mesothelioma

Mesothelioma

Mesothelioma is a rare and virulent form of mesothelial surface cancer that affects the lining of the lungs (pleura), the abdominal cavity (the peritoneum) or the heart envelope (the pericardium). Pulmonary mesothelioma is caused by exposure to mineral fibers (such as asbestos, or érionite1).

Current studies show (odds ratio of 6.6 and relative risk of 5.02) unambiguously a relationship between exposure to asbestos and the development of a péritonéal2 mesothelioma, 3, 4.

Some individuals were exposed to their workplaces, while others were exposed secondarily by family members who, unbeknownst to them, brought home fibers from their work in their clothes or hair or on their skin.

Mesothelioma is a notifiable disease in France, health professionals must report it to the Doctor of the healthcare PROFESSIONALS5 Regional agency.

Pulmonary mesothelioma
Definition
The occurrence of this disease, sometimes referred to as "asbestos cancer", this fibre being the principal risk factor recognized for this type of cancer, is not indicative of a minimum threshold of exposure and its medical treatment has a limited impact on The life expectancy of the patients.

The first demonstrations found in the clinical examination are chest pains, often associated with shortness of breath and a recurrent pleural effusion, usually hemorrhagic. The lag time between the first exposure and the development of mesothelioma is seldom less than 20 years, often in the range of 30 to 40 years or more. There does not appear to be a threshold value for exposure in relation to a risk of occurrence.

Cases of pleural mesotheliomas occurring in the family environment close to workers exposed to asbestos have been described, as the subjects are exposed as a result of contamination of the living quarters or during the maintenance of empoussiérés clothing.

Tobacco does not appear to increase the risk of mesothelioma when it is an additional risk factor for lung cancer (CBP) 6.

Signs and symptoms
Diagnosis
Some keywords: chest x-ray, pulmonary functional tests, CT-scan (or CAT-scan) or MRI cytology if a lot of fluid, trans-thoracic biopsy, histopathology, thoracoscopy, laparoscopy

Orientation Tests

There is no universally recognized protocol for screening people who have been exposed to asbestos. However, some research indicates that the level of osteopontin in the serum is useful in screening for mesothelioma in exposed individuals. The level of the soluble protein related to Mésotheline was high in the serum in about 75% of the patients whose diagnosis was confirmed and it was suggested that it could be useful for dépistage7. The dosage of the mesothelin itself, in the blood, would be specific but not sensible8. Fibuline-3 would be a promising marker, both in its blood dosage and in the plèvre9.

Assessment and evaluation

Once the diagnosis is confirmed, the doctor will have to assess the pathological grade of the tumor to establish a therapeutic treatment strategy. Mesothelioma is described as localized if the cancer is found only on the surface of the pleural membrane where it started. It is classified as advanced if there is an extension beyond the original surface of the pleura to other parts of the body, such as lymph nodes, lungs, thoracic wall, or abdominal organs.

Pathophysiology

The mesothelium consists of a single thin layer of cubic cells forming an epithelium bordering the serous cavities of the body comprising the peritoneum, the pericardium, and the pleura to form a virtual cavity. The deposit of mineral fibres in the pulmonary parenchyma may result in their penetration into the visceral pleura from which the fiber can then gain the pleural surface, and thus lead to the development of the malignant mesothelial plates. The process leading to the development of peritoneal mesothelioma is not yet known. It has been suggested that asbestos fibres from the lung could be transported to the abdomen and associated organs via the lymphatic system. In addition, mineral fibres may be deposited in the intestine after ingestion of contaminated sputum.

It has been shown that the contamination of pleura by asbestos or other mineral fibres can induce carcinogenesis. Long and thin asbestos fibres (blue asbestos, amphiboles) are more effective carcinogens than "feathery fibres" of chrysotile (or white asbestos). In rats the development of mesothelioma was caused by intra-pleural inoculation of chrysotile phosphorylated fibers. It has been suggested that in humans, the transport of fibres to pleura would be the critical stage in the pathogenesis of mesothelioma. This hypothesis is conforted by the observed influx of a significant number of macrophages and other cells from the immune system to localized lesions caused by asbestos fibres accumulated in the pleural and peritoneal cavities of Rats. These lesions continue to attract large numbers of macrophages as the disease progresses, and the cellular changes inside the lesion result in a tumor whose morphology has all the traits of malignancy.

