Mesothelioma

Mesothelioma

Mesothelioma is a form of cancer that is almost always caused by exposure to asbestos. In this disease, malignant cells develop in the mesothelium, a protective lining that covers most of the body's internal organs. Its most common site is the pleura (outer lining of the lungs and internal chest wall), but it may also occur in the peritoneum (the lining of the abdominal cavity), the heart, the pericardium (a sac that surrounds the heart ) or tunica vaginalis.
Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or they have been exposed to asbestos dust and fiber in other ways. It has also been suggested that washing the clothes of a family member who worked with asbestos can put a person at risk for developing mesothelioma.Unlike lung cancer, there is no association between mesothelioma and smoking, but smoking greatly increases risk of other asbestos-induced cancer. Compensation via asbestos funds or lawsuits is an important issue in mesothelioma.
The symptoms of mesothelioma include shortness of breath due to pleural effusion (fluid between the lung and the chest wall) or chest wall pain, and general symptoms such as weight loss. The diagnosis may be suspected with chest X-ray and CT scan, and is confirmed with a biopsy (tissue sample) and microscopic examination. A thoracoscopy (inserting a tube with a camera into the chest) can be used to take biopsies. It allows the introduction of substances such as talc to obliterate the pleural space (called pleurodesis), which prevents more fluid from accumulating and pressing on the lung. Despite treatment with chemotherapy, radiation therapy or sometimes surgery, the disease carries a poor prognosis. Research about screening tests for the early detection of mesothelioma is ongoing.

History

History

The first lawsuit against asbestos manufacturers was brought in 1929. The parties settled that lawsuit, and as part of the agreement, the attorneys agreed not to pursue further cases. It was not until 1960 that an article published by Wagner et al. first officially established mesothelioma as a disease arising from exposure to crocidolite asbestos. The article referred to over 30 case studies of people who had suffered from mesothelioma in South Africa. Some exposures were transient and some were mine workers. However prior to 1950 malignant mesothelioma was extremely rare and some experts even questioned its existence. In 1962 McNulty reported the first diagnosed case of malignant mesothelioma in an Australian asbestos worker. The worker had worked in the mill at the asbestos mine in Wittenoom from 1948 to 1950.
In the town of Wittenoom, asbestos-containing mine waste was used to cover schoolyards and playgrounds. In 1965 an article in the British Journal of Industrial Medicine established that people who lived in the neighbourhoods of asbestos factories and mines, but did not work in them, had contracted mesothelioma.

Despite proof that the dust associated with asbestos mining and milling causes asbestos-related disease, mining began at Wittenoom in 1943 and continued until 1966. In 1974 the first public warnings of the dangers of blue asbestos were published in a cover story called "Is this Killer in Your Home?" in Australia's Bulletin magazine. In 1978 the Western Australian Government decided to phase out the town of Wittenoom, following the publication of a Health Dept. booklet, "The Health Hazard at Wittenoom", containing the results of air sampling and an appraisal of worldwide medical information.
By 1979 the first writs for negligence related to Wittenoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the Wittenoom victims.

In Armley, Leeds, England the J W Roberts asbestos incident involved several court cases against Turner & Newall where local residents who contracted mesothelioma claimed compensation because of the asbestos pollution from the company's factory. One notable case was that of June Hancock, who contracted the disease in 1993 and died in 1997.

Legal issues

Legal issues

Main article: Asbestos and the law

The first lawsuits against asbestos manufacturers were in 1929. Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898 ). The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars. The amounts and method of allocating compensation have been the source of many court cases, reaching up to the United States Supreme Court, and government attempts at resolution of existing and future cases. However, to date, the US Congress has not stepped in and there are no federal laws governing asbestos compensation.

Notable people who have lived for some time with mesothelioma

Notable people who have lived for some time with mesothelioma

Although life expectancy with this disease is typically limited, there are notable survivors. In July 1982, Stephen Jay Gould was diagnosed with peritoneal mesothelioma. After his diagnosis, Gould wrote the "The Median Isn't the Message" for Discover magazine, in which he argued that statistics such as median survival are just useful abstractions, not destiny. Gould lived for another twenty years eventually succumbing to metastatic adenocarcinoma of the lung, not mesothelioma. Author Paul Kraus was diagnosed with peritoneal mesothelioma in July 1997. He was given a prognosis of less than a year to live and used a variety of complementary modalities. He continues to outlive his prognosis and wrote a book about his experience "Surviving Mesothelioma and Other Cancers: A Patient's Guide" in which he presented his philosophy about healing and the decision making that led him to use integrative medicine.

