Tuesday 23 November 2010
At the Wellcome Trust, London
Professor Dame Carol Black gave the welcome address, in which she explained the reasoning behind the workshop and how this funding became available. She explained that the £3million was being donated by four insurance companies for research into asbestos-related diseases. Professor Black also laid out the aims of the workshop:
- To understand the status of research into asbestos-related diseases
- To gain perspective on asbestos related diseases
- To gain insight from other areas of research
- To learn about new funding opportunities for asbestos related research
Mesothelioma: a personal perspective
Mrs Chris Knighton, the founder of the Mick Knighton Mesothelioma Research Fund, gave a talk about her personal experience of her husband Mick dying of the disease in 2001 and about how she subsequently established the fund.
Mrs Knighton explained how her husband, Mick developed a chest infection in June 2000 after a holiday. He promptly went to the doctor who prescribed antibiotics but, when the infection didn’t clear up, they went to Accident &Emergency. There he had a Chest X-ray that revealed that one of his lungs was, as she described it, ‘obliterated’.
She pointed out that Mick had never worked in heavy industry, but that he had most likely inhaled asbestos fibres from gun turrets when he was in the Royal Navy. The navy had admitted that it had used asbestos, but you cannot sue the crown and thus compensation was not a possibility. The couple spent as much quality time with their family as possible and Mick died on 19 March 2001, seven months after his diagnosis.
After her husband’s death, Mrs Knighton set about learning as much as possible about asbestos and the different types that exist. She pointed out that someone dies every five hours in the UK from mesothelioma in the UK, while there will be over a million deaths in Western Europe by 2035.
Mrs Knighton emphasized that a wide variety of occupations are vulnerable to asbestos exposure, including builders, plumbers and carpenters. She also gave examples of high profile people who have died of mesothelioma, showing that it was not just working men who can succumb to the disease.
In 2002 Mrs Knighton established the Mick Knighton Mesothelioma Research Fund in the memory of her husband. The fund undertakes a wide variety of activities and holds various events, such as abseiling and marathons, to raise money for the fund. To date they have raised approximately £900,000. In addition, they are campaigning to stop the postcode lottery for drugs. Mrs Knighton also outlined the purpose of her Snowdrop Fund, which helps families give lasting tributes to their loved ones.
Asbestos and industrial diseases
Professor Jon Ayres gave a background to the use and properties of asbestos in society. He explained that it is still mined in Canada, South Africa and Russia and is naturally occurring in Turkey. There are two different types of fibre; straight fibres found in blue and brown asbestos and serpentine fibres found in white asbestos. Asbestos is used in cement, plastics, cloth and insulation. Despite an increased awareness of the dangers of asbestos fibres over the years, the use of products containing asbestos has actually increased worldwide.
Professor Ayres then gave a brief history of asbestos use and disease. He charted possible cases back to the 1st century AD, where slaves who worked in asbestos mines died young of lung disease, continuing to the surge in its use in the late 19th and early 20th centuries, and then the ultimate realisation of the dangers related to asbestos exposure.
The various types of diseases associated with asbestos were highlighted:
• Asbestosis
– progressive pulmonary fibrosis
• Lung cancer
– +/- asbestosis?
• Gastric cancer?
• Pleural fibrosis
– diffuse pleural thickening
• Benign asbestos pleurisy
• Mesothelioma
– dominantly pleural
– pericardium, peritoneum, tunica vaginalis
• Pleural plaques
– benign pleural fibrous lesions
Professor Ayres went on to describe pleural plaques – the most common mark of exposure – and diffuse pleural thickening. He described the basic characteristics of asbestosis, and pointed out that there was no specific treatment, although smoking cessation, supplemental oxygen, prompt treatment of infections and a pneumococcal and influenza vaccination could help control symptoms.
On the subject of malignant mesothelioma, Professor Ayres showed that it has a latency period of between 20-30 years and occurs most commonly between the 5th and 7th decade of life. Malignant mesothelioma may mimic other tumour types and may contain relatively few cells. He then explained the differing control limits (not the same as safe limits) between blue and brown asbestos and white asbestos. Finally, Professor Ayres outlined the different types of compensation available and also who is eligible for compensation and who is not.
