Malignant Mesothelioma Following Treatment for Hodgkin's Disease0

LB Weissmann, JM Corson, AI Neugut and KH Antman

Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.

PURPOSE: Asbestos exposure is the major known risk factor for mesothelioma, but several case reports have suggested a link between radiation therapy and subsequent development of malignant mesothelioma. This report explores a possible association between radiation therapy for Hodgkin's disease and mesothelioma. PATIENTS AND METHODS: Four cases of malignant mesothelioma were observed following Hodgkin's disease at the Mesothelioma Clinic of the Dana-Farber Cancer Institute. A fifth such patient was found after a review of the literature. RESULTS: In all five cases, the mesothelioma arose in the field of prior radiotherapy. No history of asbestos exposure was elicited by careful questioning or by review of chest radiographs. Examination of lung tissue in one patient showed 250 ferruginous bodies per gram of lung tissue, consistent with no significant prior exposure. The mean interval between radiation treatment for Hodgkin's disease and development of mesothelioma was 15 years, which emphasizes the need for continued follow-up and evaluation of these patients and supports a causal relationship. CONCLUSION: Mesothelioma may need to be added to the list of second malignancies that arise following radiation therapy for Hodgkin's disease. Further support is given to a causal link between radiation exposure and mesothelioma.

Sourche: Journal of Clinical Oncology, Vol 14, 2098-2100, Copyright © 1996 by American Society of Clinical Oncology

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Canada Blocks UN Asbestos Resolution0

Members of the Canadian delegation blocked a UN resolution that would list chrysotile asbestos as a hazardous material. The resolution, called the Rotterdam Convention, lists several grades of hazardous materials. The convention rules stated that materials labeled as “Annex III” would compel exporters of toxic chemicals to warn importers of the hazards involved with the material. The resolution would also give countries that import dangerous substances the right to refuse to allow the material into their borders if they did not have adequate safety precautions in place.

Michael Stanley-Jones, a UN spokesman for the meeting, said that Canada and several other countries, including three former Soviet states, would not vote to approve listing “white” asbestos in the hazardous materials list. Mr. Stanley-Jones also said that the listing of asbestos would be tabled until the next meeting of the trade treaty signees in two years.

Labor unions, worker safety organizations and environmental activists have been working for several years to stop Canada’s exportation of asbestos. Only two asbestos mines, both in Quebec, continue to produce the dangerous fibers. Although the mines employ only about thee hundred people in small towns near Montreal, the issue of closing the mines and enforcing stricter safety regulations has created a political firestorm in Canada’s only French-speaking province.

Some pro-asbestos concerns in Quebec paint the argument as a case of English-speakers attempting to enforce their standards on independent-minded Quebec. However, Quebec exports more asbestos than it uses. Both federal and provincial officials have worked to remove the material from schools and government buildings around the country, including the Prime Minister’s residence in Ottawa. Prime Minister Stephen Harper defended the use and exportation of asbestos when he campaigned in Quebec leading up to last May’s general election.

The people who depend on the mines for their incomes believe that chrysotile can be used safely if workers employ the proper precautions. In countries that import asbestos for their shipbuilding industries, such as India, Indonesia and Pakistan, most workers do not have access to breathing masks, special coveralls, or other protective gear. Governments in those countries also either do not have adequate safety regulations in place or do not have the resources to enforce them.

A report from the World Health Organization estimates that more than 90,000 people will die of mesothelioma and other asbestos-related disorders this year. Most industrialized nations have either banned or severely restricted the use of asbestos, which was prevalent in the mid-1900s as a source of insulation and fireproofing.

Numerous scientific studies have established that asbestos exposure can lead to a rare form of lung cancer called mesothelioma. As a worker inhales asbestos dust, microscopic fibers work their way through the lung tissue and into the pleural mesothelium, the protective layer around the lungs. The fibers alter the cells and turn them into malignant tumors. The disease can lay dormant for decades, but it is often fatal by the time doctors can diagnose the problem. Most patients rarely live more than two years after they receive their mesothelioma diagnosis.

Sources:
http://www.reuters.com/article/2011/06/24/us-un-chemicals-idUSTRE75N46J20110624
http://www.thestar.com/opinion/editorials/article/1014862–canada-s-toxic-asbestos-trade
http://www.huffingtonpost.ca/2011/06/23/canada-asbestos-chrysotile-geneva-summit_n_883630.html

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Mesothelioma Statistics0

Mesothelioma (malignant mesothelioma) is a fairly rare but often lethal form of cancer that results from asbestos exposure. Statistics show that about 2,500 people die from it in the United States every year.

As pleural mesothelioma, the most common form, the tumor forms on the mesothelial linings around the lungs. As peritoneal mesothelioma, it occurs around the abdomen. As pericardial mesothelioma, it occurs around the heart.

Exact figures for each category are uncertain, since most deaths are categorized simply as mesothelioma. According to the Centers for Disease Control’s (CDC’s) National Institute for Occupational Safety and Health, deaths for the 1999-2005 period – the most recent years for which complete data are available – rose from 2,482 deaths (in 1999) to 2,704 (in 2005).

The death rate from mesothelioma remained largely stable over that period at about 14 deaths per million per year.

A number of other factors interfere with deriving accurate statistics, notably the fact that not all mesothelioma deaths are properly diagnosed (they are instead misdiagnosed as lung cancer or cancer of unknown origin), and not all diagnoses are borne out by subsequent autopsies.

The prevalence of mesothelioma in the US is higher among males (at 1.8 deaths per 100,000 individuals) than among females, who had 0.4 deaths per 100,000. The rate was also higher among whites (1.1 percent per 1,000) than among African Americans (0.5), and significantly higher among African American males (1.03 per 100,000) than among African American females, at 0.26 per 100,000.

Mesothelioma also has an extended dormancy period, up to five decades, during which the cancer progresses with few significant symptoms. When the disease is finally observed, by either the patient or a doctor, the cancer is usually well advanced. Statistics show that the incidence of mesothelioma is more than twenty times higher in individuals over 65 than in those under.

Because mesothelioma is not readily or easily diagnosed, treatments are often delayed until the disease is late in development. Most patients are given a prognosis of about a year to 18 months to live.

Five-year survival rates are the key statistic for determining a disease’s mortality. For mesothelioma, these are 7.3 for all cases, 5.7 for males, and 11.9 for females, as taken from a 1999-2005 cohort provided by a group of SEER-designated geographical areas established by the National Cancer Institute. The SEER is a statistical cancer database.

Using 1999 as a guide, it is evident that one-year survival rates (that is, mesothelioma diagnosed at one year after acquisition) are considerably improved (at 37.4) over 5-year 8.4), 10-year (6.2), 15-year (6.0) and 20-year (5.7) survival rates.

Or, to put it in layman’s terms, of all those diagnosed with mesothelioma, about 40 percent will still be alive one year later, and 20 percent will still be alive two years later. At the end of three years, only 10 percent will still be alive, and at the end of 5 years, a meager 8 percent will still be alive.

The message is clear; early diagnosis improves survival rates up to 70 percent. Unfortunately, up to now diagnosis has been limited by tests which do not definitively select for mesothelioma. However, in the past few years, a test using protein markers found in pleural effusions (the pockets of fluid that typically form, usually around the lungs, in mesothelioma patients) promises to provide almost immediate, nearly 100-percent accurate diagnoses.

It is also interesting to note that people treated at hospitals where clinical trials are conducted – particularly clinical trials aimed at lung cancer and specifically mesothelioma – tend to do better, perhaps largely because such hospitals have developed highly effective treatment protocols for the disease in conjunction with said trials.

Statistics on prevalence and longevity are only marginally useful, however, for doctors and patients interested in a prognosis. Mesothelioma affects every person differently.

Mesothelioma rates also vary by country. Many European countries now ban asbestos, but some bans are more recent than others. In Belgium, for example, the ban dates to 1998. In the EU as a whole, the legislation bans not the marketing and use of chrysotile, but 14 categories of products that contain it. In Great Britain, the ban took effect in 1999. In Australia, the ban was instituted at the end of 2003.

Great Britain, Belgium and Australia all are reported to have mesothelioma rates of about 30 per million per year, while the U.S. and Canada show about 11 cases per million. Scandinavian countries, where cancer registries were instituted quite early in the 20th century, show rates of between 10 (Finland) and 13 (Denmark).

