Asbestos & the Lungs. Dr Noemi Eiser MD FRCP. Asbestos fibres. Asbestos found in schools, hospitals & homes

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1 Asbestos & the Lungs Dr Noemi Eiser MD FRCP Retired Medical Director - British Lung Foundation & Emeritus Chest Physician University Hospital Lewisham Asbestos fibres Naturally occurring mineral which crystallises to form long thin fibres & fibre bundles Mined around the world especially in South Africa and Canada All types are pathogenic Serpentine groups of asbestos are most common Chrysotile (white) most often used Amphiboles, including crocidolite (blue) most hazardous Amosite (brown) Processed in several ways for industrial use Qualities: resistant to heat, electricity & sound Important to keep asbestos well maintained & covered with impermeable paint, to prevent the release of dust fibres, Asbestos found in schools, hospitals & homes Loose packing between floors and in partition walls Sprayed fire insulation on structural beams or girders Lagging; on pipe-work, boilers, heat exchangers, insulating jackets for cold water tanks, around ducts etc. Asbestos insulation board (AIB); ceiling tiles, partition walls, soffits, service duct covers, fire breaks, heater cupboards, door panels, lift shaft linings, fire surrounds Asbestos cement (AC); roof sheeting, wall cladding, walls & ceilings, bath panels, boiler & incinerator flues, fire surrounds, gutters, rainwater pipes, water tanks Known trade associations with asbestos-related lung disease Occupations Insulation workers Boilermakers Plumbers, pipe fitters Shipbuilders Sheet metal workers Plasterers Chemical technicians Heating/ air conditioning / refrigeration workers Industries Construction Ship building / repair Chemical manufacturing Railways Yarn, thread and fabric mills Rubber production Plastic production Trucking services 1

2 The plumber, the electrician, the joiner & the DIY enthusiast Asbestos in UK Single biggest work-based killer Kills more people than Road Traffic Accidents Present in any building built or refurbished before yr 2000 Present in 500,000 non-domestic buildings Generally, it is only a risk if disturbed or damaged (allowing fibres to be released in to the air) Asbestos in Romania Mined in Banat county (less recently) & also imported from the former USSR, Canada and Croatia Used since 1950 s, an increasingly since Institute of Work Safety Research (Bucharest) introduced guidelines for the safe handling and reduction of exposure to asbestos (complying with EU regulations) 2007 Introduction of laws (following EU directives) forbidding the sale and use of asbestos but products made before 2005 can still be used! Companies now advertising on www safe removal of asbestos Exposed workers & cases of asbestosis in Romania Artenie

3 Conditions due to asbestos exposure Pleural thickening due to inflammation and scarring Either general, diffuse pleural thickening Or localised pleural plaques Asbestosis interstitial pulmonary fibrosis when asbestos fibres are inhaled Lung cancer Mesothelioma malignant tumour of pleura or occasionally peritoneum Pleural plaques on parietal pleura Indicate previous exposure to asbestos latency yrs Fibrotic: relatively acellular and avascular mainly composed of collagen but often calcify Their presence does not mean Increased susceptibility to more serious disease More serious disease is present Serious disease will develop in the future no evidence that implies an increased risk of other asbestos-related disease Cause no symptoms Need no monitoring e.g. repeated Chest X-rays Need no treatment No compensation in England Chest X-ray showing well demarcated pleural plaques Diffuse pleural thickening visceral pleura Less common than pleural plaques but may co-exist Not sharply delineated 390 new cases in 2007 in UK ( may be an underestimate?) May enclose whole lung - unilaterally or bilaterally Constricts the lung and prevents it from expanding on inspiration reduced lung volumes & dyspnoea Treatment - nil specific except treat breathlessness Latency 1 year or years 3

4 Asbestosis Inspired fibres induce macrophage phagocytosis Macrophages enter interstitium and lymphatics Stimulate fibroblasts to deposit connective tissue Dying macrophages release cytokines & toxic free radicals Result is dense interstitial fibrosis Latency years Over the years (15-20 yrs) this produces increasing lung fibrosis and hypoxaemia Asbestosis Symptoms: breathlessness +/- cough +/- chest pain and eventually respiratory failure Finger clubbing Fine end-inspiratory crepitations or crackles Signs of Type 1 Respiratory Failure Hypoxaemia with low / normal P a CO 2 Cor pulmonale Asbestosis Restrictive lung function reduced lung volumes & gas transfer Chest X-ray may be normal but usually fibrosis at bases High Resolution CT scan necessary, esp. if CXR normal Prognosis variable depending on duration of disease and complications Asbestosis fibrosis, especially at bases Responsible for ~ 160 deaths p.a.in UK 4

