to determine the odds associated with consumption of carotenoid-containing fruits and vegetables. After statistical adjustment for occupational asbestos exposure, the odds ratio was 0.2 [95% confidence interval (CI) 0.1-0.8] for carrot consumption and 0.5 (95% CI 0.2-1.4) for tomato consumption. However, the frequency of consuming other foods that have a high vitamin A or carotenoid content was not associated with a decreased risk of cancer. These results provide some justification for the hypothesis that provitamin A or beta-carotene may decrease the risk of mesothelioma. The body mass index was unrelated to the risk of mesothelioma.
High levels of MDM2 are not correlated with the presence of wild-type p53 in human malignant mesothelioma cell lines. S. Ungar, A. Van de Meeren, L. Tammilehto, et al. 1996;74(10):1534-40. PubMed · Publisher · Free full text

Abstract

Prior analysis of 20 human mesothelioma cell lines for p53 status revealed only two mutations and one p53 null cell line, although p53 expression was detected in most cell lines. In addition, mRNA and protein expression of the retinoblastoma gene product in human mesothelioma cell lines is similar to normal controls. We have tested for p53 induction after exposure to ionising radiation and demonstrate this induction and, to a lesser extent, p21(WAF1) induction, in both normal mesothelial cells and p53-positive mesothelioma cell lines. We postulated that high levels of MDM2 might alter p53 and retinoblastoma tumour-suppressor function in mesothelioma. However, Southern blot analysis for mdm2 indicated that no amplification had occurred in 18 mesothelioma cell lines tested. Steady-state mRNA and protein levels also did not indicate overexpression. These results indicate that high levels of MDM2 are not responsible for inactivating the functions of wild-type p53 or the retinoblastoma gene product during the pathogenesis of malignant mesothelioma.
Paclitaxel for malignant pleural mesothelioma: a phase II study of the EORTC Lung Cancer Cooperative Group. J. van Meerbeeck, C. Debruyne, N. van Zandwijk, et al. 1996;74(6):961-3. PubMed · Publisher · Free full text

Abstract

The EORTC Lung Cancer Cooperative Group undertook a phase II study of paclitaxel in 25 chemotherapy-naive patients with malignant pleural mesothelioma. Paclitaxel was given intravenously at a dose of 200 mg m-2 as a 3 h infusion every 3 weeks, after standard premedication with corticosteroids and antihistamines. This regimen was well tolerated, with < 4% of cycles resulting in severe toxicity. No major objective responses were observed and ten patients had stable disease. Median survival time was 39 weeks and the 1 year survival rate was 30%. In conclusion, paclitaxel at the dose and schedule investigated in this trial had no major activity in the treatment of malignant pleural mesothelioma.
Response of Photofrin-sensitised mesothelioma xenografts to photodynamic therapy with 514 nm light. T.H. Foster, S.L. Gibson, R.F. Raubertas. 1996;73(8):933-6. PubMed · Publisher · Free full text

Abstract

We have studied the response of human mesothelioma xenografts in nude mice to Photofrin-sensitised photodynamic therapy with 514 nm light. Delays in tumour regrowth following four different 514 nm irradiation regimens were compared with results obtained with the more commonly used 630 nm light. One of these 514 nm regimens, which consisted of 1 h of irradiation at an incident fluence rate of 20 mW cm-2 and a second hour at a fluence rate of 28 mW cm-2, produced tumour volume doubling times that were statistically indistinguishable from results that were observed when tumours were irradiated for 2 h with 630 nm light at an incident fluence rate of 50 mW cm-2. The three other 514 nm light protocols tested were found to be less effective than the 630 nm regimen. The 514 nm treatment protocols were devised on the basis of attempts to equate the photodynamic dose and the dose rate at these two wavelengths, with photodynamic dose defined as the number of photons absorbed by the sensitiser. Photosensitiser extinction coefficients, photon energies and tissue optical properties were considered in these attempts. Our results indicate that, under certain conditions, photodynamic therapy performed with 514 nm light can provide tumour control that is similar to that achieved with 630 nm, with potential for diminished normal tissue damage.
Clinical evaluation of seven tumour markers in lung cancer diagnosis: can any combination improve the results?. M. Plebani, D. Basso, F. Navaglia, et al. 1995;72(1):170-3. PubMed · Publisher · Free full text

Abstract

In this study we compared the diagnostic utility of: (1) neuron-specific enolase (NSE); (2) squamous cell carcinoma antigen (SCC); (3) carcinoembryonic antigen (CEA); and (4) cytokeratin markers (CYFRA 21-1, TPA, TPM, TPS) in patients with small-cell lung cancer (SCLC) (21 cases) and non-small-cell lung cancer (94 cases). For comparison we also studied 66 patients with benign lung diseases and nine with pleural mesothelioma. NSE levels in SCLC patients were significantly higher than those in all the other groups studied. No significant variations were found among the SCC levels in all groups. CEA levels in patients with adenocarcinoma were significantly higher than those in all other groups studied. CYFRA 21-1 serum levels significantly increased in patients with squamous cell carcinoma and mesothelioma, while TPA, TPS and TPM increased in patients with lung cancer irrespective of the histological type. In patients with SCLC, high levels of all markers except SCC were found when the disease was extensive. In patients with non-SCLC, the highest levels of all tumour markers were usually found in those with advanced disease, although CYFRA 21-1 gave a sensitivity of 44% when a specificity of 95% was fixed in stage I non-SCLC patients. An analysis of receiver operating characteristic curves revealed that the highest diagnostic accuracies in distinguishing benign from malignant lung diseases were achieved with TPM (81%), CYFRA 21-1 (72%), CEA (78%) or TPA (78%) when using cut-off values of 46 Ul-1, 3.0 micrograms l-1, 2.0 micrograms l-1 and 75 Ul-1 respectively. When all patients were considered, the combined evaluation of more than one marker did not significantly improve the results obtained with TPM alone. However, taking into consideration the fact that CYFRA 21-1 is the most sensitive index of early lung tumours and that its combined determination with TPM did not worsen the overall sensitivity and specificity of the latter, the combined use of these two markers may be suggested as a useful took for the diagnosis of lung tumours.
Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study. S.H. Goey, A.M. Eggermont, C.J. Punt, et al. 1995;72(5):1283-8. PubMed · Publisher · Free full text

Abstract

Twenty-three patients with pleural mesothelioma stage I-IIA were entered in a study of continuous daily intrapleural infusion of interleukin 2 (IL-2) for 14 days, repeated every 4 weeks. IL-2 was administered according to a groupwise dose escalation schedule (group A, 3 x 10(4); group B, 3 x 10(5); group C, 3 x 10(6); group D, 6 x 10(6); group E, 18 x 10(6); and group F, 36 x 10(6) IU day-1). Each group consisted of at least three patients. Intrapleural administration of IL-2 was associated with acceptable toxicity. All patients were treated on an outpatient basis except for the patients at dose levels E and F. Dose-limiting toxicity was observed at level F, 36 x 10(6) IU daily, and consisted of catheter infection, fever and flu-like symptoms. Intrapleural IL-2 levels were high (> 20,000 IU ml-1) at levels E and F, while serum levels in most patients were not or barely detectable (< 3-30 IU ml-1). Intrapleural IL-2 levels were up to 6000-fold higher than systemic levels. Intrapleural tumour necrosis factor alpha (TNF-alpha) levels varied greatly and did not correlate with IL-2 dosage. Intrapleural mononuclear cells (MNCs) displayed IL-2-induced lymphokine-activated killer (LAK) activity in all patients. Two patients were not evaluable for response owing to catheter-related problems which precluded the delivery of IL-2. Partial response (PR) occurred in 4 of 21 evaluable patients (19%; 95% confidence interval 5-42%) with a median time to progression of 12 months (range 5-37). Stable disease (SD) occurred in seven patients with a median time to progression of 5 months (range 2-7). There were no complete responses (CRs). The median overall survival was 15.6 months (range 3.0-43). No relationship between the dose of IL-2 and response rate was observed. We conclude that IL-2 given intrapleurally is accompanied with acceptable toxicity and has anti-tumour activity against mesothelioma. In view of the refractory nature of the disease IL-2 may be a treatment option for mesothelioma. A formal phase II study is warranted. Based on the observed toxicity, the lack of dose-response relationship and the immunomodulatory effects seen at relatively low-dose IL-2, the recommended dose for a phase II study is 3 x 10(6) IU day-1 using the present treatment schedule.
Molecular cloning of a cell-surface glycoprotein that can potentially discriminate mesothelium from epithelium: its identification as vascular cell adhesion molecule 1. T. Yamada, J. Jiping, R. Endo, et al. 1995;71(3):562-70. PubMed · Publisher · Free full text