Notable people who died from mesothelioma

Notable people who died from mesothelioma

Mesothelioma, though rare, has had a number of notable patients. Hamilton Jordan, Chief of Staff for President Jimmy Carter and life long cancer activist, died in 2008. Australian anti-racism activist Bob Bellear died in 2005. British science fiction writer Michael G. Coney, responsible for nearly 100 works also died in 2005. American film and television actor Paul Gleason, perhaps best known for his portrayal of Principal Richard Vernon in the 1985 film The Breakfast Club, died in 2006. Mickie Most, an English record producer, died of mesothelioma in 2003. Paul Rudolph, an American architect known for his cubist building designs, died in 1997.
Bernie Banton was an Australian workers' rights activist, who fought a long battle for compensation from James Hardie after he contracted mesothelioma after working for that company. He claimed James Hardie knew of the dangers of asbestos before he began work with the substance making insulation for power stations. Mesothelioma eventually took his life along with his brothers and hundreds of James Hardie workers. James Hardie made an undisclosed settlement with Banton only when his mesothelioma had reached its final stages and he was expected to have no more than 48hrs to live. Australian Prime Minister Kevin Rudd mentioned Banton's extended struggle in his acceptance speech after winning the 2007 Australian Federal Election.

Steve McQueen was diagnosed with peritoneal mesothelioma on December 22, 1979. He was not offered surgery or chemotherapy because doctors felt the cancer was too advanced. McQueen sought alternative treatments from clinics in Mexico. He died of a heart attack on November 7, 1980, in Juárez, Mexico, following cancer surgery. He may have been exposed to asbestos while serving with the U.S. Marines as a young adult—asbestos was then commonly used to insulate ships' piping—or from its use as an insulating material in car racing suits. (It is also reported that he worked in a shipyard during World War II, where he might have been exposed to asbestos.[citation needed ])

United States Congressman Bruce Vento died of mesothelioma in 2000. The Bruce Vento Hopebuilder is awarded yearly by his wife at the MARF Symposium to persons or organizations who have done the most to support mesothelioma research and advocacy.
After a long period of untreated illness and pain, rock and roll musician and songwriter Warren Zevon was diagnosed with inoperable mesothelioma in the fall of 2002. Refusing treatments he believed might incapacitate him, Zevon focused his energies on recording his final album The Wind including the song "Keep Me in Your Heart," which speaks of his failing breath. Zevon died at his home in Los Angeles, California, on September 7, 2003.

Christie Hennessy, the influential Irish singer-songwriter, died of mesothelioma in 2007, and had stridently refused to accept the prognosis in the weeks before his death. His mesothelioma has been attributed to his younger years spent working on building sites in London.
Bob Miner, one of the founders of Software Development Labs, the forerunner of Oracle Corporation died of mesothelioma in 1994.

Scottish Labour MP John William MacDougall died of mesothelioma on August 13, 2008, after fighting the disease for two years.

Canberra journalist and news presenter, Peter Leonard also succumbed to the condition on 23 September 2008.

Terrence McCann Olympic gold medalist and longtime Executive Director of Toastmasters, died of mesothelioma on June 7, 2006 at his home in Dana Point, California.

Heated Intraoperative Intraperitoneal Chemotherapy

Heated Intraoperative Intraperitoneal Chemotherapy

A procedure known as heated intraoperative intraperitoneal chemotherapy was developed by Paul Sugarbaker at the Washington Cancer Institute. The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48°C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained.

This technique permits the administration of high concentrations of selected drugs into the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.

Immunotherapy

Immunotherapy

Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guerin (BCG) in an attempt to boost the immune response, was found to be of no benefit to the patient (while it may benefit patients with bladder cancer). Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended in view of the unacceptably high levels of IL-2 toxicity and the severity of side effects such as fever and cachexia. Nonetheless, other trials involving interferon alpha have proved more encouraging with 20% of patients experiencing a greater than 50% reduction in tumor mass combined with minimal side effects.