5 HRCT scan in asbestosis Interlobular short lines Long parenchymal bands Coarse honeycombing Ground glass opacities Centri-acinar nodules Sub-pleural curvi-linear shadows Asbestosis versus Idiopathic Pulmonary Fibrosis Features suggesting asbestosis: Pleural plaques Sub-pleural branching opacities Sub-pleural curvilinear lines Parenchymal bands Homogeneous sub-pleural opacities Asbestosis v IPF pathology Pathology of increasing severity of asbestosis Both have interstitial & basal sub-pleural distribution Diagnosis of asbestosis requires presence of 2 or more asbestos bodies/cm 2 in 5μm lung section Asbestosis has very little inflammation IPF more inflammation Asbestosis has only rare fibroblastic foci frequent in IPF Only asbestosis usually associated with mild fibrosis of visceral pleura Unlike IPF, asbestosis fibrosis starts in region of bronchioles & extends to involve more & more acini as progresses 5

6 Asbestosis - management Asbestosis - Reduces life expectancy due to Quit smoking progression & malignancy more common in smokers Vaccinations influenza & pneumonia Symptomatic treatment bronchodilator inhalers or steroids may help breathing a little Long-term oxygen therapy with oxygen concentrator for respiratory failure Respiratory failure in UK 134 deaths in new claims for disability in 2005 Cor pulmonale risk of Mesothelioma risk of lung cancer Asbestosis risks of lung cancer Malignant Mesothelioma of pleura UK incidence In non-smokers, asbestosis increases lung cancer risk x 3 Smokers without asbestosis have x 5.5 lung cancer risk compared with non-smokers Smokers with asbestosis have x 14 increased risk of lung cancer compared with non-smokers without asbestosis 85% mesotheliomas (in men) attributable to asbestos 83% occur in males mainly due to industrial exposure Increasing in frequency: peak expected in ~ 2000 people diagnosed in UK annually ( >5 per day) Incidence varies around country <30 >100 p.a. Takes years to develop after exposure Usually unilateral 6

7 Mesothelioma in England; Results from National Lung Cancer Audit Peake MD et al 2011 National Lung Cancer Audit in England Peake MD et al 2011 Year Number Percent of total lung cancer , , , , Mesothelioma of pleura - symptoms Breathlessness (mainly due to pleural effusion) Chest pain from various causes direct spread, neural etc Also Loss of appetite +/or weight loss Fever +/- night sweats Pain +/- swelling of abdomen Unexplained tiredness +/- clubbing +/- pericardial tamponade Progression mainly local 7

8 Mesothelioma of pleura diagnosis 1 Chest X-ray may show pleural effusion Insertion of needle into fluid cytology for malignant cells Chest X-ray of Mesothelioma with pleural effusion Slow pleural drainage of fluid to relieve symptoms & test fluid again CT scan of the chest contrast-enhanced Malignant and inflamed tissue enhances well Allows differentiation of tumour from thick pleura, effusion, and underlying collapsed or aerated lung Cannot differentiate mesothelioma from other tumours Commonest features» circumferential nodular lung encasement» pleural thickening with irregular pleuro-pulmonary margins» Pleural thickening with superimposed nodules Mesothelioma of pleura diagnosis 2 Insertion of needle directly into tumour ultrasound guided Video-assisted thoracoscopic surgery (VATS) Insertion of endoscope through chest wall under general anaesthetic to directly see & sample tumour Look, biopsy, complete fluid drainage & pleurodesis (talc) MRI limited role but gadolinium-based contrast enhances pleural malignancy avidly Mesothelioma after pleural drainage F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) Occasionally useful if results from above equivocal 8

9 Pathology of malignant mesothelioma May be difficult for pathologists to differentiate malignant mesothelioma from adenocarcinoma of lung & also from reactive mesothelial cells immuno-histo-chemistry may help Important to diagnose subtype for prognostic and treatment purposes Abram s / Cope blind needle biopsy - hit or miss; only 21-43% sensitive Pleural fluid cytology 76% sensitive Guided percutaneous fine needle biopsy 78% sensitive Guided percutaneous core biopsy 86% sensitive (100% specific) Thoracoscopic biopsy > 90% sensitivity with 10% complication rate National Lung Cancer Audit (England) Peake MD et al 2011 Mesothelioma cells (courtesy of Dr Zsuzsanna Tabi) 9