Abstract

It has long been a practical problem for surgical pathologists to distinguish mesothelium from epithelium in order to make a positive diagnosis of mesothelioma. In this study, we developed a new monoclonal antibody, designated MS-2761 (IgG1, k), against cultured non-neoplastic mesothelial cells. Immunohistochemistry and slot-blot analysis revealed that this monoclonal antibody reacted with 100% (12/12) of benign and malignant mesothelioma tissues and a mesothelioma cell line, but not with 99% (77/78) of epithelial tumour tissues and 97% (33/34) of epithelial tumour cell lines. A gene encoding the cell-surface antigen defined by this monoclonal antibody was isolated from a mesothelial cell cDNA library constructed with a mammalian cell expression vector through transfection of Cos-7 cells and immunoselection by panning. DNA sequencing and a database search revealed that the gene was identical to vascular cell adhesion molecule 1 (VCAM1, also referred to as INCAM110). The prominent VCAM1 transcript in mesothelium was 3.2 kb in size with seven Ig-like domains, in addition to a minor transcripts with six Ig-like domains. This monoclonal antibody potentially discriminates mesothelium from epithelium and may become a tool for differential diagnosis of mesothelioma.
Autocrine stimulation of a human lung mesothelioma cell line is mediated through the transforming growth factor alpha/epidermal growth factor receptor mitogenic pathway. I.A. Mórocz, D. Schmitter, B. Lauber, et al. 1994;70(5):850-6. PubMed · Publisher · Free full text

Abstract

Malignant cells frequently acquire a certain independency of exogenous growth factors via the coexpression of epidermal growth factor receptor (EGFR) and epidermal growth factor (EGF)-related molecules. In the present study we investigate a possible involvement of EGF-related molecules in the growth of human lung mesothelioma. Four well-characterised cell lines are analysed for their responsiveness to exogenous EGF and transforming growth factor alpha (TGF-alpha) as well as for coexpression of EGFR and EGF/TGF-alpha. Both growth factors are able to stimulate DNA synthesis in three cell lines, although the degree of responsiveness is very variable, but neither EGF nor TGF-alpha has an effect on the cell line ZL34. In contrast, no heterogeneity is observed in the expression of EGFR, which is similarly high in all cell lines. Analysis of cell supernatants reveals that, whereas no EGF is detected, TGF-alpha is released by two cell lines. Furthermore, these two cell lines, ZL5 and ZL34, are shown to express the membrane anchored precursor pro-TGF-alpha. Thus, coexpression of EGFR and TGF-alpha is observed on two mesothelioma cell lines. The potential autocrine mitogenic role of TGF-alpha in these two cell lines was tested using neutralising antibodies against TGF-alpha and EGFR. In ZL5 cells DNA synthesis was not affected by the presence of neutralising antibodies, indicating that an external autocrine mitogenic pathway is not active in these cells. In ZL34 cells, however, the potential autocrine loop could be disrupted, as DNA synthesis was significantly reduced in the presence of neutralising antibodies. This result gives strong evidence for an autocrine role of TGF-alpha in the growth of the mesothelioma cell line ZL34.
Effects of photodynamic therapy on xenografts of human mesothelioma and rat mammary carcinoma in nude mice. S.L. Gibson, T.H. Foster, R.H. Feins, et al. 1994;69(3):473-81. PubMed · Publisher · Free full text

Abstract

We have examined the effectiveness of photodynamic therapy against R3230AC rat mammary adenocarcinoma and human mesothelioma as xenografts in the same host. The results demonstrate that the xenografted human tumour is significantly more responsive to photodynamic treatment than the rodent mammary tumour. Studies also showed that the mesothelioma xenograft was fluence rate- and fluence-dependent while the rat tumour exposed to the same conditions demonstrated neither of these dependencies. This disparity in response was not attributable to a difference in either whole-tumour uptake or subcellular distribution of the porphyrin photosensitiser. Analysis of the effects of visible irradiation on cytochrome c oxidase activity, measured in mitochondria prepared from tumours borne on hosts injected with photosensitiser, demonstrated that photoradiation-induced enzyme inhibition was significantly greater in mesothelioma than in R3230AC mammary tumour preparations. However, in parallel studies conducted in vitro, when photosensitiser and light were delivered to previously unperturbed mitochondria, rates of enzyme inhibition were not significantly different. Both tumours were established in long-term cell culture. While the uptake of porphyrin photosensitiser was equivalent in both cell lines, the R3230AC cells displayed a significantly greater photosensitivity than the mesothelioma cells. The data presented here demonstrate that the mechanisms that govern response to photodynamic therapy are complex, but in the case of these two xenografted tumours host response to therapy is not likely to play a significant role.
A phase I study of intravenous bryostatin 1 in patients with advanced cancer. J. Prendiville, D. Crowther, N. Thatcher, et al. 1993;68(2):418-24. PubMed · Publisher · Free full text

Abstract

Bryostatin 1 is a novel antitumour agent derived from Bugula neritina of the marine phylum Ectoprocta. Nineteen patients with advanced solid tumours were entered into a phase I study to evaluate the toxicity and biological effects of bryostatin 1. Bryostatin 1 was given as a one hour intravenous infusion at the beginning of each 2 week treatment cycle. A maximum of three treatment cycles were given. Doses were escalated in steps from 5 to 65 micrograms m-2 in successive patient groups. The maximum tolerated dose was 50 micrograms m-2. Myalgia was the dose limiting toxicity and was of WHO grade 3 in all three patients treated at 65 micrograms m-2. Flu-like symptoms were common but were of maximum WHO grade 2. Hypotension, of maximum WHO grade 1, occurred in six patients treated at doses up to and including 20 micrograms m-2 and may not have been attributable to treatment with bryostatin 1. Cellulitis and thrombophlebitis occurred at the bryostatin 1 infusion site of patients treated at all dose levels up to 50 micrograms m-2, attributable to the 60% ethanol diluent in the bryostatin 1 infusion. Subsequent patients treated at 50 and 65 micrograms m-2 received treatment with an intravenous normal saline flush and they did not develop these complications. Significant decreases of the platelet count and total leucocyte, neutrophil and lymphocyte counts were seen in the first 24 h after treatment at the dose of 65 micrograms m-2. Immediate decreases in haemoglobin of up to 1.9g dl-1 were also noted in patients treated with 65 micrograms m-2, in the absence of clinical evidence of bleeding or haemodynamic compromise. No effect was observed on the incidence of haemopoietic progenitor cells in the marrow. Some patients' neutrophils demonstrated enhanced superoxide radical formation in response to in vitro stimulation with opsonised zymosan (a bacterial polysaccharide) but in the absence of this additional stimulus, no bryostatin 1 effect was observed. Lymphocyte natural killing activity was decreased 2 h after treatment with bryostatin 1, but the effect was not consistently seen 24 h or 7 days later. With the dose schedule examined no antitumour effects were observed. We recommend that bryostatin 1 is used at a dose of 35 to 50 micrograms m-2 two weekly in phase II studies in patients with malignancies including lymphoma, leukaemia, melanoma or hypernephroma, for which pre-clinical investigations suggest antitumour activity.
Phase I/II study of a short course of weekly cisplatin in patients with advanced solid tumours. A.S. Planting, M.E. van der Burg, M. de Boer-Dennert, et al. 1993;68(4):789-92. PubMed · Publisher · Free full text