Future trends regarding mesothelioma are difficult to predict, partly because of upcoming changes in cause-of-death recording status under the International Statistical Classification of Diseases and Related Health Problems. Also, many countries banned asbestos use, but with caveats. Thus, since it requires only a single exposure to acquire malignant mesothelioma, some experts expect the prevalence of the disease to rise in Japan in the next few decades, in accordance with the 400,000 tons of the product consumed in 1980 (and similar usage levels that occurred until 2000).

In the United States, between 1999 and 2005, 18,068 people died of mesothelioma, 80 percent of these deaths among males. The six states with the higher mortality rates were , the average was higher than the national standard (13.8www. percent per million), with Maine (27.5 per million residents), Wyoming (22.2), W. Virginia (21), Pennsylvania at 20.8 percent, New Jersey at 20.2 percent, and Washington State at 20.1 percent.

Industries most likely to be affected, according to NIOSH, are:

    Boat building and repairing
    Industrial and miscellaneous chemicals
    Petroleum refining
    Electric light and power

Trades showing the highest incidence of mesothelioma are:

1. Plumbers, pipefitters, and steamfitters
2. Mechanical engineers
3. Electricians
4. Elementary school teachers
5. Building construction and renovation workers

The inclusion of elementary school teachers is a significant if poorly understood anomaly. And the fact that the U.S. Environmental Protection Agency limited the use of asbestos in domestic product, in 1989, to one percent, does little to allay the damage that has resulted from the importation of tons (1,730 in 2007) of asbestos that is still being used in the construction and transportation products, namely brake pads.

Fortunately, most reputable U.S. manufacturers have found alternatives to asbestos, and most American retailers refuse to import asbestos-containing products. Thus, by 2030, the asbestos legacy in America is expected to conclude with fewer and fewer mesothelioma deaths every year, until – perhaps at the turn of the next century – the disease becomes as obsolete as tuberculosis was at the turn of this century.

Terms used in statistics.

Sources of Information on this page: Centers for Disease Control, National Cancer Institute SEER program, International Ban Asbestos Secretariat, Health and Safety Department of the European Trade Union Institute, Arkansas Medical College health library

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Asbestos0

What is Asbestos?

Asbestos is the name for a group of six different fibrous minerals which occur naturally in the environment. These fibers are impervious to heat, fire, chemicals, and biological degradation; they do not dissolve in water or evaporate, and they have no detectable odor or taste. Because of these properties, asbestos has been widely used by industry in manufactured products such as building materials, friction products, and heat resistant fabrics.

Chrysotile, or white asbestos, belongs to the serpentine family of minerals, and accounts for 95 per cent of all asbestos used in the United States. The other five, amosite, crocidolite, and the fibrous varieties of tremolite, actinolite, and anthophyllite, belong to amphibole family. While all forms of asbestos are dangerous and may cause cancer, the amphiboles are considered to be the most dangerous. More on the different types of asbestos.

Chrysotile asbestos fibers are flexible and curved, while amphibole fibers are most often brittle and have a rod or needle-like shape. Asbestos fiber masses break apart easily, and become tiny airbourne particles that may easily be inhaled or swallowed and cause serious health problems many years later.

How is Asbestos Used?

Asbestos has been mined and used commercially in North America since the late 1800s, but its use increased dramatically during and after World War II. The building and construction industry uses it for strengthening cements and plastics as well as for insulation, fireproofing, and sound absorption; the shipbuilding industry has used asbestos to insulate boilers, steampipes, and hot water pipes; the automotive industry uses asbestos in vehicle brake shoes and clutch pads. Some other applications include:

1. Asbestos cement sheet and pipe products used for water supply and sewage piping, roofing and siding, casings for electrical wires, fire protection material, electrical switchboards and components, and residential and industrial building materials;
2. Friction products, such as clutch facings, brake linings for automobiles, gaskets, and industrial friction materials;
3. Products containing asbestos paper, such as table pads, and heat-protective mats, heat and electrical wire insulation, industrial filters for beverages, and underlying material for sheet flooring;
4. Asbestos textile products, such as packing components, roofing materials, and heat and fire resistant fabrics (including blankets and curtains); and
5. Other products including ceiling and floor tile; gaskets and packings; paints, coatings, and adhesives; caulking and patching tape; artificial ashes and embers for use in gas fireplaces; and plastics.
6. More on asbestos exposure in the workplace

In the late 1970s, the U.S. Consumer Product Safety Commission banned the use of asbestos in wallboard patching compounds and gas fireplaces because these products released excessive amounts of asbestos fibers into the environment. Asbestos was voluntarily withdrawn by the manufacturers of electric hair dryers. In 1989, the Environmental Protection Agency (EPA) banned all new uses of asbestos, however, uses established prior to 1989 are still allowed. Asbestos is currently used most frequently in gaskets and in roofing and friction products.

Who Is at Risk?

Since the early 1940s, millions of Americans have been exposed to asbestos in the course of their jobs in the construction trades and in military service. Although it is known that the risk to workers increases with heavier exposure and longer exposure times, asbestos-related illnesses have been found in individuals with only brief exposures. Because of the long latency period, no signs of illness may be apparent for 20 to 50 or more years.

Family members of workers heavily exposed to asbestos also face an increased risk of developing mesothelioma. This is most often the result of asbestos dust being brought into the home on the shoes, clothing, skin, and hair of workers. This type of exposure is referred to as paraoccupational or household exposure. There is also a risk of exposure from asbestos in nature.

It is important to remember that not everyone exposed to asbestos will develop diseases related to their exposure. In fact, many will experience no ill effects whatsoever. Asbestos that is bonded into finished products such as walls, tiles, and pipes poses no risk to health as long as these products are not damaged or disturbed in such a way that fibers are released into the air. It is when asbestos fibers are released and inhaled or digested that individuals are at risk for developing asbestos disease. Once these fibers work their way into body tissues, they may stay there indefinitely.

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Mesothelioma Stages0

An open line of communication between a patient and his or her physician is vital when dealing with a serious disease such as mesothelioma. There will be many questions regarding treatment, whether palliative or aggressive, choices to deal with, and life issues to confront. Being informed and proactive in your care will give you a sense of empowerment.

Although most physicians have limited time to spend with each patient at appointments, it is important to address issues as they occur and resolve them to the satisfaction of all parties involved. Initially, this may mean going to your appointment with a list of symptoms or concerns, or questions regarding specific tests that are recommended. Once mesothelioma has been diagnosed, you may have questions regarding treatment options.

Most questions from patients stem from an initial diagnosis of mesothelioma and subsequent treatment options. Following are some frequently asked questions regarding these two important issues.

What Is My Diagnosis?

There are three types of mesothelioma. Pleural mesothelioma is a cancer of the lining of the lung (pleura), peritoneal mesothelioma is a cancer of the lining of the abdominal cavity (peritoneum), and pericardial mesothelioma is a cancer of the lining surrounding the heart (pericardium). Sub-types (or cell types) of mesothelioma are epithelioid (the most common, and considered the most amenable to treatment), sarcomatous (a much more aggressive form), and biphasic or mixed (a combination of both of the other cell types).

The structural appearance of cells under the microscope determine the cell or sub-type of mesothelioma. Epithelioid is the least aggressive; sarcomatoid, the most aggressive. The biphasic or mixed cell type shows structural elements of both of the other two. More on the histologic subtypes of mesothelioma.

MESOTHELIOMA STAGES

Treatment options are often determined by the stage of mesothelioma a patient is in. There are three staging systems currently in use for pleural mesothelioma and each one measures somewhat different variables; peritoneal mesothelioma is not staged.

Staging is the term used to describe the extent of a patient’s cancer, based on the primary tumor and its spread in the body. It can help the medical team plan treatment, estimate prognosis and identify clinical trials for which the patient may be eligible.

Staging is based on a knowledge of how the cancer develops, from the primary tumor, to the invasion of nearby organs and tissues, to distant spread or metastasis. Staging systems have evolved over time, and they continue to change as scientists learn more about cancer. Some staging systems cover many different types of cancer, while others focus on more specific cancers. The TNM (primary tumor, regional lymph nodes, distant metastasis) is the most common staging system for mesothelioma.

