Mesothelioma TreatmentOther Sources
Fifth Meeting of the International Mesothelioma Interest Group (IMIG) - October 7, 1999
IMIG report
Summary
October 6, 1999
October 7, 1999
October 8, 1999
Thursday morning began the concurrent sessions with presentations divided into IMIG and PAX. Only IMIG sessions will be described in the following summary. The session "Disease Staging and Litigation," chaired by Professor Philippe Chahinian (New York, USA) and Dr. Paul Baas (Amsterdam, Netherlands) commenced with Dr. Valerie Rusch (New York, USA), who summarized the different staging systems for pleural mesothelioma, starting with Butchart and ending with the IMIG system. The T factor has prognostic significance (T1-T2 better than T3-T4), as well as the N factor (lymph nodes negative or positive) and the epithelial cell type has the best survival rates. There was no major survival differences with the extent of surgery (extrapleural pneumonectomy versus pleurectomy-decortication).
Mr. James Early (New York, USA) then discussed legal issues associated with asbestos exposure and mesothelioma, and reviewed some early correspondence from different companies discussing the health effects of asbestos. It was clear that many asbestos related companies were fully aware of the detrimental effects of asbestos well before its use was stopped or adequate health and safety precautions implemented.
The late morning session, entitled "Gene Therapy and Free Communications," commenced with Dr. Steven Albelda (Philadelphia, USA) who presented his experience with gene therapy of pleural mesothelioma. This trial, using an adenovirus vector with the H. simplex thymidine kinase gene, is designed to transfer this enzyme to tumor cells and make them susceptible to systemic administration of gancyclovir. In the initial Phase I trial involving 26 patients, the MTD (maximum tolerated dose) was not reached. Dr. Albelda discussed also the future of this therapy using possibly other vectors (H. simplex virus or liposomes) or heat shock protein to activate the immune response. Dr. Daniel Sterman (Philadelphia, USA) described the results seen in the 26 patients treated in Philadelphia by the gene therapy approach discussed by Dr. Albelda. There was evidence of gene transfer, although it was superficial. There was one partial response, and 2 patients remained without evidence of disease at 3 years.
Dr. Jeremy Steele (London, UK) discussed the results of a Phase II trial of vinorelbine in 29 patients with mesothelioma. There were 7 partial responses (26%), which is remarkable in view of the lack of efficacy of previous vinka alkaloids in this disease. About half of the patients reported symptomatic improvement. Dr. Richard Lake (Perth, Australia) investigated the different antigens associated with mesothelioma. The majority of these were nuclear antigens, and serum reactivity was seen in 30% of patients, without an obvious prognostic implication. Miss Claire Vivo (Creteil, France) described the cellular effects of interferon gamma in human mesothelioma cell lines. There was a decrease in tritiated thymidine uptake and a G2/M block in sensitive cell lines. This was independent of p53, p21 and p27. No cell line expressed SV-40.
After lunch, Dr. Courtney Broaddus (San Francisco, USA) and Professor Bruce Robinson (Perth, Australia) chaired a "Free Communication and Poster Discussion" session. A variety of talks and posters were presented and discussed concerning mesothelioma characteristics, role of SV40, clinical information on mesothelioma, and application of new technologies to identification of surface epitopes or genetic differences.
Examining malignant mesothelioma characteristics, Dr. Katalin Dobra (Stockholm, Sweden) used subtractive hybridisation to show that mesothelioma cells with an epithelial phenotype tended to express more genes, including syndecan-2 and -4, which suggested a more differentiated state than mesothelioma cells with a fibrous phenotype. Dr. John Edwards (Leicester, UK) found higher activity of MMP-2 and -9, the gelatinases, in mesothelioma tissue than in benign pleural tissue. Dr. Pascale Harvey (Norwich, UK) similarly found that human mesothelioma cell lines expressed the gelatinases, MMP-2 and -9. In addition, all lines expressed the tissue inhibitor of metalloproteinases, TIMP-1 and -2. Hepatocyte growth factor (HGF) increased expression of some metalloproteinases and also TIMP-1. Dr. Pier-Giacomo Betta (Alessandria, Italy) showed that N- and E-cadherins, cell-cell adhesion molecules reported to be mutually exclusive markers for mesothelioma and adenocarcinoma in tissue samples, respectively, were both expressed in mesothelioma cell lines. Dr. Yasushi Inoue (Hyogo, Japan) presented data suggesting that CD44, a hyaluronate receptor, may be a useful immunohisto- chemical marker for distinguishing mesothelioma from lung cancer. Dr. M. Valle (Italy) showed that mesothelioma cells can present recall antigens and can block interferon-gamma production, presumably by the production of TGFb.