Abstract

Twenty-five patients with advanced solid tumours were entered in a phase I/II study of six, weekly cycles of cisplatin. Nineteen patients were chemonaive and six were previously treated. The starting dose was 50 mg m-2 week-1. This dose could be escalated without major toxicity to 70 mg m-2 week-1. At a dose of 80 mg m-2 myelosuppression grade 3 occurred as well as grade 1 nephro- and neurotoxicity. The maximum tolerated dose was 85 mg m-2 with dose limiting thrombocytopenia. Hypertonic saline was effective in preventing nephrotoxicity. Ondansetron was a very effective antiemetic in the first weeks of treatment but its efficacy waned later on. Responses were observed in head and neck cancer, melanoma and mesothelioma. At the dose level of 80 mg m-2 the optimal dose intensity was reached. This schedule will be tested further in phase II studies.
Expression of metalloproteinases and their inhibitors in primary pulmonary carcinomas. S.J. Urbanski, D.R. Edwards, A. Maitland, et al. 1992;66(6):1188-94. PubMed · Publisher · Free full text

Abstract

Nine primary pulmonary carcinomas, one metastatic carcinoma, and two malignant pleural mesotheliomas have been analysed for the expression at the mRNA level of metalloproteinases (MPs) and tissue inhibitors of MPs (TIMPs). In situ hybridisation showed TIMP-1 and TIMP-2 transcripts predominantly over tumour stroma and gelatinases evenly distributed over both stromal and tumour cells. While both TIMP-1 and TIMP-2 were expressed in non-neoplastic lungs (NNL) as well as in carcinomas, stromelysin 3 (ST3), 92 kDa gelatinase and interstitial collagenase were expressed only by carcinomas. Expression of these MPs by carcinomas was independent of histologic type and such tumour features as fibrosis or necrosis. The consistent expression of ST3 by all of the carcinomas examined and absence of its expression in NNL indicates that ST3 production is likely associated with the malignant phenotype. However, since 92 kDa gelatinase and interstitial collagenase transcripts were found in some but not all tumour samples, their expression is not a uniform feature of pulmonary carcinomas. The possible prognostic significance of the expression of the latter two enzymes by carcinomas remains to be established.
High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study. O.P. Solheim, G. Saeter, A.M. Finnanger, et al. 1992;65(6):956-60. PubMed · Publisher · Free full text

Abstract

From 1984 to 1989, 63 patients with diffuse, malignant mesothelioma of the pleura were treated with 4-8 courses of high-dose methotrexate (HDMTX, 3 g total dose) and citrovorum factor rescue. There were 61 male and two female patients of median age 60 years. CT scan was performed before and after treatment and used for response evaluation. Of 60 patients evaluable for response, 37% showed partial or complete remission, 32% showed no change and 32% showed progressive disease. Median survival from start of treatment for all patients was 11 months, for 42 patients with the epithelial type 12 months, and for 20 patients with sarcomatous or mixed types only 5 months. Toxicity was acceptable, with only five patients (8%) terminating therapy due to toxicity. One toxic death occurred. We conclude that HDMTX is an active regimen in malignant pleural mesothelioma. The significantly shorter survival for patients with the sarcomatous or mixed subtypes indicates that further investigations on the activity of HDMTX in mesothelioma should be limited to patients with the epithelial subtype.
Three types of human lung tumour cell lines can be distinguished according to surface expression of endogenous urokinase and their capacity to bind exogenous urokinase. R. Schwartz-Albiez, H.H. Heidtmann, D. Wolf, et al. 1992;65(1):51-7. PubMed · Publisher · Free full text

Abstract

This study evaluates the cell surface expression of urokinase-type plasminogen activator (u-PA) and the capacity to bind exogenous urokinase as possible parameters for the distinction of various types of human lung tumours. Twelve different tumour cell lines including four small cell carcinoma, two large cell carcinoma, three squamous cell carcinoma, one adenocarcinoma and two mesothelioma cell lines of lung origin were investigated. Surface expression of endogenous u-PA was determined in a cellular radioimmunoassay (CRIA) using the u-PA-specific monoclonal antibody 98/6. To estimate additional u-PA binding capacity, exogenous two-chain, 54 kDa u-PA was employed in the CRIA. The influence of phorbol ester (PMA) treatment on expression and binding of these molecules was studied. Three different groups of lung tumour cell lines could be distinguished according to their expression of u-PA and u-PA-binding ability: (i) non small cell lung carcinoma (NSCLC) cell lines of squamous cell carcinoma/adenocarcinoma origin expressed small amounts of u-PA and bound little u-PA. Large cell carcinoma cell lines expressed high amounts of u-PA and bound large amounts of u-PA. In general, expression of u-PA and u-PA binding was enhanced after PMA treatment. (ii) Mesothelioma cell lines did not express u-PA, but were able to bind u-PA. (iii) Small cell carcinoma (SCLC) lines were devoid of surface-expressed u-PA and could not bind u-PA, both under untreated and PMA-treated conditions. It could thus be demonstrated that these three groups of lung tumour cell lines differ in their ability to express u-PA and to bind external u-PA. This may reflect the different in vivo growth behaviour and origin of the respective tumour groups.
Further evidence of an excess of risk of pleural malignant mesothelioma in textile workers in Prato (Italy). E. Paci, M. Zappa, L. Paoletti, et al. 1991;64(2):377-8. PubMed · Publisher · Free full text

Summary

An earlier study found that six of 13 pleural malignant mesothelioma (PMM) cases in the Province of Florence, Italy, in 1979-1984 had worked in the Prato textile industry, five of them as rag sorters. A later hygiene survey showed that Prato textile workers were exposed to asbestos through recycled bags that had contained asbestos fibres. In this follow-up, the authors re-examined already diagnosed PMM and all cases of pleural cancerous infiltration from 1970-1988 held in the archives of the Department of Pathology of the University of Florence. Trained nurses interviewed cases or their nearest living relatives using a structured questionnaire on smoking, work history and asbestos exposure. Of 61 PMM cases (44 males, 17 females) among provincial residents, 22 (16 males, six females) had ever worked in textiles, 16 of them as rag sorters. One interview was refused, and relatives of another case could not be traced. Among the textile cases, mean age at first exposure was 31.6 years, mean duration of textile work 24.4 years and mean latency 29.8 years. Electron microscopy of the only two adequate lung samples showed 2,387 and 10,146 asbestos fibres per mg (crocidolite; crocidolite and chrysotile). Both were above the 1,000 f/mg value taken as indicating occupational exposure. Six textile cases had worked only in later production phases. The authors concluded that the results confirmed a high incidence of mesothelioma among Prato textile workers, especially rag sorters. They warned that asbestos-related tumours could arise from unknown and unexpected sources.