Some elements common to most staging systems are:

    Location of the primary tumor.
    Size and number of the tumors.
    Lymph node involvement.
    Cell type and tumor grade.
    Metastasis.

Many cancer registries, such as the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) use summary staging, a system used for all types of cancer. Summary staging groups cancer into five main categories:

    In situ – cancer that is present only in the layer of cells in which it began.
    Localized – cancer that is limited to the organ in which it began with no evidence of spread.
    Regional – cancer that has spread from the primary site to nearby lymph nodes or organs.
    Distant – cancer that has spread from the primary site to distant lymph nodes or organs.
    Unknown – cases where not enough information exists to indicate stage.

Several types of testing may be used to help doctors determine stage, and to formulate a treatment plan.

    Physical examinations. The doctor examines the body by looking, feeling and listening to anything out of the ordinary.
    Imaging techniques. Procedures such as x-rays, CT scans, MRIs and PET scans may show the location, size of the tumor and whether the cancer has spread.
    Laboratory tests. Studies of blood, urine, fluid and tissue can provide information about the cancer. Tumor markers, sometime elevated when cancer is present, may provide information.
    Pathology reports. Results of the examination of tissue samples can include information about the size of the tumor(s), extension into adjacent structures, type of cells and grade of the tumor. Results of the examination of cells in fluid, such as that from a mesothelioma-related pleural effusion, may also provide information.
    Surgical reports. Observations about the size and appearance of the tumor(s), lymph nodes and nearby organs.

Staging information should be provided to the patient by his doctor so that potential treatment plans can be discussed. Stage of the mesothelioma, as well as consideration of other factors such as age, health status and the patient’s wishes may dictate different treatment options.

The oldest staging system and the one most often used is the Butchart System which is based mainly on the extent of primary tumor mass and divides mesotheliomas into four stages. The more recent TNM system considers variables of tumor in mass and spread, lymph node involvement, and metastasis. The Brigham System is the latest system and stages mesothelioma according to resectability (the ability to surgically remove) and lymph node involvement.

Butchart System – extent of primary tumor mass

    Stage I: Mesothelioma is present in the right or left pleura and may also involve the diaphragm on the same side.
    Stage II: Mesothelioma invades the chest wall or involves the esophagus, heart, or pleura on both sides. Lymph nodes in the chest may also be involved.
    Stage III: Mesothelioma has penetrated through the diaphragm into the lining of the abdominal cavity or peritoneum. Lymph nodes beyond those in the chest may also be involved.
    Stage IV: There is evidence of metastasis or spread through the bloodstream to other organs.

TNM System — variables of T (tumor), N (lymph nodes), M (metastasis)

    Stage I: Mesothelioma involves right or left pleura and may also have spread to the lung, pericardium, or diaphragm on the same side. Lymph nodes are not involved.
    Stage II: Mesothelioma has spread from the pleura on one side to nearby lymph nodes next to the lung on the same side. It may also have spread into the lung, pericardium, or diaphragm on the same side.
    Stage III: Mesothelioma is now in the chest wall, muscle, ribs, heart, esophagus, or other organs in the chest on the same side with or without spread to lymph nodes on the same side as the primary tumor.
    Stage IV: Mesothelioma has spread into the lymph nodes in the chest on the side opposite the primary tumor, or extends to the pleura or lung on the opposite side, or directly extends into organs in the abdominal cavity or neck. Any distant metastases is included in this stage.

Brigham System: (variables of tumor resectability and nodal status)

    Stage I: Resectable mesothelioma and no lymph node involvement
    Stage II: Resectable mesothelioma but with lymph node involvement
    Stage III: Unresectable mesothelioma extending into chest wall, heart, or through diaphragm, peritoneum; with or without extrathoracic lymph node involvement
    Stage IV: Distant metastatic disease

How Was This Diagnosis Determined, and How Accurate Were the Tests?

Although you probably took many different tests leading up to your diagnosis, a tissue biopsy is normally the final determining factor. Following are some tests your doctor may recommend, and what may or may not be concluded from these tests.

    X-rays, CT scans, and MRIs – On conventional x-ray film, mesothelioma appears as a markedly thickened, nodular, irregular pleural-based mass which covers the pleural surface. The tumor often encompasses the involved lung, but is only rarely seen bilaterally. Chest wall, diaphragmatic, and mediastinal invasion may be seen in advanced cases. Moderate to large pleural effusion is often noted on the affected side. On CT scan, pleural thickening greater than 1 cm can be identified in over 90% of cases; thickening which extends into the interlobular fissure is seen in 85% of cases. Absence of pleural thickening does not preclude mesothelioma, and at times, the only CT finding is that of pleural effusion.
    Cytology – Testing of the pleural fluid for malignant cells is considered to have limited value in diagnosing mesothelioma. Negative or inconclusive readings account for nearly 85% of all fluid tested. Even with a positive fluid report, many doctors prefer to perform a confirming tissue biopsy as long as it does not compromise the patient’s health.
    Needle Biopsy – In this test, done under local anesthetic, a large hollow needle is inserted through the skin and into the chest cavity. The needle is then rotated, and as it is taken out, tissue samples are collected. Because of the small sample size of the tissue, this type of biopsy is considered to be only 25-60% accurate in diagnosing mesothelioma. Because tumor seeding may occur along the needle tract in approximately 20% of patients, local radiation therapy may be used in conjunction with this test.
    Open biopsy – This type of biopsy is considered to be the most accurate for mesothelioma diagnosis, and is the procedure of choice because it affords the pathologist a larger tissue sample.. It is done in a hospital under general anesthetic. As with a needle biopsy, local radiation may be used because of the possibility of tumor seeding.

Can I Be Treated by the Doctor Who Diagnosed My Mesothelioma?

If the doctor who diagnosed your mesothelioma is your primary physician, he will most likely refer you to a local oncologist for treatment. The oncologist may offer what he or she feels are the best treatment options, or, if their knowledge of this disease is limited, may suggest you seek out a doctor who specializes in mesothelioma. Most often these physicians are located at larger, teaching hospitals such as those listed in the Comprehensive Cancer Center Section. These facilities are ranked as state-of-the-art cancer centers, and are highly respected for their patient care and innovative cancer treatments. If your choice of treatment involves a radical surgical procedure or a clinical trial involving new, as yet unproven drugs, these facilities may be best for you. If your treatment involves an already-approved, standard form of chemotherapy, this can be carried out locally.

What Treatment Options Will I Be Offered?

Treatment options may vary according to the age and over-all health of the patient, and the extent of the disease. It is important to be informed of all available options for your particular case, so that you can make decision on the option you feel most comfortable with. Surgery, chemotherapy, and clinical trials, as well as new approaches such as photodynamic therapy, immunotherapy, and gene therapy may be offered. Speak openly with your doctor regarding suggested procedures. Questions may include:

    Why is this procedure best for me?
    What does the procedure entail?
    What are the advantages/disadvantages of this treatment (i.e, will this procedure limit my eligibility for other treatments)?
    What are the possible risks or adverse side effects?
    What are the response, survival, and mortality rates associated with this procedure?

Is Palliative Treatment an Option?

In some circumstances, age, contributing health problems, or advanced disease may make aggressive treatment impossible. In these cases, palliative care (that which treats the symptoms, but not the disease itself) may be appropriate. If you opt for palliative care, it is doubly important to communicate fully with your doctor. Many symptoms of mesothelioma can be alleviated or substantially lessened if you are completely open with your doctor. Each time you have an appointment, tell your doctor how you feel, what discomfort you are experiencing, and your level of pain. A good doctor should be willing to address your questions and concerns.

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Peritoneal Mesothelioma0

Peritoneal mesothelioma, a cancer of the lining of the abdominal cavity, is less common than the pleural form, comprising approximately one-fifth to one-third of the total number of mesothelioma cases diagnosed. According to the SEER (Surveillance, Epidemiology, and End Results) database, these diagnoses are approximately 54.7 per cent male versus 45.3 per cent female, with the median age being 65-69. The latency period appears to be shorter for asbestos-exposed individuals with symptoms appearing 20-30 years after exposure rather than the 30-40 year latency more commonly associated with pleural mesothelioma.

