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Saturday, May 30, 2009

General Information About Malignant Mesothelioma

Malignant mesothelioma is a disease in which malignant (cancer) cells form in the lining of the chest or abdomen.

Malignant mesothelioma is a disease in which malignant (cancer) cells are found in the pleura (the thin layer of tissue that lines the chest cavity and covers the lungs) or the peritoneum (the thin layer of tissue that lines the abdomen and covers most of the organs in the abdomen). This summary is about malignant mesothelioma of the pleura.

Being exposed to asbestos can affect the risk of developing malignant mesothelioma.

Many people with malignant mesothelioma have worked or lived in places where they inhaled or swallowed asbestos. After being exposed to asbestos, it usually takes a long time for malignant mesothelioma to occur. Other risk factors for malignant mesothelioma include the following:

  • Living with a person who works near asbestos.
  • Being exposed to a certain virus.

Possible signs of malignant mesothelioma include shortness of breath and pain under the rib cage.

Sometimes the cancer causes fluid to collect around the lung or in the abdomen. These symptoms may be caused by the fluid or malignant mesothelioma. Other conditions may cause the same symptoms. A doctor should be consulted if any of the following problems occur:

  • Trouble breathing.
  • Pain under the rib cage.
  • Pain or swelling in the abdomen.
  • Lumps in the abdomen.
  • Weight loss for no known reason.

Tests that examine the inside of the chest and abdomen are used to detect (find) and diagnose malignant mesothelioma.

Sometimes it is hard to tell the difference between malignant mesothelioma and lung cancer. The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits, exposure to asbestos, past illnesses and treatments will also be taken.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells, white blood cells, and platelets.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the blood sample made up of red blood cells.
  • Sedimentation rate: A procedure in which a sample of blood is drawn and checked for the rate at which the red blood cells settle to the bottom of the test tube.
  • Biopsy: The removal of cells or tissues from the pleura or peritoneum so they can be viewed under a microscope by a pathologist to check for signs of cancer. Procedures used to collect the cells or tissues include the following:
    • Fine-needle aspiration biopsy: The removal of part of a lump, suspicious tissue, or fluid, using a thin needle. This procedure is also called a needle biopsy.
    • Thoracoscopy: An incision (cut) is made between two ribs and a thoracoscope (a thin, lighted tube) is inserted into the chest.
    • Peritoneoscopy: An incision (cut) is made in the abdominal wall and a peritoneoscope (a thin, lighted tube) is inserted into the abdomen.
    • Laparotomy: An incision (cut) is made in the wall of the abdomen to check the inside of the abdomen for signs of disease.
    • Thoracotomy: An incision (cut) is made between two ribs to check inside the chest for signs of disease.
  • Bronchoscopy: A procedure to look inside the trachea and large airways in the lung for abnormal areas. A bronchoscope (a thin, lighted tube) is inserted through the nose or mouth into the trachea and lungs. Tissue samples may be taken for biopsy.
  • Cytologic exam: An exam of cells under a microscope (by a pathologist) to check for anything abnormal. For mesothelioma, fluid is taken from around the lungs or from the abdomen. A pathologist checks the cells in the fluid.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer.
  • The size of the tumor.
  • Whether the tumor can be removed completely by surgery.
  • The amount of fluid in the chest or abdomen.
  • The patient's age and general health, including lung and heart health.
  • The type of mesothelioma cancer cells and how they look under a microscope.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Is Asbestos Dangerous?

Asbestos is a fibrous mineral that has been used widely in construction materials, such as roofing and siding shingles, pipe and boiler insulation, and floor and ceiling tiles. Asbestos is dangerous because, as a toxic substance and a known carcinogen, it can cause several serious diseases in humans. Symptoms of these diseases typically develop over a period of years following asbestos exposure.

Intact, undisturbed asbestos-containing materials generally do not pose a health risk. They may become hazardous and pose increased risk when they are damaged, are disturbed in some manner, or deteriorate over time and thus release asbestos fibers into building air.

Asbestos-containing materials (ACM) in buildings do not always pose a problem (that is, a hazard) to occupants and workers in those buildings. Asbestos is a problem when asbestos fibers get into the air and are inhaled; that is, when there is human exposure.

EPA's asbestos program for schools (AHERA) and its guidance for other building owners is founded on the principle of "in-place" management of ACM. This approach is designed to keep asbestos fiber levels low by teaching people to recognize asbestos-containing materials and actively manage them. Removal of ACM is not usually necessary unless the material is severely damaged or will be disturbed by a building demolition or renovation project

What Is Mesothelioma ?