Chemotherapy

Chemotherapy

Chemotherapy is the only treatment for mesothelioma that has been proven to improve survival in randomised and controlled trials. The landmark study published in 2003 by Vogelzang and colleagues compared cisplatin chemotherapy alone with a combination of cisplatin and pemetrexed (brand name Alimta) chemotherapy) in patients who had not received chemotherapy for malignant pleural mesothelioma previously and were not candidates for more aggressive "curative" surgery. This trial was the first to report a survival advantage from chemotherapy in malignant pleural mesothelioma, showing a statistically significant improvement in median survival from 10 months in the patients treated with cisplatin alone to 13.3 months in the combination pemetrexed group in patients who received supplementation with folate and vitamin B12. Vitamin supplementation was given to most patients in the trial and pemetrexed related side effects were significantly less in patients receiving pemetrexed when they also received daily oral folate 500mcg and intramuscular vitamin B12 1000mcg every 9 weeks compared with patients receiving pemetrexed without vitamin supplementation. The objective response rate increased from 20% in the cisplatin group to 46% in the combination pemetrexed group. Some side effects such as nausea and vomiting, stomatitis, and diarrhoea were more common in the combination pemetrexed group but only affected a minority of patients and overall the combination of pemetrexed and cisplatin was well tolerated when patients received vitamin supplementation; both quality of life and lung function tests improved in the combination pemetrexed group. In February 2004, the United States Food and Drug Administration approved pemetrexed for treatment of malignant pleural mesothelioma. However, there are still unanswered questions about the optimal use of chemotherapy, including when to start treatment, and the optimal number of cycles to give.

Cisplatin in combination with raltitrexed has shown an improvement in survival similar to that reported for pemetrexed in combination with cisplatin, but raltitrexed is no longer commercially available for this indication. For patients unable to tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, or vinorelbine on its own, although a survival benefit has not been shown for these drugs. For patients in whom cisplatin cannot be used, carboplatin can be substituted but non-randomised data have shown lower response rates and high rates of haematological toxicity for carboplatin-based combinations, albeit with similar survival figures to patients receiving cisplatin.

In January 2009, the United States FDA approved using conventional therapies such as surgery in combination with radiation and or chemotherapy on stage I or II Mesothelioma after research conducted by a nationwide study by Duke University concluded an almost 50 point increase in remission rates.

Radiation

Radiation

For patients with localized disease, and who can tolerate a radical surgery, radiation is often given post-operatively as a consolidative treatment. The entire hemi-thorax is treated with radiation therapy, often given simultaneously with chemotherapy. This approach of using surgery followed by radiation with chemotherapy has been pioneered by the thoracic oncology team at Brigham & Women's Hospital in Boston. Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations with some patients surviving more than 5 years. As part of a curative approach to mesothelioma, radiotherapy is also commonly applied to the sites of insertion, in order to prevent growth of the tumor along the track in the chest wall.

Although mesothelioma is generally resistant to curative treatment with alone, palliative treatment regimens are sometimes used to relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel. Radiation therapy when given alone with curative intent has never been shown to improve survival from mesothelioma. The necessary radiation dose to treat mesothelioma that has not been surgically removed would be very toxic.

Surgery

Surgery

Surgery, by itself, has proved disappointing. However, research indicates varied success when used in combination with radiation and chemotherapy (Duke, 2008) A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed.

Treatment

Treatment

Treatment of malignant mesothelioma using conventional therapies in combination with radiation and or chemotherapy on stage I or II Mesothelioma have proved on average 74.6 percent successful in extending the patient's life span by five years or more [commonly known as remission][this percentage may increase or decrease depending on date of discovery / stage of malignant development] (Oncology Today, 2009). Treatment course is primarily determined by the staging or development. This is unlike traditional treatment such as surgery by itself which has proved only be 16.3 percent likely to extend a patient's life span by five years or more [commonly known as remission]. Clinical behavior of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favors local metastasis via exfoliated cells, invasion to underlying tissue and other organs within the pleural cavity, and the extremely long latency period between asbestos exposure and development of the disease.

Asbestos in buildings

Asbestos in buildings

Many building materials used in both public and domestic premises prior to the banning of asbestos may contain asbestos. Those performing renovation works or DIY activities may expose themselves to asbestos dust. In the UK use of Chrysotile asbestos was banned at the end of 1999. Brown and blue asbestos was banned in the UK around 1985. Buildings built or renovated prior to these dates may contain asbestos materials.

Paraoccupational secondary exposure

Paraoccupational secondary exposure

Family members and others living with asbestos workers have an increased risk of developing mesothelioma, and possibly other asbestos related diseases. This risk may be the result of exposure to asbestos dust brought home on the clothing and hair of asbestos workers. To reduce the chance of exposing family members to asbestos fibres, asbestos workers are usually required to shower and change their clothing before leaving the workplace.