Symptoms

Clinical symptoms at the time of presentation may include abdominal pain, abdominal mass, increased abdominal girth, distention of the abdomen, ascites (fluid in the abdomen), fever, weight loss, fatigue, anemia and digestive disturbances. Some patients complain of more non-specific symptoms for a number of months prior to a confirmed diagnosis. In a percentage of cases, peritoneal mesothelioma is found incidentally when the patient has sought help for another health problem such as gallbladder, hernia or pelvic mass.

Experienced doctors report that patients typically experience symptoms 6 months to 2 years before diagnosis. When the patient goes to the doctor, the patient, the family, and the doctor all usually think something else is wrong. Men often first show up with an inguinal hernia (a bulge in the groin) or an umbilical hernia (bulge around the belly button.) The first indication of a problem for some women comes during a pelvic examination when a tumor mass is discovered.

Late-stage peritoneal mesothelioma symptoms include bowel obstruction and increased tendency of the blood to clot. Blood tests show increased platelet count in half of peritoneal patients, although this is of little use in diagnosis because it can be caused by so many disorders. Anemia and low albumin levels are also found.

Diagnosis

As with all mesotheliomas, the diagnosis of peritoneal mesothelioma can be challenging. CT findings may help differentiate between the two clinical types of peritoneal mesothelioma, termed “dry” or “wet”, since their appearances are very different upon imaging. In the “dry” type, CT may reveal multiple small masses or a single dominant localized mass. There is normally little or no ascites. In the “wet” type, CT may reveal widespread small nodules, but no dominant mass. Ascites is usually present.

If fluid is present, it may be removed in a procedure called paracentesis. Unfortunately, as is the case with pleural mesothelioma, fluid analysis offers limited diagnostic value. It is normally a tissue biopsy obtained in a laproscopic exploratory that will yield a definitive diagnosis.

Staging

There is currently no established staging system for peritoneal mesothelioma, and if the disease is staged, it is normally done in accordance with the TNM system, the most common general cancer staging system. This system refers to the status of the tumor (T), lymph nodes (N) and metastases (M). There are general categories which may also be somewhat helpful in determining stage.

The first category shows a localized lesion able to be completely resected (entirely removed). In the second category, the disease is contained within the abdominal cavity on peritoneal and organ surfaces where debulking (the removal of as much, but not all of the tumor) is possible. Category three shows disease contained within the abdominal cavity with invasion of organs such as the colon or liver. Category four shows disease extending outside the abdominal cavity.

Mesothelioma specialist Clare Verschraegen wrote that she categorizes peritoneal mesothelioma into four categories. The least developed is when the tumor has not spread and can be removed with surgery. This is equivalent to stage I in the Butchart classification.

The next is when the cancer has spread to the periconal and organ surfaces and surgery will result only in a debulking of the tumor, not removal of all malignant tissue. The next stages are when the cancer metasticises to other organs, and when it gets into the lymph nodes.

Treatment
In recent years, multimodality treatment of peritoneal mesothelioma has become more common for a select patient population, since surgery alone and/or intraperitoneal chemotherapy alone have proven to be similarly ineffective. Cytoreductive (debulking) surgery involves the removal of all or nearly all visible tumor, and, depending on the physician’s choice, may be combined with Intra-Peritoneal Hyperthermic Chemotherapy (IPHC), intraperitoneal chemotherapy and/or radiation. Dr. Paul Sugarbaker has written “intraperitoneal chemotherapy gives high response rates within the abdomen because the peritoneal space to plasma barrier provides dose intensive therapy.” Since it is not always possible to remove all tumors, the prognosis for long-term survival may be based on the completeness of cytoreduction as established by the following criteria:

Complete cytoreduction:

CC-0 No peritoneal seeding is visualized within the operative fields.

CC-1 Nodules of less than 2.5 cm persist after cytoreduction. Nodules of this size are thought to be penetrable by intracavitary chemotherapy, therefore cytoreduction is termed complete.

Incomplete cytoreduction:

CC-2 Nodules of between 2.5 and 5 cm persist after cytoreduction.

CC-3 Nodules of greater than 5 cm or a merging of unresectable tumor nodules at any site within the abdomen or pelvis.

For patients found to have widespread disease, where surgery is not looked at as “potentially curative”, palliation of symptoms may be accomplished by debulking. Since peritoneal mesothelioma is a rare malignancy, specialized treatments should be conducted by doctors familiar with the disease.

More on systemic therapy for peritoneal mesothelioma.

A recent clinical trial found pemetrexed (Alimta) to be an effective chemotherapy agent in treatment of peritoneal mesothelioma, either along or with a platinum-based drug such as cisplatin. This success mirrors previous findings about pemetrexed for treatment of pleural mesothelioma.

Sources for information on this page:

Surgial Oncology Associates – Management of Peritoneal Surface Malignancy Using Intraperitoneal Chemotherapy and Cytoreductive Surgery: A Manual for Physicians and Nurses
Cancer Research UK – Peritoneal mesothelioma treatment
NCI: Malignant Mesothelioma Treatment
The Annals of Thoracic Surgery, Staging in Malignant Mesothelioma, Published March 2006.

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Pericardial Mesothelioma0

Pericardial Mesothelioma

Pericardial mesothelioma is a very rare cancerous disease of the tissue layers surrounding the heart. The mesothelium membrane is comprised of two layers, one that adheres to a moving internal organ such as the heart or lungs, and the other which forms a sac around the organ. The tissues secrete a lubricant that allows the active organ to move easily against adjacent structures, such as the rib cage and diaphragm. The peritoneum is the mesothelial layer that lines the abdominal cavity, the pleura lines the chest cavity, and the pericardium surrounds the heart. Abnormal growth (cancer) in the cells of any of these mesothelial structures is referred to as mesothelioma.

The primary cause of mesothelioma is exposure to asbestos in the workplace, even for brief periods, with symptoms sometimes taking up to 50 years after exposure to become apparent. Among the populations most effected by mesothelioma are miners who were employed in South Africa and Australia (including a large number of Italian immigrants), who often worked in dusty conditions without protective equipment. Among Americans and Europeans, most cases have arisen among those who worked with asbestos in the construction trades and shipbuilding, where asbestos was used extensively for its insulating properties and as a fire retardant. At this point, however, there is insufficient evidence to link pericardial mesothelioma to asbestos exposure. Similarly, smoking does not appear to be a risk factor for mesothelioma.

Pleural mesothelioma often spreads to the pericardium in its advanced stages. Primary pericardial mesothelioma (where the tumor starts in the pericardium) is rare, making up less than 1% of total mesothelioma cases. Histological types include epithelial, sarcomatous, and mixed.

In the history of medicine pericardial mesothelioma has also been called endothelioma, coelothelioma, and endothelial carcinoma. There are other types of pericardial tumors, but about half are mesothelioma. The others are usually sarcoma (angiosarcoma) and can be difficult to distinguish from sarcomatoid pericardical mesothelioma.

The disease occurs across all age groups, almost equally in both sexes. With the elimination of asbestos in many building products and an overall improvement in working conditions and health monitoring, it is likely that the overall incidence of mesothelioma will decline in the next decade or so. In the absence of the identification of a principle causative agent, it is less clear whether the incidence rate of primary pericardial mesothelioma will change.

Results from an extensive study of autopsy records from 500,000 people who had died from cancer showed that primary tumors of the pericardium were responsible in only 0.0022% of the cases. With respect to all pericardial and cardiac primary tumors, only 2 or 3 percent are associated with mesothelioma, well behind the numbers for angiosarcoma (33%) and rabdomyosarcoma (20%).

Symptoms

The symptoms are dyspnea and pain pleural effusion, inflammation of the pericardium (called pericarditis). A dangerous symptom is cardiac tamponade in which blood accumulates in the pericardium and can lower the heart’s pumping stroke volume. These symptoms are common to other forms of mesothelioma and to a number of other conditions affecting the heart and lungs, such as pneumonia and lung cancer. In many cases, symptoms are not apparent until the disease has progressed to advanced stages, leaving few options for effective treatment.