Epidemiology of asbestos-related disease and future projections.
Professor Julian Peto of the London School of Hygiene and Tropical Medicine addressed the issue of trends and projections in asbestos-related diseases and considered the risk of mesothelioma at current exposure levels. He said that there is a real urgency in tackling the disease noting that Australia and the UK have the highest rates of disease whereas the incidence is extremely low in South America. There are very similar rates of asbestos-related disease among men and women and certain occupations, such as carpenters, plumbers, electricians and painters, all run a high risk of developing these diseases.
Professor Peto said that in the past it had been difficult to predict the death rates for malignant mesothelioma. However, the tenth revision of ICD death coding, introduced in different countries between 1995 and 2003, includes mesothelioma as a specific cause of death, so that worldwide data are now available for the first time.
Worldwide predictions for mesothelioma deaths between 2000 and 2049 among males exposed before 1980, according to Professor Peto, are as follows:
o Australia 27,000
o New Zealand 4,000
o UK 78,000
o W Europe (except UK and Italy)154,000
o USA 90,000
o Japan 47,000
o E Europe 22,000
o Argentina 7,000
o Chile 4,000
o Mexico 14,000
Professor Peto said that 60-70% of women die of mesothelioma without obvious exposure to asbestos. He recommends that a research priority should be Transmission Electron Microscopy (TEM) on unexplained mesotheliomas in women, to see whether asbestos fibres could be detected.
Finally, he pointed out that asbestos removal in some old buildings, such as schools, can aggravate actual asbestos levels and that the relationship between lung cancer and mesothelioma remains unclear.
Challenges and solutions in other cancer trials
Professor Ian Kunkler from the University of Edinburgh talked about lessons which could be learned from trials of other forms of cancer. At the outset he outlined the barriers for participation that both clinicians and patients can encounter.
He also referred to a survey that asked patients about their attitudes to randomised clinical trials of cancer therapy. He noted that only 45% of those asked would take part in a randomised trial. The main reasons that people would consent was altruism and trust in their doctor.
After giving a brief history of the pioneers of radiation oncology and also noting the epidemiology of breast cancer world-wide, Professor Kunkler gave the example of a phase III trial concerning the ‘Impact of breast radiotherapy on quality of life.
The aim was “to investigate the effect of omitting post-operative radiotherapy from treatment for older women, in a group with a low risk of recurrence; these women received local removal of the breast lump and a course of anti-hormone therapy.
Professor Kunkler explained that this Scottish trial failed to recruit adequate numbers of patients and had to be extended to include patients from England.
They received a concerned response from the NHS Health Technology Assessment Programme (HTA), and so had to draw up a rescue plan. Following a site visit from the HTA in December 2000, a comprehensive cohort study was included.
Professor Kunkler noted that 98% of the quality-of-life questionnaires were completed and that a home visit by a research nurse had a large impact on this number. He also said that recruitment was markedly improved in the second phase of the trial.
The third trial included patients from around the world, but here the process of recruitment was slow. He explained how a chance meeting with the father of one of his son’s friends, who worked for HSBC, paved the way for collaborative research into breast cancer between the University of Edinburgh and HSBC in China, which presently has one of the highest rates in the world.
Prof Kunkler’s conclusion were
• that it is important to build a network of national and international investigators to enable particular trials
• Surgical imprimature of trial with patients
• home visits by research nurse are key to successful Quality of Life collection in older patients
• that it necessary to seek advice from funder early if there are unexpected problems in recruiting patients and, if necessary, adjust the protocol
Nanoparticles: For and Against
Professor Terry Tetley (for) and Dr Steve Coldrick (against) engaged in a brief debate, putting the arguments for and against nanoparticles as a potential threat to health in the modern era.
Professor Tetley, of the National Heart and Lung Institute, Imperial College London, explained that nano-particles are the building blocks for nano-materials which are increasingly being incorporated into everyday items. She gave examples of some of the fields in which they are used, from sportswear to construction.