Occupational

Occupational

Exposure to asbestos fibres has been recognized as an occupational health hazard since the early 1900s. Several epidemiological studies have associated exposure to asbestos with the development of lesions such as asbestos bodies in the sputum, pleural plaques, diffuse pleural thickening, asbestosis, carcinoma of the lung and larynx, gastrointestinal tumours, and diffuse mesothelioma of the pleura and peritoneum.

The documented presence of asbestos fibres in water supplies and food products has fostered concerns about the possible impact of long-term and, as yet, unknown exposure of the general population to these fibres. Although many authorities consider brief or transient exposure to asbestos fibres as inconsequential and an unlikely risk factor, some epidemiologists claim that there is no risk threshold. Cases of mesothelioma have been found in people whose only exposure was breathing the air through ventilation systems. Other cases had very minimal (3 months or less) direct exposure.

Commercial asbestos mining at Wittenoom, Western Australia, occurred between 1945 and 1966. A cohort study of miners employed at the mine reported that while no deaths occurred within the first 10 years after crocidolite exposure, 85 deaths attributable to mesothelioma had occurred by 1985. By 1994, 539 reported deaths due to mesothelioma had been reported in Western Australia.

Environmental exposures

Environmental exposures

Incidence of mesothelioma had been found to be higher in populations living near naturally occurring asbestos. For example, in central Cappadocia, Turkey, mesothelioma was causing 50% of all deaths in three small villages — Tuzköy, Karain and Sarıhıdır. Initially, this was attributed to erionite, a zeolite mineral with similar properties to asbestos, however, recently, detailed epidemiological investigation showed that erionite causes mesothelioma mostly in families with a genetic predisposition.

Epidemiology -Exposure

Epidemiology

Exposure

Asbestos was known in antiquity, but it wasn't mined and widely used commercially until the late 1800s. Its use greatly increased during World War II. Since the early 1940s, millions of American workers have been exposed to asbestos dust. Initially, the risks associated with asbestos exposure were not publicly known. However, an increased risk of developing mesothelioma was later found among shipyard workers, people who work in asbestos mines and mills, producers of asbestos products, workers in the heating and construction industries, and other tradespeople. Today, the U.S. Occupational Safety and Health Administration(OSHA) sets limits for acceptable levels of asbestos exposure in the workplace, and created guidelines for engineering controls and respirators, protective clothing, exposure monitoring, hygiene facilities and practices, warning signs, labeling, recordkeeping, and medical exams. By contrast, the British Government's Health and Safety Executive (HSE) states formally that any threshold for mesothelioma must be at a very low level and it is widely agreed that if any such threshold does exist at all, then it cannot currently be quantified. For practical purposes, therefore, HSE does not assume that any such threshold exists. People who work with asbestos wear personal protective equipment to lower their risk of exposure.

Epidemiology -Risk factors

Epidemiology

Risk factors

Working with asbestos is the major risk factor for mesothelioma. A history of asbestos exposure exists in almost all cases. However, mesothelioma has been reported in some individuals without any known exposure to asbestos. In rare cases, mesothelioma has also been associated with irradiation, intrapleural thorium dioxide (Thorotrast), and inhalation of other fibrous silicates, such as erionite.

Asbestos is the name of a group of minerals that occur naturally as masses of strong, flexible fibers that can be separated into thin threads and woven. Asbestos has been widely used in many industrial products, including cement, brake linings, roof shingles, flooring products, textiles, and insulation. If tiny asbestos particles float in the air, especially during the manufacturing process, they may be inhaled or swallowed, and can cause serious health problems. In addition to mesothelioma, exposure to asbestos increases the risk of lung cancer, asbestosis (a noncancerous, chronic lung ailment), and other cancers, such as those of the larynx and kidney.

The combination of smoking and asbestos exposure significantly increases a person's risk of developing cancer of the airways (lung cancer, bronchial carcinoma). The Kent brand of cigarettes used asbestos in its filters for the first few years of production in the 1950s and some cases of mesothelioma have resulted. Smoking modern cigarettes does not appear to increase the risk of mesothelioma.

Some studies suggest that simian virus 40 (SV40) may act as a cofactor in the development of mesothelioma.