Diagnosis

While doctors can examine fluid from the pericardial cavity (similar to the examination of pleural effusion fluid in diagnosis of pleural mesothelioma), malignant cells are found only 30% of the time, which is another reason this cancer is so hard to diagnose. CT scans can sometimes reveal thickening of the pericardium and a tumor mass is visible, although less than half of the time. Diagnosis of pericardial mesothelioma often takes place when the disease is quite advanced, at a point when the tumor and associated swelling are constricting other thoracic structures such as veins, arteries and airways. Pericardial swelling can also be associated with tuberculosis, rheumatoid arthritis, and other conditions. There was even a recent Japanese report about a patient who appeared to have pericardial constriction, which later turned out to be mesothelioma. A British case report about a young man with pericardial mesothelioma that confounded doctors “illustrates the difficulty in establishing this diagnosis by echocardiography and computed tomography.”

Pericardial mesothelioma often can appear to be rheumatic fever, lupus erythematocous, and tuberculosis pericarditis.

Radiography and other imaging techniques (e.g., echocardiography and magnetic resonance angiography) can be used to demonstrate swelling of the pericardium. In some cases, the myocardium and coronary arteries might also be involved. Isotope scans with gallium or technetium as well as cardiac catheterization can be used to measure decreased function in the heart and blood vessels. Post-contrast computerized tomography can be used to differentiate the tumor mass from the rest of the swollen tissue surrounding the heart. However, even with the identification of a tumor, the use of imaging techniques alone will not result in a definitive diagnosis because melanoma, leukemia and lymphoma can also involve the pericardium. Precise diagnosis requires demonstrating that the tumor has no relationship with the pleural surfaces.

Standard laboratory tests of blood, urine, and sputum are of little help in detecting mesothelioma. Liquid extracted from the swollen area can provide adequate cytological evidence for accurate diagnosis, but in some cases this method has resulted in a misdiagnosis, indicating other cancers (e.g., adenocarcinoma).

A biopsy carried out on a tissue sample obtained by thoracoscopy or sternoscopy is the only way to substantiate a positive identification of mesothelioma. In terms of specific laboratory indicators for the presence of mesothelioma, the cancer cells stain positive for cytokeratin, vimentin, epithelial membrane antigen, and calretinin and negative for CEA, CD15, CD34 and S-100. In 60 to 80 percent of cases, accurate diagnosis based on histological analysis of tissue samples is only accomplished after the death of the patient.

Treatment

The choice of treatment regimen is dependent on how far the cancer has progressed at the time a positive diagnosis is made, and is also be based on the age, weight, medical history, and general well-being of the patient.

With early detection, when the tumor mass is small and localized, radical surgery for removal of cancerous tissue is possible but risky, given the proximity to the heart and lungs. If the cancer has spread to the lymph nodes, lungs, chest wall, or other organs (as it does in 25 to 45 percent of cases), surgical removal is no longer an option.

A course of palliative surgery for draining fluid from the pericardium, as a means of relieving pressure on proximal structures, can be used to alleviate symptoms and as a way to obtain a tissue sample for biopsy. This procedure can be used to help prolong life while other treatment modalities are administered.

Radiation therapy can be used to kill the cancer cells and shrink tumors, but this approach carries with it the risk of damaging the heart and lungs. As well as the more familiar practice of external exposure to radioactive materials, treatment might involve delivering radioactive materials directly to the cancer site through plastic tubing (internal therapy).

No chemotherapeutic agents have been shown to be effective in the treatment of pericardial mesothelioma. There was a recent case report from India about success in one patient using a combination of pemetrexed and cisplatin, the same regimen used in treatment of pleural mesothelioma.

Prognosis

Although there are few cases of primary pericardial mesothelioma, it appears that the prognosis for this cancer is worse than it is for pleural or peritoneal mesothelioma. As a direct consequence of the difficulties in definitively diagnosing pericardial mesothelioma and the fact that it usually only minimally symptomatic until its advanced stages, the prognosis for patients is very poor, with a mean survival time of only six months following diagnosis. Death often occurs as the result of congestive heart failure or occlusion of the superior vena cava. This situation is unlikely to change without significant advances in early detection techniques and treatment regimens.

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Mesothelioma Cell Types0

The three cell or subtypes of mesothelioma, epithelial, bi-phasic (mixed) and sarcomatoid, are different not only in their aggressiveness and response to treatment but in their appearance under the microscope as well.

Although immunohistochemical staining has improved over the years and it now plays an important role in the diagnosis of mesothelioma, for many scientists, electron microscopy is considered the standard by which mesothelioma is differentiated from other forms of cancer. This is particularly true in the differential diagnosis of epithelial mesothelioma versus adenocarcinoma.

Mesothelioma Cell Types

The epithelial cell type is the most common, comprising 50% to 70% of all malignant mesotheliomas diagnosed. Because it is the least aggressive of the cell types, it generally responds the best to treatment, and offers the best prognosis. Under the microscope, this cell type appears relatively uniform, and is described as having a tubular papillary structure. Each individual cell is cube-shaped and has an easily identifiable nucleus.

By contrast, sarcomatoid mesothelioma represents 7% to 20% of cases diagnosed, and is the most aggressive subtype. It generally does not respond well to treatment, therefore, prognosis with this cell type is considered poor. The differential diagnosis of sarcomatoid mesothelioma versus other types of sarcoma is more challenging than in the epithelial variant, and chemical staining can be confusing. Microscopic analysis normally shows a spindle cell or storiform structure with enlongated nucleii not as apparent as in the epithelial type.

The bi-phasic or mixed cell type, as the name implies, is a combination of elements of both the epithelial and sarcomatoid subtypes, with components of each in the same tumor, or found in specific groupings throughout the tumor. Prognosis for biphasic mesothelioma is normally intermediate between the two types. This cell type makes up 20% to 35% of mesotheliomas.

Types of Malignant Mesothelioma

Rare histological variants of malignant mesothelioma include:

•   Small cell mesothelioma.
•   Lymphohistiocytoid mesothelioma.
•   Deciduoid mesothelioma.
•   Desmoplastic mesothelioma.

It is important not to confuse malignant mesothelioma with benign tumors that also begin in the mesothelium. Benign or low grade mesotheliomas almost always involve the peritoneal cavity, but are rare in the pleura. This group includes:

• Well-differentiated papillary mesothelioma.
• Benign multicystic mesothelioma.
• Adenomatoid tumor.

When discussing treatment options, cell type should be considered. Information regarding cell type is normally found in the ‘Final Diagnosis’ section of the pathology report.

Using Survival Statistics make a Prognosis and Determine Treatment Options.

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Malignant Mesothelioma0

Malignant mesothelioma is broadly categorized into three histologic subtypes – epithelioid, sarcomatoid, and biphasic (mixed). Although a number of unusual and rare variants have also been detected, the above classification has general diagnostic usefulness because the differential diagnosis of both benign and malignant lesions, and also the subsequent immunohistochemical analysis, is performed using this subclassification.

The most common is the epithelioid variant, which comprises around 60% of all mesotheliomas. The most common histologic appearances associated with this subtype include acinar (glandular), adenomatoid, tubulopapillary, and solid epithelioid patterns. The differential diagnosis also includes metastatic carcinomas and other epithelioid tumors in addition to reactive mesothelial hyperplasia.

Sarcomatoid mesotheliomas comprise of malignant spindle cells that may mimic malignant mesenchymal tumors, for instance, leiomyosarcoma or synovial sarcoma. Desmoplastic mesothelioma, comprising of bland tumor cells lying between dense bands of collagenous stroma, has been classified as a subtype of sarcomatoid mesothelioma. The differential diagnosis also includes sarcomatoid carcinoma and other sarcomas in addition to fibrous pleurisy.

Epithelioid and sarcomatoid characteristics have been observed in both biphasic and mixed mesotheliomas. However, larger samples and multiple tissue sections may be required to demonstrate both the characteristics. The differential diagnosis typically includes synovial sarcoma, and other biphasic or mixed tumors as well.

In case of malignant mesotheliomas that are poorly differentiated and discohesive, it becomes necessary to include non-neoplastic inflammatory disorders and lymphomas within the differential diagnosis.

Well-differentiated papillary mesothelioma is a rare tumor with a unique papillary architecture and bland characteristics which tend to spread superficially without invasion. This specific form of tumor is diagnosed more commonly in the peritoneum.