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.
Photodynamic therapy with chlorins for diffuse malignant mesothelioma: initial clinical results. H.B. Ris, H.J. Altermatt, R. Inderbitzi, et al. 1991;64(6):1116-20. PubMed · Publisher · Free full text

Abstract

Four patients underwent intraoperative photodynamic therapy after surgery with meso-tetra-(hydroxyphenyl)-chlorin (mTHPC-PDT) for diffuse malignant mesothelioma. Preliminary procedures were performed in two patients in order to establish the efficacy of mTHPC-PDT and to optimise its tumoricidal effect. The tumoricidal effect was related to the mTHPC dose, light dose and the time interval between sensitation and activation. 0.3 mg kg-1 mTHPC activated after 48 h with 10 Joules cm-2 of non-thermal laser light at 650 nm resulted in a 10 mm deep tumour infarction, due to tumour vessel necrosis and thrombosis. The mTHPC tissue concentration was up to 14 times higher in the tumour than in normal tissues. Skin photosensitivity was mild, dose dependent and occurred 3 to 10 days after administration of mTHPC. According to the results obtained, intraoperative mTHPC-PDT was performed following pleuropneumonectomy in two, pleurectomy and lobectomy in one and pleurectomy in one patient. Ten Joules cm-2 were delivered to the diaphragm and the costophrenic sulcus and 5 Joules cm-2 to the remaining thoracic cavity. The postoperative course was marked by loss of appetite, fluid retention, hypoproteinemia and severe chest pain. One patient succumbed from aspiration pneumonia. The remaining patients developed no neural or vascular alterations and no bronchial stump insufficiency during follow-up. mTHPC-PDT following surgical tumour resection deserves further evaluation in good risk patients with diffuse malignant mesothelioma.
Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody. H. Dazzi, P.S. Hasleton, N. Thatcher, et al. 1990;61(6):924-6. PubMed · Publisher · Free full text

Abstract

The expression of epidermal growth factor receptor (EGF-R) in 34 formalin fixed paraffin embedded specimens of malignant mesothelioma was examined using the F4 antibody. Eight samples of reactive pleura showed homogenous cytoplasmic staining with the antibody. EGF-R positive cells (greater than or equal to 5%) were found in 68% of the mesotheliomas examined. EGF-R positivity was more commonly seen in the epithelial histological subtype than in the sarcomatous or mixed subtypes. Patients with less than 5% of mesothelioma cells staining positive for EGF-R had a significantly shorter survival (median 299 days) compared with patients whose tumours had a greater number of cells positive for EGF-R (median 446 days) (P = 0.04). However, when the histological subgroup was also taken into consideration (epithelial type had a significantly longer survival than the sarcomatous or mixed) the survival difference in relation to EGF-R positivity was no longer significant (P = 0.08). EGF-R could not be used to distinguish between malignant and benign mesothelial tissue and was not an independent prognostic factor for survival.
Phenotypic stability and metastatic behaviour of serially xenografted rat mesotheliomas. R.E. Edwards, R.J. Hill, D.G. Brown, et al. 1990;62(2):201-4. PubMed · Publisher · Free full text

Abstract

Mesotheliomas induced in rats by intrapleural injection of the fibrous zeolite, erionite, were serially transplanted in nude mice for up to ten generations. The cell phenotypes (epithelial or sarcomatous) were well maintained during passaging, as determined morphologically and by the expression of the cytokeratin markers demonstrated in normal mesothelial cells. Some of the tumours occasionally produced metastasis in nude mice. In contrast, a cloned epithelial cell mesothelioma and sarcomatous cell mesothelioma, the original cells of which were isolated in tissue culture, both produced regular multiple metastases when passaged in nude mice. These metastases were frequently found on the visceral pleura, rather than in the lung parenchyma, in nude mice. The high metastatic rate of the xenograph mesotheliomas derived by in vitro isolation of cells from mesotheliomas is atypical of the usual behaviour of xenografts of mesotheliomas.

1980s

Chromosomal abnormalities and their correlations with asbestos exposure and survival in patients with mesothelioma. M. Tiainen, L. Tammilehto, J. Rautonen, et al. 1989;60(4):618-26. PubMed · Publisher · Free full text

Abstract

Cytogenetic findings of our 30 previously reported and eight new patients with malignant pleural mesothelioma were summarised and correlated with asbestos fibre burden in lung tissue and survival. Successful cytogenetic analyses were performed on cells obtained from the tumours and/or pleural effusions of 34 of the 38 patients. Clonal chromosomal abnormalities were detected in 25 patients, 19 of them studied before treatment. Nine patients, seven of them studied before treatment, had normal karyotypes and/or non-clonal chromosomal abnormalities. Most of the karyotypic findings in the patients with clonal abnormalities were complex and heterogeneous, and no chromosome aberration specific to mesothelioma could be demonstrated. The following numerical abnormalities in decreasing order of frequency were preferentially present in karyotypic changes: -22, +7, -1, -3, -9, +11 and -14 (-/+ denoting partial or total loss or gain). Translocations and deletions involving a breakpoint at 1p11-p22 were the most frequent structural aberrations. Statistically significant correlations were found between high content of asbestos fibres in lung tissue and partial or total losses of chromosomes 1 and 4, and a breakpoint at 1p11-p22 (P = 0.0001, P = 0.003, P = 0.009, respectively). The number of copies of chromosome 7 short arms was inversely correlated with survival (P = 0.02). In this study no diagnostic cytogenetic markers of mesothelioma were found, instead the copy number of chromosome 7 short arms turned out to be a possible prognostic factor in malignant mesothelioma.
Expression of the small cell carcinoma antigens of cluster-5 and cluster-5A in primary lung tumours. A. Maier, U. Schmidt, R. Waibel, et al. 1989;59(5):692-5. PubMed · Publisher · Free full text

Abstract

The expression of the small cell carcinoma (SCLC) antigens cluster-5 (antibody LAM8) and cluster-5A (antibody SWA20) was examined on a panel of routinely processed biopsy or surgical specimens of 290 lung tumours by immunoperoxidase staining. Antigen expression was largely restricted to SCLC. Of over 150 tissue samples evaluated, moderate or strong antigen expression was found in 49% (cluster-5) and 45% (cluster-5A). Concordance in expression of the two antigens was seen in 71% of SCLC samples, with 35% expressing both antigens strongly, 8% moderately and 28% being negative for both antigens. Antigen expression was independent of the morphological subtype of SCLC. Primary lung tumours of other histology, including squamous cell carcinoma, large cell carcinoma, adenocarcinoma, mesothelioma or carcinoid had no significant antigen expression. Of 135 tumours, strong or moderate expression of both antigens was seen only in two cases. 20%, mostly carcinoids, were weakly positive for cluster 5 and 4% for cluster 5A antigen. The remainder were antigen negative. No significant antigen expression was seen in 25 normal lung tissues. The membrane antigens of SCLC cluster 5 and 5A are markers for SCLC and their expression in tissues is tumour-associated.
Induction of mesothelioma by intraperitoneal injections of ferric saccharate in male Wistar rats. S. Okada, S. Hamazaki, S. Toyokuni, et al. 1989;60(5):708-11. PubMed · Publisher · Free full text

Abstract

Iron appears to play a major role in catalysing free radical production, leading to lipid peroxidation and DNA damage. We, therefore, investigated the effect of colloidal iron deposited in the peritoneum. Wistar male rats were given either ferric saccharate, ferric saccharate and nitrilotriacetic acid (NTA), NTA or saline. NTA was shown previously to 'free' iron to promote lipid peroxidation and an iron chelate of NTA is known to be carcinogenic to the kidney. Iron at a dose of 5 mg kg-1 day-1, and saline at a dose of 0.5 ml day-1 were injected i.p. for 3 months. NTA at a dose of 83.5 mg kg-1 day-1 was give i.p. for 5 months. All the rats were killed about a year later for histological examination. In nine of the 19 rats treated with ferric saccharate, mesothelial tumors were induced in the serosa of the tunica vaginalis or the length of the spermatic cord. Among rats treated with ferric saccharate and NTA, seven had localised mesotheliomas in the above locations and six had wide-spread peritoneal mesotheliomas. No mesothelial tumors developed in either NTA treated or saline treated rats. No pleural mesotheliomas were found in any group. These findings add to the evidence that iron is involved in some carcinogenic processes.
A study of guanidinobenzoatase during development of mesothelioma induced in the rat by fibrous erionite. F.S. Steven, R.J. Hill. 1988;58(5):610-3. PubMed · Publisher · Free full text