The role of SV40 in mesothelioma pathogenesis was also discussed. In several studies, PCR amplification of SV40 from mesothelioma tissue was presented. Dr. Luciano Mutti (Borgosesia, Italy) found a trend in the appearance of SV40 and decreased one-year survival from mesothelioma. Dr. Rudy Foddis (Pisa, Italy) was able to amplify SV40-like sequences from paraffin-embedded mesothelioma tissue. Dr. Kazuhiko Takabe (Ibaraki, Japan), also found SV40 sequences in paraffin-embedded mesotheliomas. Interestingly, SV40 sequences could be amplified from peripheral blood cells in 3 (12%) patients: one with mesothelioma, one with malignant lymphoma and one with non-malignant disease. In contrast, in another study, no evidence of SV40 could be found. Dr. Roland Hbner (Antwerpen, Belgium) varied the methods of genomic DNA extraction, used several primers specific for SV40 or inclusive of other polyomaviruses BK and JC, included positive controls, used different stringencies and sequenced every amplicon. No SV40 DNA was found, although JC viral DNA was identified in one human mesothelioma. The discussion of this talk and the posters addressed the importance of incorporating controls in these studies (e.g. non-mesothelioma tumors, non-malignant tissues), as well as sequencing all amplified DNA to distinguish SV40 from other polyoma viruses. Indeed, standardisation of techniques and sharing of tissues appears necessary to resolve different results.
With the application of new techniques to mesothelioma, Dr. Joost Hegmanns (Rotterdam, Netherlands) presented a phage-antibody-display approach to isolating antibodies specific to cell surface molecules. Phages bound to mesothelioma cells were eluted, propagated and repeatedly selected and purified. Currently, 7 mesothelioma-specific phage antibody clones have been identified. This approach may provide useful reagents for diagnosis, for immunotherapy and for investigating mesothelioma-specific membrane proteins.
Dr. Kettunen's poster, presented by Dr. Sakari Knuuttila (Helsinki, Finland) showed findings of cDNA microarray technology analysis of 4 mesothelioma lines. Approximately 20 genes that were down regulated compared to benign mesothelial cells (< 0.5 expression) included VEGF R-2, PDGF-alpha receptor, retinoic acid receptor, tenascin-C and MMP-19. Approximately 30 genes that were most upregulated (> 3 times expression) included cytokeratin 4, FGF-3, JNK1, PDGF-beta receptor, NGF-2, cdc25b and cyclin D1 and D3.
Under the heading of "Epidemiology, clinical presentation and treatment of mesothelioma", Dr. Valeria Ascoli (Rome, Italy) reported an interesting cluster of 5 cases of mesothelioma in a family that has a strong history of respiratory tract cancer, suggesting a genetic predisposition as well as an environmental influence. Dr. John Edwards (Leicester, UK) presented retrospective data on 140 patients with mesothelioma in Leicester. Median survival was 4.9 months and one year survival was 25.7%. When these patients were stratified into published prognostic groups, they had equivalent survival statistics to those of other western countries. Dr. Edwards also reported that a measure of angiogenesis, Chalkley microvessel counts, correlated inversely with prognosis in mesothelioma. Dr. Gunnar Hillerdal (Stockholm, Sweden) found that a group of immigrants from Turkey with a high risk of mesothelioma due to erionite exposure did not have benign pleural changes on chest radiograph, suggesting that mesothelioma can develop without prior benign pleural disease.