Based on research, histologic criteria have been defined to differentiate between reactive mesothelial hyperplasia and epithelioid malignant mesothelioma, and also between fibrous pleurisy and the desmoplastic variant of sarcomatoid mesothelioma:

Factors that can lead to reactive mesothelial hyperplasia include connective tissue disease, infections, drug reactions, pulmonary infarct, subpleural lung carcinomas, pneumothorax, traumatic injury, or surgery.

Factors that can induce fibrous pleurisy include infection, exposure to asbestos, traumatic injury, or connective tissue disease.

The detection of stromal invasion is the most reliable criterion for differentiating fibrous pleurisy and reactive mesothelial hyperplasia from malignancy. While detection of stromal invasion can be demonstrated through positive cytokeratin staining, the best way to achieve a definitive diagnosis would involve sufficient biopsies that would include some underlying fibroadipose tissue, or, in specific situations, the pulmonary parenchyma.

Immunohistochemistry
The utilization of immunohistochemical panels plays a vital role in the diagnosis of malignant mesothelioma.
Currently, there is no standalone marker that has adequately high sensitivity and specificity for malignant mesothelioma. As such, it is general practice for pathologists to use a panel of markers (both positive and negative). Different institutions have different opinions when it comes to selecting the markers and panels are usually refined as various studies are published comparing the effectiveness of different markers. The general rule is that the marker should have either sensitivity or specificity more than 80% for the specific tumors being targeted. The utility of individual markers is further categorized into panels, which is more useful when the tumor is suspected to be epithelioid, sarcomatoid, or poorly differentiated.

Pancytokeratin stains have been used successfully in the diagnosis of mesothelioma and these can stain a significant percentage of all mesotheliomas. In case the tumor is pancytokeratin negative, the screening panel should be expanded to include more stains that would help exclude melanoma, lymphoma, angiosarcoma or epithelioid hemangioendothelioma. Some rare sarcomatoid mesotheliomas have been identified, and these are cytokeratin negative, especially those with osteosarcomatous differentiation.

In case of epithelioid mesothelioma, common positive immunohistochemical markers which can be utilized to support a malignant mesothelioma diagnosis include the Wilms’ tumor-I (WT1) antigen (nuclear staining), CK5/6, D2-40 (podoplanin) and calretinin. Effective markers that are positive in case of pulmonary adenocarcinoma include carcinoembryonic antigen, CD15 (Leu-M1), B72.3, Ber-EP4, TTF-1, BG8, and MOC-31. If the differential diagnosis is expanded to include other subtypes of lung tumors, for instance squamous cell carcinoma or metastases from other major sites such as ovary or kidney, then the panel should focus more on those specific requirements. Also, the usefulness of a negative or positive result should be carefully examined.

In case of sarcomatoid or biphasic mesothelioma, cytokeratin reactivity may not necessarily distinguish malignant mesothelioma from other sarcomas, especially if the cytokeratin staining is focal. Since cytokeratin expression can be weak, focal or variable, multiple cytokeratin antibodies, for instance CAM5.2 (or CK 18), AE1/3, and CK7 must be used. Considerable cytokeratin positivity can also been observed in metastatic sarcomatoid renal cell carcinoma or sarcomatoid carcinoma. Calretinin and D2-40 are the most reliable of the positive mesothelioma markers. Although calretinin and D2-40 demonstrate overlap reactivity with other forms of sarcoma, obtaining a positive result may help in confirming a sarcomatoid mesothelioma diagnosis when combined with significant cytokeratin positivity. The potential presence of synovial sarcoma can typically be established via molecular testing for the specific X:18 translocation.

Electron microscopy
With the increase in the number of antibodies appropriate for immunohistochemistry on standard formalin-fixed paraffin embedded tissue as well as the inclusion of additional positive mesothelioma markers, immunohistochemistry has practically replaced electron microscopy in its conventional use as the “gold standard” in the diagnosis of malignant mesothelioma.

If immunohistochemical results are equivocal, electron microscopy is still useful in specific situations for confirming the diagnosis of well-differentiated to moderately-differentiated epithelioid tumors. The electron microscopic characteristics of malignant mesothelioma have been clearly illustrated. The primary epithelioid form comprises of polygonal cells that have several long surface microvilli, abundant tonofilaments, and prominent desmosomes.

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Erionite in North Dakota roads may increase risk of mesothelioma0

As school buses drive down the gravel roads in Dunn County, North Dakota, they stir up more than dirt. The clouds of dust left in their wake contain such high levels of the mineral erionite that those who breathe in the air every day are at an increased risk of developing mesothelioma, a type of cancer of the membranes around the lungs, new research shows. Erionite is a natural mineral fiber that shares similar physical similarities with asbestos. When it's disturbed by human activity, fibers can become airborne and lodge themselves in people's lungs. Over time, the embedded fibers can make cells of the lung grow abnormally, leading to mesothelioma, a form of lung cancer most often associated with the related mineral asbestos.

Michele Carbone, M.D., Ph.D., director of the University of Hawaii Cancer Center in Honolulu, has previously linked erionite exposure in some Turkish villages to unusually high rates of mesothelioma. Recently, he and colleagues turned their attention to potential erionite exposure in the U.S., where at least 12 states have erionite-containing rock deposits. His research team-which includes scientists from the National Institute of Environmental Health Sciences, Environmental Protection Agency, New York University, University of Chicago, University of Iowa, and University of Hacettepe-focused their efforts on Dunn County, North Dakota, when they learned that rocks containing erionite have been used to produce gravel for the past 30 years. More than 300 miles of roads are now paved with the gravel. The new study, reported in the July 25, 2011 issue of Proceedings of the National Academy of Sciences (PNAS) is the first to look at the potential hazards associated with erionite exposure in the U.S.

The scientists compared the erionite in North Dakota to erionite from the Turkish villages with high mesothelioma rates. They measured airborne concentrations of the mineral in various settings, studied its chemical composition, and analyzed its biological activity. When mice were injected with the erionite from Dunn County, their lungs showed signs of inflammation and abnormal cell growth, precursors to mesothelioma. Under the microscope, the fiber size of the erionite from North Dakota was similar to that of the Turkish erionite. Overall, the researchers found no chemical differences between the North Dakota erionite and samples of the cancer-causing mineral from Turkey. The airborne levels of erionite in North Dakota were comparable to levels found in Turkish villages with 6-8 percent mortality rates from mesothelioma, the researchers reported.

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Two-Stage Nanoparticle Improves Chemotherapy Delivery0

A clinical study at the Massachusetts Institute of Technology showed that the use of a two-stage nanoparticle drug delivery system was 40 times more effective than a system using a single nanoparticle. The “Stage One” nanoparticle seeks out the tumor cells, and then signals the “Stage Two” portion to deliver the chemotherapy drugs. Researchers tested the delivery system on mice with cancer and found that the two-stage system was more effective in shrinking the tumors than the single-stage method.

Dr. Sangeeta Bhatia, the lead author of the study, and her research team found that the dual-stage method increased the amount of the drug delivered to tumor cells 40 times over the standard procedure. The method also insures that only the tumor cells receive the potentially lethal chemotherapy drugs, without harming the healthy cells surrounding the malignant tumor. When the first-stage particle locates a tumor cell, it sends a signal to the drug-carrying particle for it to deploy its medicine.

“We use the body’s natural amplification processes to get more drug to the target,” Dr. Bhatia said.  She also mentioned that she saw the body’s blood clotting system as inspiration for the dual-stage method.  When an open wound occurs, the body signals the blood clotting system to close off the blood flow. The system involves an enzyme known as Factor XIII, which crosslinks with a protein called fibrin, which starts the clotting process.

Dr. Bhatia and her team coated their drug-delivery nanoparticle in a version of Factor XIII.  When the “scout” particle located a tumor cell, it attacked the tissue and made it bleed. The Factor XIII acted as an attractant to the blood in the tumor cells, thus drawing the drug-delivery particle. The particle then released its payload, with the fibrin clotting the tumor cell and forming a wall to keep the medicine within the tumor site.