Abstract

Exposure to the fibrous mineral erionite is known to induce mesothelioma in man and laboratory animals. Previous studies demonstrated the presence of a trypsin-like protease associated with tumour cells. This protease could be demonstrated by the use of fluorescent probes which located cells possessing this enzyme. We have employed this fluorescent probe technique to follow the early events in the lungs of rats exposed to erionite. The evidence presented shows that the mesothelial cells initially lack this enzyme but the enzyme can be detected within hours of exposure of the rat to erionite. The number of mesothelial cells possessing the enzyme steadily increased after a single exposure to the mineral until the animal finally died with a massive pleural tumour. This is the first study of such fluorescent probes in the early stages of tumour induction.
Progressive growth of a human pleural mesothelioma xenografted to athymic rats and mice. C.J. Lindén, L. Johansson. 1988;58(5):614-8. PubMed · Publisher · Free full text

Abstract

A human malignant pleural mesothelioma was xenografted serially in athymic nude Rowett rats for 27 passages during 33 months. After the two initial passages (P), the take rate during P3-9 was 100% (192/192). The tumour grew progressively during P3-9 in 99% (190/192) and regressed totally in 1% (2/192). The take rate for the tumour xenografted to athymic BALB/c mice was also 100% (17/17) and no regressions were observed. During serial passaging in nude rats, the tumour-volume doubling time (TD) decreased from 6 days in P2 to 3 days in P8-9 (P less than 0.001) and then remained around 3 days during P10-25. A TD of 11 days in P1 (man-mouse) for tumours grown in mice decreased during 10 passages in rats to 4 days (P less than 0.005) when the tumour was transplanted to mice in P11. Light microscopic morphology of the tumour was retained in rats and mice. We believe that our experimental tumour model using the nude rat as a carrier of the xenograft will be useful for studies of human mesothelioma.
The role of catalytic iron in asbestos induced lipid peroxidation and DNA-strand breakage in C3H10T1/2 cells. C.J. Turver, R.C. Brown. 1987;56(2):133-6. PubMed · Publisher · Free full text

Abstract

The involvement of catalytic iron in the vitro activities of crocidolite asbestos has been investigated. Exposure of C3H10T1/2 cells to either the UICC crocidolite standard reference sample or a non fibrous (milled) derivative resulted in an increase of thiobarbituric acid reactive substances. This catalytic activity was inhibited by pretreatment with the iron chelator desferrioxamine. The effect of this activity on cellular DNA was measured in an assay based on the production of DNA-strand breaks. Increased levels of DNA-strand breaks were detected in cultures treated with both the milled and UICC crocidolite. Inclusion of desferrioxamine with the asbestos inhibited DNA-strand breakage. It is concluded the catalytic iron present on the dust is capable of damaging both lipid and DNA and that this could be an important mechanism in asbestos pathogenicity.
The in vitro genetic effects of fibrous erionite and crocidolite asbestos. K.T. Kelsey, E. Yano, H.L. Liber, et al. 1986;54(1):107-14. PubMed · Publisher · Free full text

Abstract

Epidemiologic evidence has recently identified an association between an endemic outbreak of pleural and peritoneal mesothelioma in the Urgup region of Turkey and exposure to zeolite fibres. This malignancy is usually associated with exposure to asbestos dusts whose mineralogical characteristics differ from those of zeolites. The present study further defines the in vitro biologic activity of erionite, a common zeolite fibre found in the Urgup region of Turkey. Both erionite and crocidolite asbestos fibres were clastogenic in synchronous Chinese hamster ovary (CHO) fibroblasts. Both fibres also altered CHO ploidy. Erionite, unlike crocidolite or Min-U-Sil quartz, caused a slight increase in sister chromatid exchanges in synchronous CHO cells. Neither erionite nor crocidolite was mutagenic in a human lymphoblastoid cell line. Erionite fibres thus produced in vitro cytogenic changes similar to those caused by asbestiform mineral dusts and, like asbestos fibres, did not induce mutations in human lymphoblastoid cells.
Correlation of in vitro genotoxicity and oncogenicity induced by radiation and asbestos fibres. T.K. Hei, C.R. Geard, R.S. Osmak, et al. 1985;52(4):591-7. PubMed · Publisher · Free full text

Abstract

The in vitro cytotoxicity and oncogenic potential of both native and acid leached asbestos fibres were studied using the C3H 10T1/2 cell model. Both native and leached fibres induced a dose-dependent toxicity. At high fibre concentrations, acid leached fibres were significantly less toxic than their untreated counterparts. While asbestos fibres alone do not induce oncogenic transformation at the concentration examined, it was found that both leached and native fibres substantially enhanced the oncogenicity of gamma-irradiation in a more than additive fashion. Although no significant chromosomal aberrations or sister chromatid exchanges (SCE) were found in asbestos treated cultures, a significantly higher number of SCEs was observed in cells treated with both asbestos and radiation compared to cells receiving radiation alone. The results suggest that the enhancement in radiation induced oncogenicity by asbestos fibres may be attributed to the mere physical presence of the fibres rather than any chemical contaminants the fibres may contain. Furthermore, the carcinogenicity of asbestos may be unrelated to genotoxicity.
Erionite exposure and mesotheliomas in rats. J.C. Wagner, J.W. Skidmore, R.J. Hill, et al. 1985;51(5):727-30. PubMed · Publisher · Free full text

Abstract

Epidemiological and environmental surveys in the Cappadocian region of Turkey have linked the high incidence of pleural and peritoneal mesothelioma in the occupants of some villages with the zeolite fibres released from the locally occurring volcanic tuff. In view of the low ambient fibre concentrations and the extraordinary incidence of mesothelioma a study to test the hypothesis of high biological activity for the zeolite fibres was required. Experimental studies using both intrapleural inoculation and inhalation techniques have been undertaken with the erionite from this region and from Oregon in the United States. Additionally a non-fibrous zeolite from Japan and a synthetic non-fibrous zeolite of similar chemical composition to erionite have been included in the experiments. In these studies the samples from Oregon and Turkey produced a very high incidence of tumours. All the rats inoculated intrapleurally with Oregon erionite and almost all those inoculated with the Turkish fibre died with a mesothelioma. Inhalation of the Oregon erionite induced a similar effect. No other dusts we have investigated have produced this high incidence of tumours particularly following inhalation. These studies demonstrate that we now have a valuable new fibre for experimental study and a possible hazard to man in regions other then Turkey.
Mesothelioma of the peritoneum during 1967-82 in England and Wales. M.J. Gardner, R.D. Jones, E.C. Pippard, et al. 1985;51(1):121-6. PubMed · Publisher · Free full text

Abstract

The time-trend and geographical distribution of mesothelioma of the peritoneum during the years 1967-82 in England and Wales have been studied from the Mesothelioma Register held by the Medical Division of the Health and Safety Executive. Over the 16-year period the annual number of cases registered rose from about 15-20 to about 30-50. Although the number occurring in men was double that in women, the trend was similar for both sexes. There is likely to be some further increase before any improvement due to the recent diminished usage of asbestos is seen. Local Authority areas with raised rates have been identified, and the geographical pattern is similar to that of the distribution of the asbestos-using industry in the past. In both sexes there are high registration rates on the east side of London but, in contrast to mesothelioma of the pleura, a concentration of cases among men in the major ports where shipbuilding and ship repairing were carried out is not so apparent.
Multipotential behaviour of cloned rat mesothelioma cells with epithelial phenotype. D.G. Brown, N.F. Johnson, M.M. Wagner. 1985;51(2):245-52. PubMed · Publisher · Free full text

Abstract

Reference cultures derived from a transplantable rat mesothelioma were obtained by cloning cells three times in soft agar. Each line, designated "CARM-Lines", was selected on the basis of their epithelial or fibroblastic phenotype, and their uniform morphology. Three epithelial lines were used for more detailed in vitro studies comparing morphological and biological criteria at early and late passages. All three lines exhibited both epithelial and fibroblastic elements after 10-14 passages in vitro, demonstrating that the dimorphic histology of these tumours could be derived from a single aberrant cell. Morphology and growth characteristics of these cells were density-dependent. Anchorage dependent and independent clonogenic assays did not correlate. Anchorage dependent colony formation was the only parameter which differed markedly from the original parent line in the assays described. In vivo evidence of chondrogenesis and attempted ossification support the concept of a multipotential cell contributing to the diverse primary tumour morphology by cellular modulation or differentiation.
Trend and distribution of mesothelioma in Denmark. M. Andersson, J.H. Olsen. 1985;51(5):699-705. PubMed · Publisher · Free full text