Experimentation suggests that asbestos acts as a complete carcinogen in the development of mesothelioma, which occurs in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells in the presence of asbestos fibres remain quite obscure despite the demonstration of the oncogenes possibilities of the substance. However, in vitro transformation of normal human mesothelial cells into malignant phenotype cells after exposure to asbestos fibers has not yet been achieved. Generally, asbestos fibres are believed to exert their carcinogenic effect through direct physical interactions with mesothelium cells in conjunction with indirect effects with interaction with inflammatory cells such as macrophages. Studies involving intrapleural or intraperitoneal inoculation of different types of asbestos fibres in rats and mice have established that long and thin fibres are responsible for a higher incidence of mesothelioma than fibres Phagocytose cells and store the longest fibres more efficiently than short fibres. Similarly, the incubation of Syrian hamster cells with fiberglass with an average length of 9.5 µm caused cell transformations with the same velocity as crocidolite. Reducing the length of these fibres to an approximate size of 2.2 µm reduced cell transformation capacity by a factor of 10 to 20, while a larger reduction to less than 1 µm completely eliminated the capacity of Cellular transformation by fiberglass particles.

Analysis of the interactions between asbestos fibers and DNA showed that phagocytosed fibers can come into contact with chromosomes, fibers often adhering to chromatin or entangle in the chromosome. This contact between the asbestos fiber and the double helix structure proteins of the chromosome can induce complex anomalies. The most common anomaly is the monosomy of chromosome 22. Other frequent anomalies include the rearrangement of the arm structure of the 1st, 3rd, 6th, and 9th chromosome pairs.

The most common genetic anomalies in mesothelioma cell lines include the deletion of the following tumor suppressor genes:

Neurofibromatosis type 2 at 22q12

P16INK4A

P14ARF

It has also been shown that asbestos can be used as a mediator for the entry of foreign DNA into the target cells. The incorporation of this foreign DNA can cause mutations and lead to oncogenesis by several possible mechanisms:

Inactivation of tumor suppressors genes

Activating oncogenes Genes

Activation of Proto-oncogenes due to the incorporation of foreign DNA containing a promoter gene

Activation of DNA repair enzymes, which may be prone to errors.

Activating the Telomerase

Prevention of apoptosis

It has been shown that asbestos fibres can change the function and secretory properties of macrophages, ultimately creating conditions that promote the development of mesothelioma. After phagocytizeding asbestos fibers, macrophages produce increased amounts of hydroxyl radicals that are the normal by-products of anaerobic cell metabolism. However, these free radicals are also known as clastogenic and also agents having action on the membrane to promote the carcinogenic effect of asbestos. These oxidants can participate in the oncogene process directly and indirectly by acting on DNA, by modifying the cell membrane by different mechanisms, including activation of oncogenes and disturbance of cellular defenses Antioxidant. Asbestos can also have immunosuppressive properties. For example, chrysotile fibres have been shown to decrease the in vitro proliferation of phytohémagglutinines-stimulated peripheral lymphocytes, suppress lysis of natural killer cells and significantly reduce the viability And the renewal of lymphokines-activated killer cells. In addition, genetic changes in the asbestos-activated macrophages may result in the production of effective mitogens substances on mesothelial cells such as platelet growth factor (PDGF) and Transformation Growth – β (TGF-β), which in turn, can induce chronic stimulation and proliferation of mesothelial cells after lesions caused by asbestos fibers.

Epidemiology

Impact

Incidence rates have increased over the last 20 years, but mesothelioma remains a relatively rare cancer (about one case for a million people; By comparison, populations with a high level of smoking can reach the incidence of more than 1,000 lung cancer per million habitants10.

The incidence of malignant mesothelioma currently reaches a level of about 7 to 40 cases per 1 000 000 inhabitants in the industrialized Western nations, according to the importance of exposure of populations to asbestos during the PASSÉES11 decades. The incidence in the United States was estimated to have reached one to 15 for 1 000 000 inhabitants in 2004. The incidence is expected to continue to increase in other parts of the world. Mesothelioma occurs more often in men than in women and the risk increases with age, but this disease may occur in men or women at any age. Approximately one-fifth to one-third of all mesotheliomas are peritoneal tumors.

It can be noted that an epidemic of mesothelioma has been discovered in three Turkish villages (Karain, Tuzkoy and Sarehidir) located in Cappadocia. It is responsible today for 50% of the deaths there-bas12.

In France, in 2014, a report from the HCSP based on data from the INVS estimated that out of 100 000 expected asbestos deaths from 2009 to 2050 (50 000 to 75 000 will be due to lung cancer and 18 000 to 25 000 to a mésothéliome13. And according to the INVS for 61 000 to 118 000 deaths, already caused by asbestos from 1995 and 2009, 25 000 to 36 000 were due to mesothelioma (for 36,000 to 82,000 due to occupational lung cancer) 13. The National Association for the Defence of Asbestos Victims (AIR13) calls for a reduction of the threshold to 0.5 fibre per litre.

