Mesothelioma TreatmentOther Sources
Fifth Meeting of the International Mesothelioma Interest Group (IMIG) - October 8, 1999
IMIG report
Summary
October 6, 1999
October 7, 1999
October 8, 1999
The Friday morning session began with several presentations on "Mesothelioma Epidemiology." Professor Julian Peto (Belmont, UK) presented data demonstrating that the rate of new cases of mesothelioma at age 40 was higher in 1990 than it had been in 1940. Asbestos exposure had increased progressively up to those having started work in approximately 1965. Lifetime risk of dying from mesothelioma was increasing with birth year up to 1% for 1945. Currently there are 1300 UK deaths per year, and the number is still rising. Professor Peto believes that this was due to peak unregulated use of asbestos materials in building trades during the 1960's. The situation in Europe appears similar, although based not on true mesothelioma incidence but on the broader "pleural cancer". Projections of increasing incidence and mortality may be slightly exaggerated due to increasing awareness of the disease and hence increasing diagnosis.
Dr. James Leigh (Sydney, Australia) presented the most recent data from the Australian Mesothelioma Register, the most complete mesothelioma registry extant. In Australia, crocidolite was removed from new use in 1967; peak use was in 1965. By 1975, asbestos use peaked at 700,000 tons per year; mainly chrysotile. Chrysotile use continued until at least 1985. Mesothelioma incidence, lagged 40 years, almost perfectly matches asbestos consumption with mean latency 37 years, and as in Europe and the United Kingdom incidence is still increasing. By 2020, 10,000 new cases are expected. Dr. Leigh corrected some misimpressions of the Australian situation concerning Wittenoom. For the years 1980-1999, 38% of all cases came from New South Wales, and only 16% from Western Australia (where the mine was located). Even within Western Australia, only about half of all cases had been exposed in or around Wittenoom. Thus, more than 90% of cases of mesothelioma in the last two decades have come from other areas and exposures.
Dr. Bruce Case (Montreal, Canada) reported pathology validation for 19 female pleural and peritoneal malignancies within and 104 outside asbestos mining regions in Quebec, 1970-1990. Less than 25% of female mesotheliomas were associated with asbestos exposure. Cases were circulated, double-blind, to Drs. Andrew Churg and Victor Roggli. Agreement between expert pathologists was 'substantial' (86.84% vs. 53.22% predicted; Kappa 0.72, p<.0001) for next-adjacent category on a four-point scale. Churg and Roggli found over-diagnosis of mesothelioma at the local hospital level by approximately 28%. Pleural and peritoneal tumours classified as other tumours by local hospital pathologists were conversely under-diagnosed. Measurable improvement in diagnosis with the introduction of immunohistochemical assays after 1985 was offset by a falling autopsy rate. Diagnostic accuracy at the local level for definite asbestos-exposed cases was very high. Dr. Case concluded that pleural and peritoneal tumours diagnosed prior to 1985 should be regarded with extreme caution in epidemiological study: expert pathology review is mandatory. Conversely, knowledge of putative 'environmental" asbestos exposure leads, at least in this population, to over-diagnosis of mesothelioma.
The late morning session entitled "Gene Regulation" was chaired by Dr. Steven Albelda (Philadelphia, USA) and Dr. Marjan Versnel (Rotterdam, Netherlands). Inactivation of the tumour suppressor gene p16 has been reported to be one of the most common molecular abnormalities found in mesothelioma tissues and cell lines. Two abstracts addressed this issue. Dr. Kazuhiko Takabe (Ibaraki, Japan) used immunohistochemistry and PCR to ask the question whether the loss of p16 was due to genomic loss or hypermethylation of the promoter. The analysis confirmed loss of p16 in 75% of mesothelioma tumours. Hypermethylation was actually rare; most cases showed genomic loss of p16. Dr. Agnes Kane (Providence, USA) used a murine model of mesothelioma to study p16 along with the associated proteins p15 and p19. Mesotheliomas were induced by weekly intraperitoneal injections of asbestos. Sixteen cell lines obtained from these animals were established and studied. Approximately one half of these cell lines showed deletions in p16 with no expression of mRNA. Many of these lines had associated loss of p15 and p19. These studies confirm that loss of the p16 gene locus is common in malignant mesothelioma and may have an important role in pathogenesis of tumour progression.
Dr. Martin Dyer (Sutton, UK) presented work on a newly identified tumour suppressor gene bcl-10, which in vitro, was pro-apoptotic, an inducer of NF-kB and transforming upon truncation. In malignant mesothelioma, loss of heterozygosity of the 1p22 region, where bcl-10 has been mapped, has been described. cDNA of malignant mesothelioma cell lines exhibited the following sequence abnormalities: three alternative splice sites, alterations within the homopolymeric runs and point mutations. This phenomenon has been interpreted to be molecular misreading as in genomic DNA a much lower mutational frequency was found. In 50% of the primary malignant mesotheliomas bcl-10 has been found to be deleted. Knock out mice for bcl-10 will reveal more on the role of bcl-10 in malignancy. Professor Anton Berns (Amsterdam, The Netherlands) introduced a method for the production of conditional tumour suppressor gene knock out mice. Using this method genes can be switched in a time-controlled and tissue specific manner. Candidate genes for the production of a mesothelioma mouse model are NF2, pRb, p16 and p53. Intraperitoneal and intrathoracic injection of NF2 and Rb or NF2 only resulted in multiple foci of tumour growth in the mesothelium. Although further characterization of the tumour cells must be performed, these results indicate that NF2 contributed to the development of these mesotheliomas.