Abstract

The time trend and the distribution of malignant mesothelioma in Denmark are described on the basis of all notifications of cancer cases to the Danish Cancer Registry during the period 1943-1980. The age and sex adjusted incidence rates of pleural as well as peritoneal mesothelioma are increasing with time and reached in the latest 3-year registration period 1978-1980 a remarkably high total incidence of 14.7 cases per million men and 7.0 cases per million women. Towards the end of the observation period, however, the rate of increase was stagnating and for the younger age-groups even a fall in incidence of this malignancy was noted, perhaps reflecting the introduction of compulsory hygienic precautions in the handling of asbestos in Denmark. The incidence and time trend of peritoneal mesothelioma was similar among males and females while pleural mesothelioma was three times more common among males compared with females and showed an increase in incidence 15 years previous to females. For pleural mesothelioma in men notified through the 10-year period 1968, 1977, a significant excess was associated with residence in areas with high degrees of urbanization and in ship building towns.
Asbestos, radiation and oncogenic transformation. T.K. Hei, E.J. Hall, R.S. Osmak. 1984;50(5):717-20. PubMed · Publisher · Free full text

Summary

This short communication reported a laboratory study of how asbestos and gamma radiation interact in damaging cells and making them cancerous (oncogenic transformation). The authors wanted to clarify how asbestos causes cancer and whether its known synergism with cigarette smoke also occurs with agents other than chemicals. They used C3H 10T1/2 mouse embryo fibroblasts and UICC standard samples of crocidolite and amosite. Crocidolite at 2.5-50 µg/ml for 24 h caused a sharp, dose-dependent fall in colony survival and slowed cell growth, without appreciably changing saturation density. Amosite was similarly cytotoxic. For the transformation assays, cells received 5 µg/ml of fibres for 24 h, 4 Gy of gamma rays from a cesium-137 source, or both, and transformed foci were scored after 6 weeks. Five experiments involving 1,500 dishes were included. Neither fibre alone raised transformation significantly above the spontaneous rate. Fibre pretreatment followed by irradiation gave significantly higher transformation frequencies than radiation alone (P<0.001 for crocidolite, P<0.01 for amosite). Per surviving cell, these were 5.18-6.42 x 10^-4 with crocidolite plus radiation and 3.10-5.04 x 10^-4 with amosite plus radiation, against 1.47-1.70 x 10^-4 with radiation alone. Adding 0.1 or 1.0 µg/ml fibres 3 days after 2 Gy of radiation produced no enhancement. The authors concluded that asbestos acted as a co-carcinogen rather than a promoter in this system.

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.
The effect of fibre size on the in vivo activity of UICC crocidolite. J.C. Wagner, D.M. Griffiths, R.J. Hill. 1984;49(4):453-8. PubMed · Publisher · Free full text

Abstract

Standard (UICC) crocidolite was subjected to ball milling to reduce the length of the fibre. These milled materials and the original standard sample were injected into the pleural cavity of rats to determine their ability to induce mesothelioma. Previous in vitro work on the same materials had suggested that biological activity was related to fibres greater than 6.5 microns in length and that the material milled for 4 and 8 h did not contain fibres in this range and was biologically inactive. The results of the animal work, however, did not follow this pattern; mesotheliomas occurred in rats in all treatment groups including the 4 and 8 h milled samples. Examination of the tissues and the dust recovered from them showed the presence of fibres greater than the suggested threshold. Attention is drawn to the problems associated with drawing conclusions from size distributions and in vitro studies without considering in vivo mechanisms.
HLA-A and B antigen frequencies and mesothelioma in relation to asbestos exposure. M.M. Wagner, C. Darke, R.M. Coles, et al. 1983;48(5):727-30. PubMed · Publisher · Free full text

Summary

This short communication asked whether HLA-A and HLA-B tissue types are associated with mesothelioma in relation to asbestos exposure. The authors HLA typed 71 mesothelioma patients from 7 UK centres (Belfast, Cardiff, Carlisle, Derby, Liverpool, London and Plymouth). Diagnosis was confirmed by post-mortem histology in 54 cases and by biopsy in 11, with agreement required between at least two pathologists; in 6 cases only pleural effusion cytology was available. Asbestos exposure was graded with an exposure rating (exposure code x years in job). Patients were compared with pooled random unexposed control populations (5,863 individuals). The 27 Plymouth (Devonport Dockyard) patients were also compared with five local asbestos-exposed groups, including a 135-person case-control group and 230 dockyard workers with radiographic abnormalities, and with 298 unexposed people from South West England. The 18 Liverpool patients were compared with 616 local blood donors. Typing covered 14 HLA-A and 30 HLA-B antigens. Using uncorrected P<0.05, the total mesothelioma group showed a slight decrease in HLA-A11 (2.8% vs 12.1%) and an increase in BW21 (9.9% vs 3.8%). HLA-B12 was associated with the occupationally exposed group (59.1% vs 29.8%). Plymouth patients showed increased HLA-A2 (74.1%) and decreased HLA-B8 (7.4%) compared with the exposed and unexposed local groups. The Liverpool patients showed no differences. All differences became non-significant after correction for the number of antigens tested. The authors suggested that HLA may be associated with variations in the 'walling up' of fibres in the pleural cavity, and noted that the differences were clearly associated with the Devonport population.

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In vitro genotoxic activities of fibrous erionite. A. Poole, R.C. Brown, C.J. Turver, et al. 1983;47(5):697-705. PubMed · Publisher · Free full text

Abstract

A high incidence of mesothelioma has been reported from some villages in Cappadocia, Turkey. This type of cancer is usually associated with the inhalation of asbestos, but on the basis of the most prevalent fibre in the dust from these villages, the Turkish outbreak has been attributed to the inhalation of zeolite fibres. A counter hypothesis, based on the detection of very small quantities of chrysotile and tremolite in strata samples and human lung tissue, postulates a significant role of these minerals as one of several factors contributing to pleural disease. A respirable fraction of erionite, (from Oregon, USA, but with similar characteristics to the fibres found in Turkey), has some in vitro genotoxic properties associated with many conventional carcinogens. In this study these fibres caused an increase in morphological transformation and unscheduled DNA repair synthesis (UDS) in C3H10T1/2 cells and UDS in the human lung cell line--A549. It is therefore suggested that exposure to fibrous erionite alone may be sufficient to cause the high incidence of pleural tumours observed in Turkey.
Biological effects of tremolite. J.C. Wagner, M. Chamberlain, R.C. Brown, et al. 1982;45(3):352-60. PubMed · Publisher · Free full text

Abstract

Tremolite is an amphibole which has been implicated in a variety of disease patterns in different parts of the world. It occurs in a number of phases, which are chemically identical but have specific physical characteristics. In an attempt to clarify the epidemiological findings, tremolite fibres of 3 specific forms--A, B and C--were characterized and studied for biological activity by: (i) in vivo intrapleural injection of rats (2 separate experiments--1 with poor survival). (ii) in vitro enzyme release from mouse peritoneal macrophages (iii) in vitro giant-cell formation in A549 cultures (iv) in vitro cytotoxicity for V79-4 cells. Sample C, which contained more long thin fibres than A and B, was alone in producing mesotheliomas. C, but not A or B, induced LDH and B-glucuronidase enzyme release, and induced giant cells. A was not cytotoxic, B moderately cytotoxic and C as highly cytotoxic as UICC crocidolite. The in vivo studies were marred by being split between 2 experiments, of which the second had poor survival. We are aware of the weakness of our in vivo data, but as Tremolite C was being considered for commercial use on the European market we felt it timely to submit our findings for publication.
Cimetidine and therapy of rodent tumours. D. Hannant, K. James, R.E. Bolton, et al. 1982;45(4):613-4. PubMed · Publisher · Free full text
Histology and ultrastructure of serially transplanted rat mesotheliomas. J.C. Wagner, N.F. Johnson, D.G. Brown, et al. 1982;46(2):294-9. PubMed · Publisher · Free full text