Professor Tetley then put the size of nano-wires into context, saying that 50% of inhaled nano-sized objects will reach the gas-exchanging part of the lungs (alveoli). After a comparison between the structure of asbestos fibres and nano-particles, Professor Tetley compared their properties.
In one experiment, mice were exposed to carbon nanotubes and then the space between the linings of their lungs (pleura) was examined. It appeared that carbon nano-tubes can exhibit similar structure to dangerous types of asbestos and that inhalation results in:
o carbon nanotubes getting into the pleural space
o deposition of carbon nanotubes under the surface of the pleura
o the formation of small areas of inflammation called granulomata
o scarring of the pleura called pleural fibrosis
o molecular changes related to the development of cancer, carcinogenesis
Professor Tetley concluded that Carbon nanotubes exhibit damaging effects, similar to those observed followed asbestos exposure. This possibility should be seriously considered and thoroughly tested, particularly in an environment where there could be high exposure levels.
Dr Coldrick said that on such an issue it is important to look at the end point and what we should bare in mind. He said that even today some people suggest that some asbestos is safe.
Delay in action happens, Dr Coldrick said because of outside interests, and also because of a knowledge lag. In the 1960s it was common testimony that people didn’t know about the about the dangers of asbestos. He added, “we can’t afford to wait and see if there is a problem with – the principle of caution”.
Dr Coldrick said that banning was not the solution, but control was, and that people must have the right knowledge, attitude and behaviour. Precaution is the key – risk management should be preferred to prohibition.
Mesothelioma: Focus on Current Research
Dr. Dean Fennell and Dr. Daniel Longley of the Centre for Cancer Research and Cell Biology, Queen Mary’s University Belfast discussed their research into specific areas, including:
Biomarkers – personalizing cytotoxic therapy
Death receptor pathway targeting
Targeting MCL-1 addiction
Synthetic lethal strategies
Dr Fennell commented that holistic care for mesothelioma is poor and that there is a lot of nihilism because of poor response rates.
Dr Longley then spoke about his research, supported in part by the BLF, targeting the death receptor pathway. .
Drs Fennell and Longley summarised their research as follows:
● Cytotoxic therapy may be customised according
to biomarker expression esp. Relapsed setting
● HDACi target FLIP – may be critical for
proapoptotic efficacy in mesothelioma
● Subsets of mesothelioma may be MCL-1 addicted
and targeted by obatoclax
● Synthetic lethality is a promising strategy
● Deep sequencing efforts could identify novel
oncogenic drivers and strategies for therapy
New funding opportunities from the BLF
Professor Nick Morrell, chairman of the BLF scientific committee, briefed on the launch of asbestos-disease related grants, including the conditions for application. Professor Morrell outlined the three year bio-resource grant. This is being established to fund the establishment of an asbestos-related disease tissue/blood biobank database and registry. The application deadline is Friday 25 March 2011.
The project grant will have a maximum funding of £200,000 for up to three years, to fund established research teams to carry out research into asbestos-related disease for up to 3 years. Applications seeking the maximum amount or duration are welcomed, as are those seeking smaller amounts of funding or shorter duration. The deadline is Friday 25 February 2011.
In addition, there will be £100,000 PhD studentships. Non-clinical awards will cover student stipend, university fees and research consumables, up to £12,000 per year. The total award for 3 years cannot exceed £100,000. By contrast, clinical awards will cover applicant’s salary, plus consumables, up to £12,000 per year. The deadline for PhD applications is also Friday 25 February 2011.
Pump-priming grants of up to £25,000 will be awarded to fund smaller projects either with direct benefit to patients, or to fund proof-of-concept studies intending to facilitate future larger studies. The deadline is Friday 18th February 2011.
Programme grants of £500,000 for up to five years will fund established research teams to carry out larger programmes of research into asbestos-related disease for up to 5 years.
The Review process for the grants involve:
o Applications to be scored by the BLF Scientific Committee (including new members with expertise in asbestos-related disease).
o Shortlisted applications to be sent for international review.
o Shortlisted applications will be considered and ranked by BLF Scientific Committee.
After the review process Professor Carol Black closed the workshop.