Epidemiology -Incidence:

Epidemiology

Incidence:

Although reported incidence rates have increased in the past 20 years, mesothelioma is still a relatively rare cancer. The incidence rate is approximately one per 1,000,000. The highest incidence is found in Britain, Australia and Belgium: 30 per 1,000,000 per year. For comparison, populations with high levels of smoking can have a lung cancer incidence of over 1,000 per 1,000,000. Incidence of malignant mesothelioma currently ranges from about 7 to 40 per 1,000,000 in industrialized Western nations, depending on the amount of asbestos exposure of the populations during the past several decades. It has been estimated that incidence may have peaked at 15 per 1,000,000 in the United States in 2004. Incidence is expected to continue increasing in other parts of the world. Mesothelioma occurs more often in men than in women and risk increases with age, but this disease can appear in either men or women at any age. Approximately one fifth to one third of all mesotheliomas are peritoneal.

Between 1940 and 1979, approximately 27.5 million people were occupationally exposed to asbestos in the United States. Between 1973 and 1984, there has been a threefold increase in the diagnosis of pleural mesothelioma in Caucasian males. From 1980 to the late 1990s, the death rate from mesothelioma in the USA increased from 2,000 per year to 3,000, with men four times more likely to acquire it than women. These rates may not be accurate, since it is possible that many cases of mesothelioma are misdiagnosed as adenocarcinoma of the lung, which is difficult to differentiate from mesothelioma.

Pathophysiology

Pathophysiology

The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.

Pleural contamination with asbestos or other mineral fibres has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers). However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System. Dr. Fein has treated several patients for "World Trade Center syndrome" or respiratory ailments from brief exposures of only a day or two near the collapsed buildings.
Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibres. It has been suggested that in humans, transport of fibres to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localised lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumour.

Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibres remain unclear despite the demonstration of its oncogenic capabilities. However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibres has not yet been achieved. In general, asbestos fibres are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.

Analysis of the interactions between asbestos fibres and DNA has shown that phagocytosed fibres are able to make contact with chromosomes, often adhering to the chromatin fibres or becoming entangled within the chromosome. This contact between the asbestos fibre and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.

Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:

Staging

Staging

Staging of mesothelioma is based on the recommendation by the International Mesothelioma Interest Group. TNM classification of the primary tumor, lymph node involvement, and distant metastasis is performed. Mesothelioma is staged Ia–IV (one-A to four) based on the TNM status.

Screening

Screening

There is no universally agreed protocol for screening people who have been exposed to asbestos. Screening tests might diagnose mesothelioma earlier than conventional methods thus improving the survival prospects for patients. The serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma. The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening. Doctors have begun testing the Mesomark assay which measures levels of soluble mesothelin-related proteins (SMRPs) released by diseased mesothelioma cells.

Diagnosis

Diagnosis

Diagnosing mesothelioma is often difficult, because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient's medical history. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytology if this fluid is aspirated with a syringe. For pleural fluid this is done by a pleural tap or chest drain, in ascites with an paracentesis or ascitic drain and in a pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure).
If cytology is positive or a plaque is regarded as suspicious, a biopsy is needed to confirm a diagnosis of mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologis. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples.

If the cancer is in the abdomen, the doctor may perform a laparoscopy. To obtain tissue for examination, the doctor makes a small incision in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.
　
Typical immunohistochemistry results

Positive Negative
EMA (epithelial membrane antigen)
in a membranous distribution CEA (carcinoembryonic antigen) WT1 (Wilms' tumor 1) B72.3 Calretinin MOC-3 1 Mesothelin-1 CD15 Cytokeratin 5/6 Ber-EP4 HBME-1 (human mesothelial cell 1) TTF-1 (thyroid transcription factor -1)

Signs and symptoms

Signs and symptoms

Symptoms of mesothelioma may not appear until 20 to 50 years after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space are often symptoms of pleural mesothelioma.

Symptoms of peritoneal mesothelioma include weight loss and cachexia, abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Other symptoms of peritoneal mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.
These symptoms may be caused by mesothelioma or by other, less serious conditions.

Mesothelioma that affects the pleura can cause these signs and symptoms:
Chest wall pain
Pleural effusion, or fluid surrounding the lung
Shortness of breath
Fatigue or anemia
Wheezing, hoarseness, or cough
Blood in the sputum (fluid) coughed up (hemoptysis)

In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread, to other parts of the body.
Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:

Abdominal pain
Ascites, or an abnormal buildup of fluid in the abdomen
A mass in the abdomen
Problems with bowel function
Weight loss
In severe cases of the disease, the following signs and symptoms may be present:
Blood clots in the veins, which may cause thrombophlebitis
Disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs Jaundice, or yellowing of the eyes and skin
Low blood sugar level
Pleural effusion
Pulmonary emboli, or blood clots in the arteries of the lungs
Severe ascites
A mesothelioma does not usually spread to the bone, brain, or adrenal glands. Pleural tumors are usually found only on one side of the lungs.