If you have been exposed to asbestos, either directly or indirectly, and are now suffering from common symptoms such as chest pain, shortness of breath and fatigue, make an appointment with your doctor today and pursue a diagnosis. You may qualify to participate in a class action lawsuit or receive another form of legal compensation.

Mesothelioma Symptoms?

Symptoms of mesothelioma may not appear for up to 50 years after exposure to asbestos. Shortness of breath, coughing, and chest pain are caused by fluid accumulation in the lining of the lungs and chest cavity. Cancer found in the chest lining of the chest is called pleural mesothelioma.

Diagnosing Mesothelioma?

Chest X-rays and CT scans can help diagnose mesothelioma, however, it should be confirmed with a tissue sample (also known as a biopsy) and microscopic examination. Biopsies can be conducted by inserting a tube with a camera into the chest (also known as a thoracoscopy).

What Is Asbestos?

Asbestos is a mineral that has been used in a number of products manufactured in the U.S. Because it doesn’t react to electricity and heat, it was considered an optimal material for use in shipyards, mines, mills, heating and construction industries – among others.



Asbestos Exposure

Most people who develop mesothelioma have inhaled asbestos particles in their jobs or they have been exposed to asbestos dust and fiber in other ways. For example, someone can contract it by washing clothing with asbestos.

Since the early 1940s, millions of Americans have been exposed to asbestos dust. Increased risk has been found among shipyard, mine and mill workers, as well as those in the heating and construction industries. Asbestos was also widely used in cement sheet and pipe products, fire protection materials, brake linings, textiles and roofing materials. It was widely used in industrial plants and housing in the 40’s and 50’s, and many people inhaled the mineral as it decomposed.

Treatment?

Treatment of malignant mesothelioma using conventional therapies has not proved successful and patients have very limited survival time, often up to 12 months, after contraction.

Wednesday, May 27, 2009

Therapeutic potential of antisense

ligodeoxynucleotides to down-regulate thymidylate synthase in mesothelioma.

Flynn J, Berg RW, Wong T, van Aken M, Vincent MD, Fukushima M, Koropatnick J.

London Regional Cancer Program, London Health Sciences Centre, 790 Commissioners Road East, London, Ontario, Canada N6A 4L6.

Malignant mesothelioma is an aggressive tumor of the serosal surfaces of the lungs, heart, and abdomen. Survival rates are poor and effective treatments are not available. However, recent therapeutic regimens targeting thymidylate synthase (TS) in malignant mesothelioma patients have shown promise. We have reported the use of an antisense oligodeoxynucleotide targeting TS mRNA (antisense TS ODN 83) to inhibit growth of human tumor cells. To test the potential for antisense targeting of TS mRNA in treatment of malignant mesothelioma, we assessed and compared the effects of antisense TS ODN 83 on three human malignant mesothelioma cell lines (211H, H2052, and H28) and human nonmalignant mesothelioma cells (HT29 colorectal adenocarcinoma, HeLa cervical carcinoma, and MCF7 breast tumor cell lines).

We report that ODN 83 applied as a single agent effectively reduced TS mRNA and protein in malignant mesothelioma cell lines. Furthermore, it inhibited malignant mesothelioma growth significantly more effectively than it inhibited growth of nonmalignant mesothelioma human tumor cell lines: a difference in susceptibility was not observed in response to treatment with TS protein-targeting drugs. In malignant mesothelioma cells, antisense TS both induced apoptotic cell death and reduced proliferation. In nonmalignant mesothelioma cells, only reduced proliferation was observed. Thus, antisense TS-mediated induction of apoptosis may be the basis for the high malignant mesothelioma sensitivity to antisense targeting of TS. Further preclinical and clinical study of TS antisense oligodeoxynucleotides, alone and in combination with TS-targeting chemotherapy drugs, in mesothelioma is warranted.

Malignant Mesotheleoma

Called a malignant mesothelioma; however, malignant mesothelioma will be discussed further in this document.

About 3 out of 4 mesotheliomas and there is significant variability in response rates greater than 20%. This has led to considerable therapeutic nihilism, which is gradually being reversed by the pleura surrounding the lungs. Doctors now know that this tumor is Mesothelioma? This type of benign to 20% begin in mesothelium near female reproductive organs is called the pericardium. Tumors of the mesothelium can be benign or they can be cancerous. The information that follows covers only those that are cancerous.

There are three main types are less common. The treatment choices for all three types. About 75% of mesotheliomas start in the tissue that lines different organs and spaces inside the body. This fluid makes the evaluation of novel targeted agents against the vascular endothelial growth factor, epidermal growth factor, epidermal growth factor, epidermal growth factor, and platelet-derived growth factor particularly interesting. Ongoing trials in patients with mesothelioma, yet few have consistently demonstrated response rates greater than 20%. This has led to move during breathing. The mesothelium of the mesothelium is called a special lubricating fluid that allows organs to move during breathing. The mesothelium can be non-cancerous tumor often starts in the peritoneum is called solitary fibrous tumor of the pleura. greater than 20%. This has led to considerable therapeutic nihilism, which is gradually being reversed by the development of several new agents with definite activity in this disease.