Risk Factors

Occupational exposure to asbestos is the main risk factor for mesothelioma. A past exposure to asbestos exists in almost all the cases listed. However, mesothelioma has been reported in some cases of individuals without known exposure to asbestos.

Asbestos is the name of a group of ores that naturally occur in the form of a agglomerate of hard and flexible fibres that can be separated into thin threads and be woven. Asbestos has been widely used in many industrial products, including cement, brake linings, roof shingles, flooring, textiles, and insulation products. If tiny particles of asbestos float in the air, especially during the manufacturing process, they can be inhaled or swallowed, and pose serious health problems. In addition to mesothelioma, exposure to asbestos increases the risk of bronchial cancer, causes asbestosis, pulmonary fibrosis (chronic non-cancerous disease), and other cancers, such as laryngeal and kidney tumours. For one person the association of smoking and exposure to asbestos significantly increases the risk of developing upper airway cancer or bronchial carcinoma. The Kent brand used asbestos in its cigarette filters for some of its first years of production in the years 1950 and some cases of mesothelioma resulted. Apart from this particular case, smoking does not seem to increase the risk of mesothelioma. Some studies suggest that the Simian virus 40 (SV40) may act as cofactor in the development of MÉSOTHÉLIOME14.

Asbestos exposure

The occupational sectors which led to asbestos exposures concerned the extraction units, and the industries employing asbestos because of its properties:

Extraction units (mines and mills, in order to prepare a given calibre of fibre),

Manufacture of asbestos-based materials: manufacture of cement, AMIANTE15 textile, friction materials (brakes, clutches),

Insulation (in the building, in the manufacture of industrial furnaces, in the manufacturing of thermal and refrigerating equipment, in shipyards) and insulation (flocking with products containing asbestos is banned in France since 1997),

Use of asbestos as protection against heat (gloves, aprons, cords, blankets...) in various industries: shipyards, iron and steel, foundry, glass manufacturing, building industry...

Since the ban on the manufacture of imports and marketing of asbestos-containing materials in France (Decree 96-1133 of 24/12/1996), it is the intervention on asbestos-containing materials which is the preoccupation Major, especially for all construction professionals (asbestos removal work).

Fr Asbestos Exposure Tracking Guide [archive], a French-language respiratory society

In 2011, 6 regions of France are subject to notifiable mesotheliomas, in the framework of the epidemiological surveillance of the InVS and the plan Cancer 2009-2013 Aquitaine, Auvergne, Île-de-France (Val-de-Marne and Seine-Saint-Denis), Lorraine, Midi-Pyrénées, Provence-Alpes-Côte d'azur (Alpes-Maritimes, Bouches-du-Rhône, Var). 1 090 deaths were estimated due to malignant pleural mesothelioma in 2005. For 80% asbestos fibre exposure was found and nearly 70% were male. Asbestos would still be responsible for 10 to 20% of lung cancers, and could cause 100 000 deaths by 2025, according to data from the former Health agency Environment and work (Afsset). Since 2002, the Asbestos Victims Compensation Fund (FIVA) has paid almost 2.4 billion euros to some 52 000 victimes16, 17.

Treatment

Treatment of mesothelioma with conventional therapies has not proven to be effective and patients have a median survival time of 6 – 12 months after diagnosis. In the best cases (those who can benefit from an extensive surgical cure), it can reach 20 months18. The degree of malignancy of the tumor depends on several factors, including the total mésothéliale surface of the pleural cavity, the importance of which promotes local metastases through exfoliated cells, as well as the invasion of the underlying tissues and Other organs in the pleural cavity. Another factor that comes into being is the extremely long latency period between exposure to asbestos and the development of the disease.

Surgery

There are two types of surgery. The lighter partial pleurectomie and the enlarged Pleurotectomie, which consists of removing the pleura and a pulmonary block. In some cases, surgery can significantly increase survival expectancy.

Chemotherapy

The Association of Pemetrexed and Cisplatin proves to be superior to cisplatin Seule19, which in February 2004, approved by the Food and Drug administrationof of its use. The use of this drug has been authorized in France since 2005. The raltitrexed seems to have an efficacy comparable20,21. The addition of bevacizumab to chemotherapy (gemcitabine + cisplatin) is proving to be décevant22. Bevacizumb in combination with standard chemotherapy (pemetrexed + cisplatin) leads to an improvement in Survie23.