Anyone who has used Google AdWords knows that:

Anyone who has used Google AdWords knows that:

• High Quality Score = Lowest possible pay-per-click advertising costs

• Low Quality Score = Absurdly high pay-per-click advertising costs!

...and given a choice, it's obvious which one we'd all choose. The problem is, however, few aspects of PPC marketing cause more confusion, frustration, and wasted ad money than Google's seeming inexplicable AdWords Quality Scoring System for pricing AdWords PPC ads.

Yet, clearly, PPC marketing is a critical element of a successful search engine marketing (SEM) campaign. And, Google's Quality Score stands between most online professional marketers and their profits! The cryptic formula remains shrouded in mystery that forces advertisers to "guess" what Google actually means by such vague terms as quality or relevance.

Naturally that vagueness has led to much speculation about what it takes to boost your critically important Quality Score. Numerous misconceptions abound. This article will trade misconceptions for realities to help you proceed with confidence as we show you how to get more clicks for less money with your AdWords campaigns.

Now, let's debunk some myths!

The 10 Most Common Quality Score Myths

Myth #1. Each AdWords account has just one Quality Score that affects all keywords.

Actually, nearly every aspect of your AdWords campaign has its own Quality Score. There's an overall Account Quality Score, an Ad Group Quality Score (used for ranking in the Content Network), and aKeyword Quality Score (used for ranking in the Search Network, plus a few others we'll discuss.

Your Keyword Quality Score, combined with your maximum Cost-Per-Click (CPC), is what determines the position of your ad on the search network. Each keyword has its own Quality Score, which you can access by following Google's instructions on how to view your keyword's Quality Score.

Each keyword is rated either 'Great', 'OK', or 'Poor'. Your Keyword Quality Score is made up of...

• Your ad copy's relevance to your keywords.
• Your keyword click-through rate (mostly your click-through rate over the past 2 weeks, but lifetime click-through rate is also a factor).
• Your overall Account Quality Score.
• Other relevancy factors (such as geotargeting and demographic targeting; factors that have only minor impact on Quality Score).

Your Account Quality Score is essentially a summary of all your individual Keyword Quality Scores added up. It's used to determine initial minimum bids for those keywords that Google doesn't have a lot of existing data on.

Keep in mind that if you leave a lot of low Quality Score keywords active in your campaign, that can cause your overall Account Quality Score to tank-thereby affecting the Quality Scores of all your keywords, even your good ones. So ditching low Quality Score keywords that aren't performing is generally a good idea.

Note that the relationship between Keyword Quality Score andAccount Quality Score is circular in that each affects the other.Account Quality Score is made up of the sum of all your KeywordQuality Scores, but your Keyword Quality Scores are in turn affected by your Account Quality Score.

If you've got just a few low Quality Score keywords, they're unlikely to drag down your Account Quality Score. But if you have large number of poorly performing keywords, that can have a negative impact on your Account Quality Score, which can then drag down the Quality Scores of your good keywords. (Are we dizzy yet?)

So if you've got a lot of keywords rated 'Poor', you may want to ditch them to elevate your Account Quality Score. Of course, don't ditch them if they're still bringing in the kind of traffic that converts into money. But also don't leave them hanging around if they're not doing you any good-because they could be hurting your campaign by increasing your PPC costs.

You should also bear in mind that Account Quality Score is primarily how Google determines minimum bid prices for new keywords where Google doesn't have much existing data. So, if you're regularly adding large numbers of keywords to your account, you'll want to maintain a goodAccount Quality Score to keep those initial minimum bids low.

Finally, there's also a Landing Page Quality Score, which impacts your keywords' minimum bid price-but does not affect your ad's actual position in the search results.

Myth #2. The quality of your landing page impacts your Quality Score and your ad's position in the search results.

This is a common misunderstanding. While it's true that landing page quality does impact your Quality Score in the Content Network(aka AdSense), it has no impact on your Quality Score in the Search Network. And getting your ads to show up in Google's search results is important because that's typically where the highest levels of traffic and conversions are.

However, while landing page quality does not impact your Search Network Quality Score, it does have an effect on your minimum bid (the minimum amount you can pay and still have Google allow your ads to appear on the Search Network). Clearly, you want your minimum bids to be as low as possible, so landing page quality is still important even if it doesn't effect your Quality Score.