10 National Lung Cancer Audit (England) Peake MD et al 2011 Mesothelioma of pleura -UK mortality In 2002, total of 2,333 deaths from occupational lung disease (3/4 were due to Mesothelioma) 70% increase in mesothelioma deaths in 10 yrs ( ) But 30 men and 30 women p.a. die from mesothelioma with no obvious asbestos exposure Mesothelioma of pleura no cure symptomatic R x Management of the pleural effusion Drainage often repeated or with indwelling tube Prevention of future build up by pleurodesis - talc or other agent injected between the 2 coats of pleura sometimes via VATS (under general anaesthetic) Active symptom control Breathlessness (steroids, opiates) Pain - analgesics Lack of appetite / constipation from opiates Anxiety / depression Mesothelioma of pleura 2 Radiotherapy used To prevent tumour tracking along needle route Directed at tumour to reduce size & pain +/- breathlessness (50% response rate expected) Chemotherapy only Pemetrexed (Alimta) considered for those with good performance status 20-40% response rate expected 10

11 Tract metastases - Wide range reported after tube / needle Biopsy = 0-48% (Lee 2009) Metintas (2008) 13% - most received DXT - Conflicting results from previous unsatisfactory trials Prophylactic irradiation of tracts (PIT) National Cancer Research Network funded by National Institute for Health Research Primary Endpoint = rate of chest wall metastases Secondary Endpoints time to chest wall metastases locality of metastases to DXT field pain from chest wall metastases toxicity of treatment Mesothelioma of pleura surgical treatment low success rate Surgery - only suitable for very few fit people Extra-pleural pneumonectomy (EPP) resection of all pleura, underlying lung, diaphragm and pericardium» 60% post-operative complication rate» Operative mortality 4-9%» Median survival (after post-op DXT & chemor x ) 19/12 De-bulking (cyto-reductive) or decortication surgery» Less radical performed via thoracotomy or VATS» All tumour removed but not diaphragm or pericardium Surgery should be considered only as part of randomised controlled trial & as part of DXT + chemor x package Worse survival after more extensive surgery 11

12 Peritoneal mesothelioma 1:12 incidence compared with pleural MARS 1 EPP(+DXT)patients worse survival than those only chemor x 85% epithelioid cell type Localised, multi-nodular or diffuse Sited on under-surface of diaphragm and may spread to pelvis, omentum or right sub-hepatic space Symptoms non-specific pains, weight, ascites Prognosis worse than pleural mean survival 7 months No treatment shown to improve prognosis Carbon nanotubes (CNT) Carbon nanotubes the next hazard? Allotrope of carbon with cylindrical nanostructure Member of fullerene structural group Either single or multi-walled Multi-walled are multiple concentric nanotubes precisely resting within one another so that inner can slide within outer with almost no friction thus perfect linear or rotational bearing The most dominant properties of carbon nanotubes are their extraordinary tensile strength, lightness & unique electrical properties 12

13 CNT multiple uses current & potential For their strength and lightness bicycle components, boats, construction Hybtonite Carbon Nanoepoxy resins wind turbines, marine paint, sports gear (skis, golf clubs, etc possibly stab and bullet proof vests) In electrical circuits - carbon nanotube field-effect transistors, electrical wires, cables, paper batteries Solar panels, ultra-capacitors, hydrogen storage, radar absorption CNT can enter cells & accumulate in cytoplasm cell death (Porter 2007) In rodents CNT produce inflammation, epithelioid granulomata and lung fibrosis (Zumwalde & Hodson 2009) 7 female workers exposed to nanoparticles in air spray of poly-acrylic paste for 5-13/12 developed pleural effusions. Trans-bronchial Biopsy showed nonspecific pulmonary inflammation, fibrosis, foreign body granulomata & nano-particles in cytoplasm of mesothelial cells and pleural fluid (Song et al 2009) Medical applications British Lung Foundation Supports people of all ages affected by lung conditions with 230 Breathe Easy Groups BLF Nurses Helpline Funds basic and clinical research > 25 million pounds Promotes greater understanding of lung disease Information website and printed Campaigning for people with lung disease Awareness raising 13