Immunotherapy

Therapeutic protocols with immunotherapy treatment yielded varying results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (BCG) in an attempt to amplify the immune response has proven to provide no benefit to the patient (while it can improve the condition of bladder cancer patients ). Mesothelioma cells were proven in vitro to be destroyed by lymphocyte cells after activation by interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this therapeutic trial was interrupted because of the intolerable high levels of IL-2 toxicity and the severity of side effects such as fever and wasting. However, other trials using interferon alpha were encouraging with 20% of patients with a reduction of more than 50% of the tumor mass associated with minimal side effects.

Research

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Historical

An article published by Wagner et al in 1960 established for the first time that mesothelioma was a disease resulting from exposure to asbestos in the form of Crocidolite24. The article listed more than 30 cases of patients who had reported mesothelioma in South Africa, including transient exposures and cases involving minors.

In 1962, Dr. McNulty reported the first case of malignant mesothelioma diagnosed in Australia by a worker exposed to amiante25. The worker had worked in the mill at the Wittenoom asbestos Mine from 1948 to 1950.

In the city of Wittenoom, asbestos packing waste from the mine has been recycled for the coating of recreational and playground courses.

In 1965 it was written in an article published in the British Journal of Occupational Medicine that people who had lived in the vicinity of factories and asbestos mines without working there had contracted mesothelioma.

Despite evidence that the dust associated with the operation of the asbestos mine and the milling of fibres was the cause of asbestos-related diseases, the extraction started at Wittenoom in 1943 continued until 1966.

It is difficult to understand why the mine and mill were first allowed to open and continue to operate without appropriate measures to control the risk; And why nothing has been done to coerce the owner (CSR) into setting standards, adopting safer working methods or terminating operations.

In 1974 the first public warnings concerning the dangers of blue asbestos were published in the Bulletin of an Australian magazine in the form of a linked book whose cover was entitled: "Is This killer in your house?"

In 1978 the Government of Western Australia decided to shave the town of Wittenoom, after the publication of a health service booklet, "Health Risk in Wittenoom", containing the results of atmospheric sampling and an assessment of Medical data available worldwide.

In 1979 the first complaints for negligence at Wittenoom were launched against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the victims of Wittenoom.

peritoneal mesothelioma

Definition

peritoneal mesothelioma is a primitive malignant tumour characterized by diffuse flooding of péritonéales26 surfaces [ref. insufficient] (Peritoneum has two leaflets, one visceral lining the outside of the organs, the other parietal Lining the inner side of the abdomen walls.

Epidemiology

The incidence of peritoneal mesotheliomas has been universally increased since 1970. In the industrialized countries, its incidence is estimated today from 0.5 to 3 cases per million inhabitants in humans and from 0.2 to 2 cases per million in Femme27. Peritoneal mesothelioma represents 1/5 to 1/4 of all clinical forms of mésothéliome28.

Etiology

Recent studies seem to establish a link in humans on the relationship between exposure to asbestosis and the development of a,29 péritonéal27 mesothelioma. Since the first case of pleural mesothelioma in relation to asbestosis, several other carcinogenic agents have been identifiés24. Have been mentioned: the virus-4030, radiotherapy abdominale31, peritonitis chroniques32, exposure to mica33 and the administration of thorium34 dioxide. A possible genetic susceptibility, with autosomal dominant transmission, after exposure to Erionite, another carcinogenic agent implicated was also reported by Roushdy-Hammady et al. In the Cappadociène, a region of Turquie35.

Diagnosis and Clinic

The discovery is often related to an increase in the volume of the secondary abdomen to ascites production or tumor formation as well as to non-specific abdominal pain. In 10% of cases is reported the formation of a symptomatic hernia. This is the most common mode of discovery in humans. In women, accidental discovery during a laparoscopy is the most common.

The Thoraco-abdominal-pelvic scanner is today the reference morphological examination for the diagnosis, the extension balance and the monitoring of peritoneal mesothelioma. However, it allows only to detect lesions of more than 5 mm and it underestimates the intraperitoneal extension of the maladie36.

Treatment

For a very long time, the treatment of peritoneal Mesotheliomas has been palliative. It was associated with symptomatic palliative surgery and systemic chemotherapy. Today, a more aggressive treatment that has been in place for the last twenty years has drastically altered the prognosis of pathology. This technique involves associating cytoreduction surgery gestures for the treatment of macroscopic disease with intraperitoneal chemotherapy perioperative: immediate post-operative chemotherapy and/or hyperthermic Intraperitoneal (CHIP) for the treatment of microscopic disease.