There may be times when you see that a keyword has a high Quality Score but Google still wants a very high minimum bid (more than $1.00) in order to activate the keyword for search. That almost always means you've got landing page problems. Fix those problems and you'll often be able to get that keyword for fairly cheap.

While your landing page does not directly effect your Quality Score for search, it still plays a big role in keeping your clicks affordable, since you want to achieve the lowest minimum bids possible. If you're not sure what your minimum bids are, Google has a great tutorial on how todetermine your keywords' minimum bids.

Myth #3. Creating an individual Ad Group for each of your keywords can improve your Quality Score

False. What's most important is that your ad groups contain keywords that are highly relevant to each other and to the ads you're displaying for them. Take a look at your ad group. Does each keyword match the theme of the ad it's triggering? Although it isn't necessary for the keyword itself to be found in the actual ad (although it helps), it is necessary that it be highly relevant to what the ad is offering.

If some of your keywords don't closely match the ads in your ad group, you should probably move those keywords into their own ad group. This generally means your ad groups will be small-but creating an ad group for every single keyword is not only overkill, it's also an account management headache.

On the opposite end of the spectrum, neither is the long tail approachto keyword research the best approach. Every AdWords campaign starts with a 50k keyword limit, which can be adjusted upwards later by your account rep. But if you're dumping hundreds or thousands of keywords into your ad groups you're going to have a hard time keeping them all relevant to the ads and to each other.

You're much better off starting with a smaller set of keywords and keeping any long tail keywords limited to 2-4 word phrases. Once you start using 5 word phrases or longer, Google won't likely have enough historical data on such specific phrases to avoid assigning them lower quality scores and high minimum bids right from the beginning.

Once we've established high Quality Scores for our initial smaller set of keywords, we can then branch out to a broader range of keywords. The many keyword tools available today make it easy to create huge keyword lists, but when it comes to PPC marketing, bigger is not always better.

We like to keep most of our ad groups limited to about 10 keywords, and rarely go over 20 keywords for any ad group. Some marketers we know use up to 100 keywords per ad group and it works for them, but we find our targeting is most effective when we keep our ad groups small.

Most importantly, we make sure all the keywords in the ad group are tightly targeted to each other as well as to the ad itself. This point can not be emphasized enough, as it is almost always the most effective way to boost your Quality Score.

Myth #4. PageRank and incoming links to your landing page impacts Quality Score.

This one surprised us a bit, as it's been our experience that starting an AdWords campaign on a site with established links made it easier to maintain a high Quality Score. But Google's official position is that organic search and paid search rely on two completely separate algorithms, and that links to the landing page itself do notimpact Quality Score.

However, the results from our testing do suggest that landing pages on domains with established links outperform landing pages on domains with no links at all. But it isn't necessary that the landing page itself performs well in the organic search in order to perform well in paid search. So it appears that links to the domain help somewhat, but pointing them at the actual landing page is not strategically important. And, we are still testing this to determine for sure.

Obviously this is one area where we differ slightly with the official Google line of information. Even though Google says PageRank and inbound links don't affect Quality Score, we continue to begin our own PPC campaigns on an established domain with lots of inbound links and unique content whenever possible.

We can say for certain that linking out from your landing page to other relevant and unique articles on your site does indeed boost your landing page's Quality Score. So try not to make your landing pages stand-alone islands that don't link out. We suggest you link to your Privacy Policy, Contact Us, and About Us pages, as well as 10-20 relevant articles with unique content.

Bear in mind that it isn't necessary to link out to all 20 articles from every landing page. Instead you can just link to a single page which in turn links to your article content. We typically put these links in the footer of our landing pages.

Myth #5. Click-through rates on broad match keywords impact your Quality Score.

The truth is that Quality Score is based on exact match impressions only. However, this does not mean that Quality Score is only calculated on keywords you have set to exact match. Instead, it means quality score is only impacted when someone does a search for the exact keyword phrase you have listed in your ad group-regardless of whether your keywords are set to exact, phrase, or broad match.

Setting some of your keywords to expanded broad match can be a great way to find new keywords. Doing so will expose your ads to a broad range of queries related to the keywords you're targeting. If you closely track the keywords which are leading to sales, you'll often find many new converting keywords

However, when doing keyword research using expanded broad match, be sure to closely monitor your budget and make use of negative keywords to block irrelevant queries so that you don't end up losing money.