Dr. Aija Knuuttila (Helsinki, Finland) reported that, although irinotecan (CPT-11, an active metabolite of ethylcamptothecin) appeared to be highly active against mesothelioma cells in vitro, it was disappointing in clinical trials. Irinotecan combined with docetaxel was toxic and not active in 15 patients with mesothelioma. The discussion included comments by those who find value in irinotecan and proposed that different dosing schedules should avoid limitations of toxicity.
The late afternoon session focussed on "Pathogenesis and Carcinogenesis of Mesothelioma." Papers presented in this session were related to markers in mesothelioma, potential new ways to challenge tumor proliferation, and effects of asbestos fibers on mesothelial cells in vitro and in vivo.
The poor effects of chemotherapy in mesothelioma may, in part, be explained by less efficient apoptotic mechanisms. Dr. Courtney Broaddus (San Francisco, USA) presented her studies on the effects of the TNF-related Apoptosis-inducing Ligand (TRIAL). This factor was given to tumour cell cultures alone and in combination with bleomycin or doxyrubicin or when simultaneously hindering apoptosis with a proteasome inhibitor (MG132). TRAIL caused a substantial decrease in cell viability in two out of three cell lines, while no such effect could be obtained with TNF. The effect was due to apoptosis, and it was further enhanced when combined with chemotherapy and MG132.
Dr. Stephen Faux (Leicester, UK) exposed rat pleural mesothelial cells to carcinogenic crocidolite and erionite and non-carcinogenic milled crocidolite and chrysotile in vitro and examined EGR-R and PCNA expressions by confocal microscopy. In low serum conditions, carcinogenic samples produced enhancement of EGF-R and PCNA staining compared with the non-carcinogenic preparations. The data suggest an activation of the cell proliferation cascade by the carcinogenic fibers.
The effects of crocidolite and chrysotile asbestos fibers and non-fibrogenic particles on MCP-1 secretion was examined in rat pleural mesothelial cells (RPMCs) in vitro by Professor Elliot Kagan (Burlington, USA). Asbestos exposure upregulated both expression and secretion of MCP-1, a stimulation that appeared faster in the presence of TNFα. RPMCs challenged with asbestos fibers also showed increased attachment of leucocytes, which was correlated to a simultaneous upregulation of VCAM-1. The findings suggest that MCP-1 secretion and leucocyte adhesion have a role in asbestos-related lesions.
Early studies on the expression of cyclo-oxygenase-2 (cox-2) in MM, a factor that downregulates immunity and upregulates angiogenesis, were presented by Dr. John Edwards. Cox-2 staining was demonstrated by immunohistochemistry in all 10 samples of surgically resected mesothelioma investigated in this study. These results support a role for cox-2 in the pathogenesis of mesothelioma and it was proposed that cox-2 antagonists may be novel candidates as therapeutic agents.
Mr. Vincent Williams (Perth, Australia) presented a careful assessment of the association between retained total lung fiber burden and the risk of mesothelioma. The study was based on 138 cases of mesothelioma and 248 controls. The odds ratio was 1.23 for log(asbestos bodies/g; 95% CI = 1.04 - 1.44) and 1.65 for log(crocidolite fibers/g; 95% CI = 1.33 - 2.04). There was no evident threshold value.
Dr. Benjamin Nissam (Jerusalem, Israel) investigated a series of serum tumour markers in 228 patients with different respiratory diseases. Tissue polypeptide specific antigen (TPS) showed the highest sensitivity (63%) in mesothelioma followed by CYFRA21-1 (53%) and CA125 (26%). Interestingly, thrombocytosis and levels of TPS, CA125 and CYFRA21-1 increased with the progression of the disease. Thus measurement of TPS and CA125 allowed the authors to monitor the effect of chemotherapy and the sensitivity in such monitoring could be increased by the combination of 2 markers: TPS and CA125 (84%). The analysis of CEA in combination with TPS or CYFRA21-1 was suggested as a tool to discriminate MM from lung carcinoma.