Summary

This short communication described how the microscopic appearance of rat pleural mesotheliomas changed over repeated transplantation. Syngeneic PVG/C Norwegian hooded rats (26 males and 17 females, aged 6-7 weeks) were given an intrapleural injection of 20 mg of UICC crocidolite. Seven pleural mesothelioma tumour lines were established and maintained by subcutaneous serial passage, six of them for more than 20 generations. Tissue from primary tumours and from random tumour generations was examined by light microscopy, including staining for hyaluronic acid. Eight tumour generations were also examined by electron microscopy. All primary tumours were of mixed cell type. Three were mainly epithelial, three were predominantly spindle-celled, and one was an equal mixture that became predominantly spindle-celled. Some tumour lines alternated between mainly one cell type and the other in successive generations. A high mitotic rate was noted for all tumours by the third generation. The average time to reach the required size fell from 65 days in the first two generations to 35 days in later generations. Electron microscopy showed cells ranging from poorly differentiated epithelial-like cells to well-differentiated mesodermal cells. The secretory tumour contained intracellular lumens lined with microvilli. The authors concluded that the dimorphic pattern characteristic of mesotheliomas was maintained after subcutaneous transplantation. They also described a primitive cell with few distinguishing features and discussed its possible origins.

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Mesothelioma mortality in asbestos workers: implications for models of carcinogenesis and risk assessment. J. Peto, H. Seidman, I.J. Selikoff. 1982;45(1):124-35. PubMed · Publisher · Free full text

Abstract

Mesothelioma death rates in asbestos workers appear to be proportional to the 3rd or 4th power of time from first exposure under a wide range of conditions of exposure for both pleural and peritoneal tumours, though the peritoneal:pleural ratio depends on fibre dimension and type. Age at first exposure has little or no influence, however, which supports the "multi-stage" model of carcinogenesis under which the increase in most cancer incidence rates with age is due to a constant incidence of genetic or epigenetic accidents, rather than to progressive generalized changes in regulatory or immune function. These relationships provide a simple basis for risk assessment, and support the suggestion that mesotheliomas may constitute a high proportion of cancer deaths resulting from early exposure to asbestos.
Mortality from mesothelioma of the pleura during 1968-78 in England and Wales. M.J. Gardner, E.D. Acheson, P.D. Winter. 1982;46(1):81-8. PubMed · Publisher · Free full text

Abstract

The geographical distribution of mortality from mesothelioma of the pleura during the years 1968-78 in England and Wales has been studied using extracts from the death records held by the Office of Population Censuses and Surveys. Using the national death rate as standard, Local Authority areas with raised mortality are identified. The patterns are somewhat different for each sex. In men the high-mortality areas are mainly the major ports where shipbuilding and repairing have been concentrated, whereas in women areas where gas masks are manufactured are predominant. In both sexes there are also high death rates on the eastern side of London. Nearly all the areas of high mortality are known to have had a major asbestos-using industry in the past. Over the 11-year period the annual number of deaths from pleural mesothelioma rose by approximately 75%. This marked increase was virtually confined to men, in whom the number of deaths had reached almost 200 per annum by 1978. The indications are that the effect of past high exposures, in particular to amphibole asbestos, have not yet reached a peak in terms of mortality. On the other hand imports and usage of amphiboles, particularly crocidolite, have decreased rapidly since the mid-1960s, and dust levels in the working environment have improved even more radically.
The age-mortality curve of endemic pleural mesothelioma in Karain, Central Turkey. R. Saracci, L. Simonato, Y. Baris, et al. 1982;45(1):147-9. PubMed · Publisher · Free full text

Summary

This short communication examined how pleural mesothelioma mortality varied with age in Karain, a small village in Central Turkey (population 554 in 1978) with endemic mesothelioma. Earlier work had linked the village to airborne fibres resembling erionite, a zeolite mineral. Peto and colleagues had reported that mesothelioma rates rose as about the 3.2 power of time since first exposure in asbestos-exposed worker cohorts, and as a similar power of age in Los Angeles cases with no reported asbestos exposure. The authors included pleural mesothelioma deaths from 1970 to 1978: 24 cases identified mainly through retrospective record review (1970-74) without histology, and 26 cases investigated directly (1975-78), of which 19 (73%) had histopathological confirmation. They fitted maximum-likelihood linear regressions of log mortality rate on log age for ages 20-69, using population estimates from the local Health Centre Register. The best-fitting exponents of age were 1.86 for males, 3.07 for females and 2.39 for both sexes combined, with 95% confidence limits of ±1.4, ±1.8 and ±1.1. There was no evidence of departure from log-linearity. None of the estimates differed significantly from the exponent of 3.2 ± 0.7 reported for North American insulation workers. The authors concluded that the data were consistent with a common mesothelioma process that, without recognized occupational exposure, begins at or soon after birth.

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Failure to demonstrate tumour-associated transplantation antigens on asbestos-induced mesotheliomas in rats. D.G. Brown, J.C. Wagner, M.M. Wagner. 1980;42(5):797-801. PubMed · Publisher · Free full text
Treatments affecting the rate of asbestos-induced mesotheliomas. J.C. Wagner, R.J. Hill, G. Berry, et al. 1980;41(6):918-22. PubMed · Publisher · Free full text

Abstract

256 Wistar rats received a single injection into the right pleural cavity of UICC crocidolite in order to induce mesotheliomas. They were then given right intrapleural injectons of BCG, crystalline silica, talc, carrageenan or saline (as a control). There was no significant change in the mesothelioma rate in the rats exposed to BCG, silica or talc, but there was a 3-fold increase in mesothelioma incidence in the group injected with carrageenan.

1970s

Thymectomy and asbestos-induced mesotheliomas in rats. M.M. Wagner. 1979;39(3):337-41. PubMed · Publisher · Free full text
Mass and number of fibres in the pathogenesis of asbestos-related lung disease in rats. J.M. Davis, S.T. Beckett, R.E. Bolton, et al. 1978;37(5):673-88. PubMed · Publisher · Free full text

Abstract

Five groups of rats were treated by inhalation for 12 months, with the U.I.C.C. preparations of the 3 main commercially used asbestos types, chrysotile, crocidolite and amosite. The experiment was designed so that the effects of both fibre mass and fibre number could be examined. The results indicated that chrysotile dust caused far more lung fibrosis than either amphibole type even when the fibre numbers in the dust clouds were similar. All malignant pulmonary neoplasms found during this study occurred in animals treated with chrysotile. The fibre-number calculations used for the generation of dust clouds were evaluated using the parameters recommended by the Health and Safety Executive in 1976, by which all fibres over 5 microgram long are counted using a phase-contrast light microscopy. When fibre-length distributions were calculated using a scanning electron microscope, however, it was found that the chrysotile clouds used in this study contained many more fibres over 20 microgram long than either of the amphibole clouds. The results, therefore, support previous suggestions that long asbestos fibres are more dangerous than short. They also indicate that neither a single mass standard, nor the present fibre-number standards are satisfactory.
Treatment of transplanted rat tumours with double-stranded RNA(BRL 5907). II. Treatment of pleural and peritoneal growths. M.V. Pimm, R.W. Baldwin. 1976;33(2):166-71. PubMed · Publisher · Free full text

Abstract

Intrapleural growth of transplanted rat tumours was prevented or retarded by intrapleural administration of double-stranded RNA. A similar suppression of growth was achieved with peitoneal tumours by the intraperitoneal injection of the compound. These studies indicate the possible potential of this form of treatment of thoracic and peritoneal tumours for clinical application in the treatment of mesothelioma.
Part III: 7th Walter Hubert lecture. Pott and the prospects for prevention. R. Doll. 1975;32(2):263-72. Historical article PubMed · Publisher · Free full text
Proceedings: Asbestos carcinogenesis. J.C. Wagner. 1975;32(2):258-9. PubMed · Publisher · Free full text