By the way, we've learned exact match, phrase match and broad match don't offer much value to having the same keyword phrase listed three times in your ad groups. Instead, we like to use phrase matchwith negative keywords added in so our ad isn't displayed for irrelevant searches. And if we're researching the niche, we might use broad match as mentioned above.

Myth #6. Dynamic Keyword Insertion automatically makes ads more relevant and boosts Quality Score.

Dynamic Keyword Insertion is an AdWords feature that automatically places the user's search query in your ad if the query matches the keyword you are bidding on. While this can make your ad appear more relevant to users, it doesn't effect Google's perceived relevancy of the ad.

Google expects you to have ad groups tightly themed around a specific set of related keywords and does not consider Dynamic Keyword Insertion as a substitute for this. We recommend you work on creating small ad groups with keywords highly relevant to each other as well as to the ad. This is the best possible way to boost your quality score.

Used wisely, however, Dynamic Keyword Insertion can help boost your click-through rate which, in turn, can boost your keyword ad performance and Quality Scores. So, indirectly, Dynamic Keyword Insertion can have a positive impact on Quality Score.

Myth #7. You must bid high when you first launch your campaign in order to boost click-throughs and achieve a high Quality Score.

In the past all it took to push ads to the top and get lots of clicks was to bid high. Once you established a high click-through rate, you could lower your bids while continuing to maintain high positions due to your keywords' great click-through rates.

These days, Google takes into account that ads displayed lower on the page are less likely to get clicked. Now Google simply expects you tomaintain a good click-through rate relative to what other ads in your position are achieving. So if you're getting a 2.5% click-through rate in position 9, Google might consider that great. But that same click-through rate when you're in position 3 may be looked upon poorly.

Google also expects different click-through rates for different keywords. Highly specific keywords with a great deal of commercial intent (likebuy Canon EOS 40D) are expected to have higher click-through rates than a generic keyword like camera.

Note that click-throughs on Google's Content Network or search partners does not impact your ad's ranking. Where you rank is determined only by clicks that are tracked on Google's own search pages

So while a high click-through rate is going to be important to your ad's success, you don't need to bid yourself to the top of the page right away. Just make sure your ad does well for the position you're currently in

Be sure to factor in the reality that low-positioned ads often won't get much traffic, so it can take a while to determine if that keyword is worth bidding on. Thus, you may want to bid higher to speed up the process of determining if the keyword is target worthy

Although Google tracks the lifetime click-through rate history of your keywords when determining ad ranking, it places the most emphasis on how that keyword performed over the past two weeks. So, it is possible to salvage keywords sometimes, even if they've done poorly in the past

Myth #8. Optimizing your campaigns will delete your keyword history.

To optimize your various Quality Scores within AdWords campaigns, you must rearrange your keywords into tightly focused ad groups. You must also hone your ads to make them increasingly more relevant to specific keywords and ad groups.

Of course, you might have built up some nice history on those keywords which is helping you achieve low minimum bids-and you don't want to have to start over. Fortunately, you don't have to. Provided that you never delete anything you can optimize your campaign without losing your history.

Whenever you move a keyword into a different ad group, use the Cutfeature in AdWords Editor to move it. Do not insert it into an ad group and then delete it in the old ad group (or vice versa) because when you delete something you lose the history that is attached to it.

Google has detailed instructions on moving keywords in this tutorial. If you cut and paste the keywords from one ad group to another without deleting them, you should be able to hang onto the history for those keywords

Myth #9. You need a long performance history with AdWords in order to achieve high Quality Scores.

Actually, it typically only takes about two weeks to establish your performance history. While it appears that Google likes accounts that have been around a while and have lots of history for Google to reference, once your new account has been live for two weeks you shouldn't be at any significant disadvantage to competitors with more seasoned accounts.

Myth #10. Each landing page must be unique and devoid of duplicate content.

Partially true-but it only applies when you're duplicating your content on outside domains. As Google says in their landing page guidelines...

Feature unique content that can't be found on another site.

So if you've got multiple landing pages with very similar content that you're using to split-test, that won't cause you duplicate content problems. But if the same content is being displayed on other sites, then you are in violation of Google's rule.

The Key to Slashing PPC Costs

Achieving an optimum Quality Score can have a supremely positive impact on your PPC campaign. We're are not surprised to see click costs drop by a factor of 10 once a keyword's Quality Score is fully optimized. The best part is that oftentimes it only takes only a day or two after making improvements to see click costs go down and profits go up.