This application of nanoparticle technology cold not only lead to more efficient treatments, but also to better tools for early detection. Dr. Francesca Greco, a nanotechnology specialist as the University of Reading in England, said that the dual-stage method, especially the first-stage approach of locating tumor cells, could lead to improvements in early cancer detection. She called the approach “interesting and versatile, with potential applications in tumor diagnostics”.

Despite the early appearances of success behind the dual-stage nanoparticle treatment method, some scientists are still wary of this new development.  One argument against it is the level of complexity involved in the delivery system.  Dr. Omid Farokhzad of the Brigham and Women’s Hospital in Boston, said that the system “is on the right path”, but that the translation of this method from experiments in mice to clinical trials in humans will take “a lot of work”.

Another issue with this method is how it uses the blood-clotting system to signal the delivery of the chemotherapy drugs.  Dr. Anil Sood, an oncology specialist at the MD Anderson Cancer Center in Houston, said that the system should make sure it only triggers blood clots near the tumors and not in more sensitive areas, such as the heart, lungs or brain.  “If you’re going to trigger coagulation, you want to be very selective, so that you don’t cause damage in other parts of the body.”

Sources:

http://www.nature.com/news/2011/110619/full/news.2011.374.html
http://www.rsc.org/chemistryworld/News/2011/June/20061101.asp
http://www.genengnews.com/gen-news-highlights/scientists-develop-communicating-nanoparticles-that-boost-targeted-drug-delivery-to-tumors/81245326/

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New potential anti-tumor agents might effectively treat mesothelioma0

Researchers from the lab of Antonio Giordano, M.D., Ph.D., the Founder and Director of the Sbarro Institute for Cancer Research and Molecular Medicine, have identified new potential anti-tumor agents that might be effective in treating mesothelioma, one of the deadliest cancer tumors.

Scientists tested new pyrazolo [3,4-d ]pyrimidine derivative inhibitors of the SRC kinase, a well-established molecular target in cancer therapy. They found that these SRC inhibitors effectively induced cell death, through apoptosis, in mesothelioma cell lines without affecting the normal mesothelial cells, thus supporting a possible use of these agents as a safe treatment for mesothelioma. Their findings appear in the journal Oncogene.

Interestingly, the researchers also found that the SRC inhibitors induced cell death was accompanied by an increase in the nuclear stability of the cyclin-dependent kinase inhibitor p27. This is "particularly intriguing considering that the loss of nuclear p27 expression is a well established adverse prognostic factor in mesothelioma and p27 nuclear localization is crucial for its tumor suppressive function." said the leading author of the study, Paola Indovina, Ph.D. of the University of Siena and assistant Professor at the Sbarro Institute.

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Prognosis of Mesothelioma0

Prognosticating mesothelioma remains difficult, with rapid rates of mortality. The median survival of patients diagnosed with malignant mesothelioma from time of first diagnosis is one year; in male patients or those with elevated white-cell counts, thrombocytosis or anemia, the prognosis is far worse. The presence of certain biochemical markers, as well increased vascularity or the presence of the SV40 virus in the tumor, are other indicators that the prognosis would be more serious.

A variety of factors affect a patient’s prognosis. The most important iinclude the site where the cancer has developed, the stage or extent of cancer (has the cancer metastasized to elsewhere in the body, and the histology of the cancer (epithelial, sarcomatoid, or bi-phasic). Other factors such as the patient’s general health, age and response to treatment can also affect prognosis.

Studies indicate the epithelial cell type have been associated more often with a favorable prognosis. The fibrosarcomatus type carries the worst prognosis, while the mixed (a combination of both kinds) comes in between them. The younger the age of the person diagnosed, the better the prognosis. There has not been, to this point, a study showing a difference between the survival rates for men and women diagnosed with malignant mesothelioma.

There were several other indicators that leaned toward a more favorable prognosis. An absence of weight loss and a lack of involvement of the visceral pleura were found in clinical studies to indicate the cancer was not as extensive.

To this point, no biomarker has been developed to serve as a consistent predictive or prognostic method to indicate the presence of malignant mesothelioma. However, a four-gene grouping has been identified which correctly classified a training sample into good and poor prognostic groups. The gene signature was subsequently tested on 29 sample and it correctly predicted the correct outcome in a notable number of cases.

A second study found that the signature was indeed accurate. This supports the identification of disease-specific and treatment-specific molecular marker candidates. A third study used two different kinds of microarray analysis to identify a common subset of 27 genes that could be used to predict both the progression and survivability of malignant mesothelioma. Significant questions remain, however, as to whether this new find can be clinically applicable.

Does it help to be aware of the prognosis?

Mesothelioma patients, along with their loved ones, have to face up to many unknown situations. Understanding the disease and its expected course can help both patients and their loved ones in planning treatment, making lifestyle changes, and make critical decisions related to their finances and quality of life. Many individuals diagnosed with cancer generally want doctors to tell them their prognosis. These individuals find it easier to deal with their specific situation when they are aware of the statistics. Patients can ask their doctors for statistics such as survival rates or they can search for these on their own. On the other hand, some people consider statistical information as frightening and confusing, and they feel that such data is too impersonal to be of any significant use to them.

The doctor who may be most familiar with the specific situation of a patient is the right person to discuss the prognosis and also to describe what exactly the statistics imply. Again, it is important to be aware of the fact that even the doctor may not be able to tell what exactly to expect. In reality, an individual’s prognosis may change in case the cancer progresses or if the disease responds to treatment. More on mesothelioma survival rates.

It is a personal decision to seek information about the prognosis. It is for the patient to decide what details he/she would want to know and how to deal with that information. More on understanding survival statistics and using them to make a prognosis.

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Chemotherapy Drug Shortage Puts Patients At Risk0

A report from the American Society of Health-System Pharmacists (ASHSP) shows a growing number of vital chemotherapy drugs are in short supply. Paclitaxel (brand name: Taxol), a drug used extensively in patients with colon, lung, breast and ovarian cancers, has been added to a list of 196 other major drugs considered to be in short supply. The drugs on the shortage list include anesthetics, antibiotics, pain medications and chemotherapy drugs for leukemia.

Cynthia Reilly, director of the ASHSP’s practice development division, called the shortages a “public health crisis”. “There are cancer patients who will die because of this (shortage),” Reilly said. “This could change their survival.” The shortage also extends to many generic drugs, which offer a cost-effective alternative for patients over the brand-name prescriptions. Some chemotherapy drugs, such as cytarabine and daunorubicin for leukemia, are also in short supply and do not have effective substitutes.

The shortage has forced some hospitals and cancer centers to select which patients have greater need for their life-saving medication. Dr. Michael Link, a pediatric oncologist at Stanford University’s Lucile Packard Children’s Hospital, said that the shortage in leukemia medication has put him and his staff at risk of making some difficult choices. “We’re hoping to get more so we don’t face that awful crisis. Other practices have.”

The lack of available medications has become a nationwide problem, but the shortages have disproportionately affected smaller facilities. According to Dr. Link, several patients have had to drive to other states to get the medication they need. He noted that larger facilities and hospitals that have access to multiple suppliers tend to have less of an issue with shortages, but smaller treatment centers and oncology practices “tend to operate more on an order-as-needed basis.”

Even the bigger hospitals are not immune to these shortages. The MD Anderson Cancer Center in Houston, Texas, one of the largest cancer treatment facilities in the country, reported that their stockpiles of at least four different chemotherapy drugs are at severely depleted levels, with another twenty also in short supply. The Cancer Therapy and Research Center at the University of Texas Health Sciences Center in nearby San Antonio reported “rationing the use of” paclitaxel.

Some hospitals are taking emergency measures to insure that they have an adequate supply of paclitaxel on hand. The Beaumont Hospital in suburban Detroit is currently paying more than three times its normal rate for paclitaxel. At the Ochsner Clinic Foundation and Hospital in New Orleans, doctors work together to move available drugs from one physician’s patient to another’s in greater need. Dr. Jay Brooks, Ochsner’s chairman of oncology, said that he had never seen shortages this severe in his 25-year career in cancer treatment.

A spokesperson with the US Food and Drug Administration (FDA) said that some of the makers of generic-label paclitaxel have some of the drug on hand and that the shortage was “not a complete national outage”. One paclitaxel supplier, Bedford Laboratories of Bedford, Ohio, announced that they had numerous backorders for the drug. A spokesman announced that the company hopes to have a supply of the drug ready for market by 1 July.