Summary

This summary of a talk at the 16th Annual General Meeting of the British Association for Cancer Research reviewed cancers in people exposed to asbestos dust and whether they were linked to specific fibre types. Lung carcinoma was first reported in cases of asbestosis in 1935. By 1964, 60% of UK workers diagnosed with asbestosis to a degree warranting compensation developed carcinomata. Cigarette smoking and asbestosis were recognized as having a multiplicative carcinogenic effect. The carcinomata occurred in cases of definite asbestosis, all major commercial asbestos types were implicated, and incidence was higher in industry than in mining areas. Diffuse mesotheliomata of the pleura and peritoneum, first reported as a series from South Africa in 1960, could occur without lung scarring. They were more clearly associated with crocidolite from the Cape Province and, to a lesser extent, from Western Australia. They appeared long after first exposure, sometimes after exposure as brief as 6 weeks. A dust dosage relationship had been shown, and there was no evidence of an association with smoking. Surveys showed a slight but significant increase in gastrointestinal tumours, while a study of women asbestos workers showed no increase in ovarian tumours. In animals, intrapleural inoculation of all asbestos types produced mesotheliomata. Very fine chrysotile produced the most, and finer fibres gave more tumours. Inhalation studies produced lung carcinomata in rats, mostly in animals with moderate asbestosis, and a few mesotheliomata.

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Proceedings: B.C.G. treatment of pleural and peritoneal tumour growth in rats. M.V. Pimm. 1974;30(2):183. PubMed · Publisher · Free full text
The effects of the inhalation of asbestos in rats. J.C. Wagner, G. Berry, J.W. Skidmore, et al. 1974;29(3):252-69. PubMed · Publisher · Free full text

Abstract

Two experiments in which SPF Wistar rats were exposed by inhalation to dust clouds of the UICC standard reference samples for periods of between one day and 2 years are described. All the samples of asbestos produced asbestosis which continued to progress after removal from exposure but only a little fibrosis was observed in control rats. Lung tumours, ranging in severity from adenomata to squamous carcinomata, were produced by all samples but in the controls there were only a few adenomata and none of the more serious tumours. Of the 20 tumours which metastasized, 16 occurred after exposure to one or other of the 2 chrysotile samples. In addition, a total of 11 mesotheliomata occurred, 4 of which were with crocidolite and 4 with Canadian chrysotile. Two of the mesotheliomata occurred with only one day's exposure to asbestos. There was a positive association between asbestosis and lung tumours.
Mesotheliomata in rats after inoculation with asbestos and other materials. J.C. Wagner, G. Berry, V. Timbrell. 1973;28(2):173-85. PubMed · Publisher · Free full text

Abstract

Four experiments in which SPF Wistar rats were inoculated intrapleurally with asbestos or other materials are described. Mesotheliomata were observed in a considerable proportion of animals with all the samples of asbestos used and with a sample of brucite. A few were produced with synthetic aluminium silicate fibres and single ones with barium sulphate, glass powder and aluminium oxide. The risk of developing a mesothelioma at a given time after injection was approximately proportional to the dose. Of the UICC standard reference samples, crocidolite was the most carcinogenic and removal of the oils by benzene extraction did not alter the carcinogenicity of these samples. Chemical properties also seem unlikely to be the main factor producing mesotheliomata but the results support the hypothesis that the finer fibres are the more carcinogenic, and this is additional to the known aerodynamic advantage which the finer fibres have in penetrating to the periphery of the lung.
Nasal and other tumours in rats given 3,4,5-trimethoxy-cinnamaldehyde, a derivative of sinapaldehyde and of other alpha,beta-unsaturated aldehydic wood lignin constituents. R. Schoental, S. Gibbard. 1972;26(6):504-5. PubMed · Publisher · Free full text
Migration of asbestos fibres from subcutaneous injection sites in mice. K. Kanazawa, M.S. Birbeck, R.L. Carter, et al. 1970;24(1):96-106. PubMed · Publisher · Free full text

Abstract

Crocidolite asbestos fibres, suspended in physiological saline, were injected subcutaneously into one or both flanks of 95 CBA/Lac female mice; 75 control mice received injections of saline only. Most animals were killed at chosen intervals of between 2 and 42 days after injection but some were left for longer periods of up to 623 days. At autopsy, many lymphoid and non-lymphoid structures were removed and examined for the presence of asbestos by the following techniques: haematoxylin and eosin staining followed by conventional and polarized light microscopy; Perl's stain; microincineration followed by phase-contrast microscopy; maceration with KOH followed by phase-contrast microscopy; and electron microscopy.A combination of haematoxylin and eosin staining and microincineration was found to be the most convenient and reliable method for demonstrating asbestos fibres in the tissues. Electron microscopy was essential for detecting very small fibres and for locating them to specific intracellular structures.The morphological findings indicate that some migration of asbestos fibres away from the initial site of injection takes place. Dissemination is usually along lymphatic pathways and fibres tend to accumulate in the lymphoid tissues, particularly in the regional (axillary) lymph nodes; smaller amounts were found in inguinal, mediastinal and lumbar nodes. The fibres were usually intracellular, lying inside the phagosomes of macrophages, but larger fibres weresometimes encountered lying free. Small numbers of fibres were seen in the spleen and also in non-lymphoid organs such as the liver, kidneys and brain-suggesting that some asbestos may enter the blood stream. There was no evidence of massive or selective spread to subserosal tissues in the thorax or abdomen, though trapping of asbestos fibres was observed in pleural "milky spots" in long-term survivors. The possible role of milky spots in the development of pleural plaques and mesotheliomata is discussed.

1960s

Contaminating organic material in asbestos. B.T. Commins, G.W. Gibbs. 1969;23(2):358-62. PubMed · Publisher · Free full text

Abstract

Evidence is presented that shows that asbestos contains organic material, some of which arises by contamination when the fibre has been stored in bags made of polythene. The contamination comprises not only the constituents of polythene, but also some of their oxidation products formed when they make contact with asbestos. Some of these products have been identified. It is known that organic material extracted from asbestos is weakly carcinogenic; it is not known however whether the oxidation products of some constituents of polythene are carcinogenic, but the implications of this finding are discussed.

PubMed has no abstract for this study. This is the authors' abstract, copied from the article.
Mesotheliomas in rats following inoculation with asbestos. J.C. Wagner, G. Berry. 1969;23(3):567-81. PubMed · Publisher · Free full text

Abstract

SPF and Standard rats were inoculated intrapleurally with samples of amosite, chrysotile, crocidolite (natural and with the oils extracted) and saline. With all types of asbestos an appreciable proportion of animals developed a mesothelioma but none of the saline controls developed such a tumour. The histological features of these tumours are described. The survival times have been analysed by sub-dividing the mortality into two independent components, one due to mesotheliomas and the other to natural causes. For all types of asbestos there was a rapid onset of mesotheliomas after an initial period during which none occurred, but this initial period was dependent on the type of asbestos, being longer for amosite than for chrysotile or crocidolite. No evidence was provided of any difference in effect between the natural and oil extracted forms of crocidolite.

PubMed has no abstract for this study. This is the authors' abstract, copied from the article.
The application of a mathematical model describing the times of occurrence of mesotheliomas in rats following inoculation with asbestos. G. Berry, J.C. Wagner. 1969;23(3):582-6. PubMed · Publisher · Free full text

1950s

Carcinoma and asbestosis of the lung; report of a case. T.K. Owen. 1951;5(4):382-3. PubMed · Publisher · Free full text

1940s

Squamous cell carcinoma occurring in asbestosis of the lung. R.J. Cureton. 1948;2(3):249-53. PubMed · Publisher · Free full text

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