14 British Lung Foundation UK asbestos awareness survey of trades-people 2007 Telephone survey of 399 trades-people in UK Plumbers / joiners / carpenters / electricians / gas fitters Striking variation in knowledge between regions, age groups and professions 34% admitted poor knowledge of asbestos hazards 30% believed most had been removed from buildings 28% believed that there was a safe exposure level 88% unaware that exposure could be fatal 74% had had no formal training regarding asbestos risk BLF survey among >2000 UK homeowners regarding asbestos risk 2008 No. of respondents Know asbestos used as building material (%) Not confident to identify asbestos (%) Would ask for professional to dispose of asbestos (%) Has never had information on how to identify/manage asbestos (%) Have not heard of mesothelioma (%) Table 1; Asbestos knowledge of home owner respondents Total 16-24yrs 25-34yrs 35-44yrs 45-54yrs >55yrs Studies recently funded by The British Lung Foundation through 3 million grant given by Association of British Insurers over 3 years & through Mick Knighton memorial Dr Zsuzsanna Tabi: Cardiff University 5T4 is a glycosylated onco-foetal antigen Expressed in tumour tissue and specifically associated with malignant cells (n=23) Expressed on the surface of epithelioid and sarcomatoid mesothelioma cells (n=17) Co-expressed with other mesothelioma markers, such as mesothelin (n=7) Recognised on mesothelioma cells as an immune target by cytotoxic T cells 14

15 Bio-bank being set up to facilitate future research on mesothelioma specimen from through the UK network 15

16 Professor Julian Peto: London 200K for 2 years His team already has a database of over 1300 Mesothelioma patients, 1250 lung cancer patients and 1400 controls Asbestos fibre counts from lung biopsies available from about 260 lung cancer patients and 140 Mesothelioma patients. Control biopsies are being obtained from people operated for pneumothorax They will observe relationship between lung burden of asbestos and Mesothelioma risk in those born before 1965 Then they will measure lung burden of asbestos in various jobs and in general public born after 1965 when asbestos use ceased Estimate future risk of malignant Mesothelioma from current working practices and environmental exposure Prof Anthony Chalmers: Glasgow 200K for 3 years Mesothelioma cells do not readily die in response to DXT Can a new drug increase the effectiveness of radiotherapy (DXT) in the treatment of malignant Mesothelioma? Treating cancer cells with TRAIL increases the killing of malignant Mesothelioma cells by DXT without affecting normal cells and so does not cause more side effects The effect of TRAIL + DXT will be studied on cells growing in the laboratory from samples taken from patients with mesothelioma and also in mice with mesothelioma Dr Brian Huntly. Cambridge 93.1K for 3 years In order to grow, cells need special structures called organelles one of these, endoplasmic reticulum (ER), produces protein. Evidence of ER stress (when cells can t make protein normally) is found in Mesothelioma samples GADD34 protein is increased during ER stress and is also found in Mesotheliomas The researchers will observe whether GADD34 increases with tumours growth and, if so, how. Could this be a target for development of anti-mesothelioma drugs? Dr David Waugh: Belfast 188K for 30 months Aim to overcome the resistance to drug treatment of Mesothelioma and develop a novel, effective treatment Mesothelioma cells protect themselves from apoptosis (cell death) by surrounding themselves with inflammatory cells; these cells produce a group of proteins called IAPs Malignant Mesothelioma cells depend on IAPs to survive and therefore anti-aip drugs may be of use to kill these cells 16

17 Dr Peter Campbell: Cambridge 145K for 2 years Pump-priming Award funded: John Edwards Sheffield 24K for 18 months The mutations in cancer genes determine how it will grow, spread and respond to treatment DNA sequencing techniques are now available to identify every genetic change in cancer genes Sub-typing Mesotheliomas using these methods may have implications for diagnosis, monitoring and treatment Is it better to use a combination of up to 5 different treatments rather than the usual way to relieve pain in Mesothelioma patients from an early stage of disease? Pain from various causes direct tumour spread, inflammation, damage to nerves and destruction of bone ribs, spine etc Aim to show that early, combined treatment monitored by palliative care specialists more effective than current approach & that quality of life improves The END 17

18 Occupational lung disease Allergic Asthma Baking wheat and rye protein Solder - colophony Paints / dyes / isocyanates Plastics / latex / print Interstitial lung disease Farmer / mushroom pickers Bird breeders Humidifier/air conditioner Chemical workers Bagassosis / byssinosis Non-allergic Irritant cough / asthma Chlorine Ammonia NO 2 SO 2 Fibrotic Coal miners pneumoconiosis Silicosis Asbestosis Beryllosis siderosis Legal aspects of asbestos-related diseases (UK) Control of Asbestos Regulations (2006) require mandatory information, instruction & training for anyone likely to be in contact with asbestos at work Asbestos-related diseases are proscribed therefore eligible for compensation (except pleural plaques in England) For compensation must establish diagnosis and causation as a balance of probability biopsy not essential Compensation Industrial injuries disablement benefit via Benefits Agency from Dept of Social Security War pensions scheme +/- incapacity +/or disablement benefit Sue through Common Law Must get legal advice promptly and start proceedings within 3yrs Must prove the negligence of employer failure to comply with H&S regulations 18

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