The afternoon session concentrated on "Clinical Studies" and was chaired by Dr. Daniel Sterman (Philadelphia, USA) and Dr. Per-Fredrik Eckhold (Fredrikstad, Norway). Professor Bruce Robinson (Perth, Australia) in his overview of new therapeutic approaches to mesothelioma, proposed that the problem was not that the body does not recognize the tumour, but that its response to the tumour is inadequate and needs to be modulated/stimulated to cause rejection. For in vivo evaluation of the anti-tumor immune response, he and his colleagues transfected murine mesothelioma cells with the influenza hemagluttanin (HA) gene so that the cellular and humoral response to HA could be followed in transgenic mice with T cell receptors specific for HA. They also used a technique called CFSE to monitor in vivo analysis of antigen presentation and proliferation of antigen specific T cells. In Professor Robinson's model of transgenic mice challenged with HA-positive tumour cells, significant T cell proliferation could be detected, sometimes even in the absence of gross tumour at the injection site. He was also able to show that T cell proliferation would not be maintained unless CD4 helper T cells were also present to potentiate the response.
Professor Robinson also discussed his group's experience with chemotherapy and cytokine therapy. He reported a partial response (42%) with gemcitabine and cisplatin treatment and his studies with either direct infusion or viral-mediated transfer of cytokine genes; GM-CSF and interleukin-2 (IL-2) did not show any evidence of tumour regression.
The next speaker was Dr. Phillippe Chahinian (New York, USA) who presented his data regarding the use of the nude mouse model of human mesothelioma for testing of new chemotherapy agents and combinations. He described the use of xenotransplantation of human mesothelioma tumours into the flanks of T-cell deficient ('nude') mice to test the efficacy of single and combined agent chemotherapy to look for synergy. Significantly, testing of the combination of mitomicin and cisplatin together with alpha interferon and also paclitoxel (Taxol) revealed a significantly greater anti-tumour activity than either agent used alone. This model, therefore, appears to be a useful testing ground for new chemotherapeutic agents and combinations in malignant mesothelioma.
Dr. Takashi Nakano (Hyogo, Japan) presented his groups experience with the use of the topoisomerase I inhibitor CPT-11 as part of combination chemotherapeutic regimens for patients with mesothelioma. In a recently completed pilot study of CPT-11 combined with the topo II inhibitor, adriamycin (ADR), a partial response has been seen with 2 from 9 mesothelioma patients.
Dr. Gunnar Hillerdal (Stockholm, Sweden) presented a Scandinavian Phase ll study with high dose methotrexate and alfa and gamma-interferons. Objective response rate was 28% and stable disease 56% of a total of 39 patients. The duration of the response was more than 100 days on average but survival has not yet been finally analyzed. Dr. Castagneto (Casale Monferrato, Italy) evaluated the toxicity of a fixed dosage of an escalation dose of mitomycin using a thoracic stop-flow technique in five patients. One patient had neurological grade 4 toxicity, but other side effects were mild. The dose finding study will continue. Dr. John Edwards (Leicester, UK) evaluated palliative debulking surgery in 35 patients with stage lll and lV MM. Decortication was done in 26 and pleurectomy in 9. The operations gave symptom relief in both dyspnoea and pain of more than 50% evaluated at six weeks and three months. The results were thought to be due to expansion of the lung for reducing dyspnoea and decompression of nerves for the reduction of pain. A randomized study comparing debulking surgery with best supportive care was proposed.
In the closing remarks it was stated that we need bigger multicenter Phase ll studies before we move on to Phase lll randomized studies to establish standards for MM treatment. IMIG should play an active role to promote co-operation between different centers.
Dr. Marjan Versnel closed the meeting by thanking everyone for attending and invited them to attend the 6th IMIG meeting to be held in Chicago in September 2001.
NEW INVESTIGATOR AND POSTER PRIZE
Congratulations go to Miss Claire Vivo (Crteil, France) for winning the IMIG New Investigators Prize of 300 for her presentation "Cell cycle analysis in interferon gamma (IFNg) treated human mesothelioma cell lines (HMCLs)."
A single poster prize was split between two worthy posters; Dr. Roland Hbner (Antwerp, Belgium), for his poster injecting caution into the field of SV40 amplification from mesothelioma and Dr. Kettunen (Helsinki, Finland) for her work on microarray analysis of mesothelioma. Our congratulations go to these two worthy recipients together with 50 each and a text book on serosal injury generously donated by Professor Gere diZerega (Los Angeles, USA).