Sources:

http://abcnews.go.com/Health/CancerPreventionAndTreatment/chemo-drug-taxol-shortage-leaves-doctors-scrambling-cancer/story?id=13906891
http://www.kgoam810.com/rssItem.asp?feedid=116&itemid=29683184
http://cancer.about.com/b/2011/06/23/taxol-shortage-may-affect-ovarian-and-breast-cancer-patients.htm
http://www.medpagetoday.com/HematologyOncology/Chemotherapy/27249

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New NCCN Clinical Practice Guideline on Malignant Pleural Mesothelioma0

The National Comprehensive Cancer Network® (NCCN®), with the support of the NCCN Foundation, announces the latest addition to the library of NCCN Guidelines for Patients™, the NCCN Guidelines for Patients™: Malignant Pleural Mesothelioma. This resource is a patient-friendly, easy-to-understand translation of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Malignant Pleural Mesothelioma, which physicians use when determining appropriate cancer treatment. The NCCN Guidelines for Patients™ aim to help people with cancer and their loved ones discuss the best treatment options for them with their physicians.

The NCCN Guidelines for Patients™: Malignant Pleural Mesothelioma are supported by Baron & Budd, P.C., attorneys dedicated to protecting the rights of people who suffer from cancers like mesothelioma and lung cancer, which are often attributable to environmental toxins.

Mesothelioma is a rare cancer of the mesothelium, or the tissue that covers most organs inside the body, most commonly the lungs. It occurs in about 2,500 people in the United States every year. Although rare, mesothelioma is deadly, with about half of those diagnosed dying within one year. People diagnosed with mesothelioma have usually worked with asbestos approximately 20 to 40 years prior to diagnosis.

"Baron & Budd is committed to helping people affected by asbestos-related cancers understand both their medical and legal options. We are honored to have sponsored this important resource for patients," said Russell Budd, president and managing shareholder of Baron & Budd.

Russell Budd is a member of the Board of the NCCN Foundation and has been a shareholder of Baron & Budd since 1985 and president and managing shareholder since 2002. Over the last decade, Mr. Budd has played a significant role in protecting the rights of people injured by exposure to asbestos.

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Mesothelioma Treatment0

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 known as remissionpercentage 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 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.

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.

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 chest drain 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 radiotherapy 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.

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.

Immunotherapy

Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (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.
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.

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Latency Period of Mesothelioma0

Mesothelioma is a cancer arising from asbestos fibers inhaled or ingested into the body and trapped in the mesothelial linings of the lungs (pleural mesothelioma), abdomen (peritoneal mesothelioma), and heart (pericardial mesothelioma).

Pleural mesothelioma is most common, occurring in 75 percent of cases, with peritoneal mesothelioma occurring in about 15+ percent of cases, and pericardial mesothelioma occurring in less than 10 percent.

Mesotheliomas affect thousands of people each year. Mesothelioma was not tracked as a cause of death by federal health officials until 1999, but numbers from that year show an estimated death rate of 2,343 individuals out of a population of about 273 million, based on new reporting. Projecting a rate of increase (from 1990 to 1999) over the subsequent decade, from 2000 to 2010, experts estimate 35,000 yearly deaths from mesothelioma in the long term. More on mesothelioma statistics.

Mesothelioma, in all forms, has an extremely long latency period compared to other cancers. This latency period is generally thought to range from 5 years to 40 years, with a 2007 study from Italy showing an latency period of 43 years for those exposed through their work, and 48 for those who suffered environmental and household exposure.

The U.S. Department of Labor’s Occupational Safety and Health Administration, or OSHA, concurs, noting that mesothelioma has a much longer latency compared to other lung cancers, or 40 years as compared to an average 15 to 20 years.

So does the state of Arizona, noting on its web pages that symptoms of asbestos-related disease like mesothelioma do not usually appear until about 10 to 40 years after first exposure, and adds the caveat that children present an exception to this long latency rule due to their rapid rate of growth.

The U.S. Environmental Protection Agency, or EPA, the premier national agency for health effects from hazardous chemical exposures (of which asbestos is one), shows the latency period as being between 15-30 years, and adds that asbestos is the only known cause of mesothelioma. The Minnesota Department of Health agrees, noting that all asbestos diseases have a latency period, and that that period is generally between 10 and 40 years.

Experts estimate that more than 28 million Americans have been exposed to asbestos, either through their work, the environment, use of products like ironing board covers and oven gloves (to name a few), or through a family member who brought asbestos fibers home on clothing. A 2004 OSHA report says 1.3 million people are exposed to asbestos through their work.

Mesothelioma symptoms tend to mimic other diseases or illnesses, and mesothelioma is usually isolated as the cause a mere two to three months before a tumor is found, which leads to poor prognoses. The average survival time for people diagnosed with mesothelioma is about 1 to 2 years and mesothelioma is almost always fatal, though scientists and researchers expect, with a new test available to detect mesothelioma, survival rates may improve in the future.

Asbestos itself occurs naturally in six different forms: amosite, chrysotile, crocidolite, and the fibrous varieties of tremolite, actinolite, and anthophyllite (the latter three also occurring naturally in non-fibrous forms). Widely used during most of the last century in various building materials and automotive products, to name a few, the mineral is further classified into friable and non-friable forms.

The first category, and the most dangerous (since it readily releases fibers when broken), includes anything containing more than one percent of asbestos (a limit established in 1989 by the EPA for all domestic product); product that, when dry, can be crumbled by mere hand pressure, and; substances like drywall, blown-in insulation, boiler pipe wrapping, and (acoustical) ceiling tiles or insulative and sound-proofing textured ceilings.

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Mesothelioma Epidemiology0

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.
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, gaskets, 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.
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.
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.
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.
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.
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.

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Anonymous donor makes generous gift for mesothelioma research0

The UH Cancer Center has received a $3.58 million gift from an anonymous donor to support the mesothelioma research of Dr. Michele Carbone, director of the UH Cancer Center. Carbone and colleagues, who include Drs. Haining Yang and Giovanni Gaudino, have made a series of recent scientific breakthroughs that will lead to new ways to prevent and treat the disease.

"This generous gift is critical to support our efforts to generate discoveries that will aid in the prevention of mesothelioma and the development of new therapies," said Dr. Carbone. Mesothelioma is a cancer of the cells that line the chest and abdominal cavities. It results in one of the most aggressive types of tumors, and current median survival from diagnosis is just twelve months. Exposure to airborne asbestos or erionite particles increases one's risk of developing mesothelioma.

The gift is the second largest in UH Cancer Center history. "Mesothelioma is a serious public health problem," said Dr. Virginia Hinshaw, Chancellor of UH Mānoa. "We're proud that Dr. Carbone's team is leading the world in this area of discovery. This gift validates their efforts and will help them remain at the forefront of thoracic oncology research."

Dr. Carbone and colleagues have studied mesothelioma for more than a decade. Significant findings have come from studies conducted in the villages of Capadoccia, a region of Turkey. Dubbed "death villages," nearly 50% of the area's residents develop and die of mesothelioma. The epidemic is caused by exposure to a fiber called erionite that is even more potent than asbestos in causing mesothelioma. Erionite is a naturally occurring mineral found in rock formations and homes built of rock material in the region. The team's findings led to a response from the Turkish government that included building the villagers new homes and a regional health center to conduct treatment.

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Mesothelioma Pathophysiology0

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 fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber 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 fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.

Pleural contamination with asbestos or other mineral fibers 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 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 fibers. It has been suggested that in humans, transport of fibers 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 localized lesions of accumulated asbestos fibers 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 tumor.

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 fibers 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 fibers has not yet been achieved. In general, asbestos fibers 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 fibers and DNA has shown that phagocytosed fibers are able to make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. This contact between the asbestos fiber 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:

    Neurofibromatosis type 2 at 22q12
    P16INK4A
    P14ARF

Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:

    Inactivation of tumor suppressor genes
    Activation of oncogenes
    Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region
    Activation of DNA repair enzymes, which may be prone to error
    Activation of telomerase
    Prevention of apoptosis

Asbestos fibers have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.

Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.

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