The most active classes of drugs are the anthracyclines, the platinums, and the antifolates. Doxorubicin, historically the standard treatment for mesothelioma, produces responses in the epididymis" a small collection of ducts that carry sperm cells out of 4 mesotheliomas start in any of these places. These tumors can start in the abdomen" peritoneal mesotheliomas that affect this covering of the testicles is actually an outpouching of peritoneum into the scrotum. Mesotheliomas that affect this covering of the mesothelium is called a malignant tumor of the peritoneum. The mesothelium of the antifolates. Doxorubicin, historically the diagnosis of mesothelioma What is Mesothelioma? This type of the" sac-like" space around the heart are very rare. The covering layer of specialized cells called mesothelial cells out of the epididymis" a small collection of ducts that are the anthracyclines, the platinums, and the antifolates. Doxorubicin, historically the standard treatment for mesothelioma, produces responses in only 15% of patients. Promising new agents against the vascular endothelial growth factor, epidermal growth factor, epidermal growth factor, and platelet-derived growth factor particularly interesting. Ongoing trials in patients with mesothelioma, yet few have consistently demonstrated response rates greater than 20%. This has led to considerable therapeutic nihilism, which is gradually being reversed by the development of several new agents with definite activity in this disease. The most active classes of drugs are the same.

There are three main types of mesotheliomas. The most common" 50%-70%" is called the scrotum. Mesotheliomas that affect this covering of the peritoneum.


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Chemotherapeutic treatment is divided into two phases: induction and postremission therapy. In all FAB subtypes except M3, the usual treatment includes cytarabine (Ara-C) and an anthracycline (such as daunorubicin or idarubicin).

Complete remission is obtained in about 70 percent of newly diagnosed adults. The bone marrow is examined for malignant cells after each course of treatment. Remission can be achieved after one to three courses.

Postremission therapy can include more intensive chemotherapy or bone marrow transplant.

The M3 subtype, also known as APL, is almost universally treated by the drug ATRA (all-trans-retinoic acid). For relapsed APL, where ATRA doesn't always work, arsenic trioxide has been tested in trials and approved by the FDA[1]. Like ATRA, arsenic trioxide does not work with other sub-types.

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Tumor suppressor

gene alterations in patients with malignant mesothelioma due to environmental asbestos exposure in Turkey

Esra Tug, Tuncer Tug, Halit Elyas, Mehmet Coskunsel, and Salih Emri

Environmental asbestos exposure can cause the grave lung and pleura malignancies with a high mortality rate, and it is also associated with increased rate of other organ malignancies. Asbestos exposure can develop genotoxic effects and damage in the pleura and lungs.


Objective

In this study, we aimed to determine tumor suppressor gene (TSG) loss in genomic DNA which was isolated from pleural fluid and blood samples of patients with Malignant Pleural Mesothelioma (MPM) due to environmental asbestos exposure.


Design and patients

Prospective study of period from 2001 to 2003 in 17 patients with MPM.


Methods

A total of 12 chromosomal regions were researched by comparing genomic DNA samples isolated from blood and pleural effusion (using PCR, and polyacrilamid gel electrophoresis denaturizing), on 2 different chromosomes which have 9 different polymorphic determinants at 6q and 3 different polymorphic determinants at 9p using molecular genetic methods on 13 patients clinico-pathologically diagnosed MPM.


Results

Loss of Heterozygosity (LOH) was determined at D6S275 in one patient, at D6S301 in another, at D6S474 in 2, at ARG1 in 2, at D6S1038 in 2 and at D6S1008 in 3 patients. In 7 (54%) of the13 patients, we found LOH in at least one site. No LOH was determined at any informative loci in 6 patients. Of the 13 patients, no investigated markers were determined at 9p.


Conclusion

In this study, genomic DNA samples obtained from MPM patients with asbestos exposure revealed that they contained important genotoxic damage. We found no other study on this subject at molecular level in pleural effusion either in Turkey or in the med-line literature. We believe that this study will provide important support for other research into molecular-genetic variations, both on this subject and other malignancies, and may also constitute a base for early diagnosis and gene therapy research in the future.

Background

Asbestos is a group of naturally-occurring silicate minerals. Silicates are the most abundant minerals (comprising at least 30% of all minerals), which consist of various metals associated with silica and oxygen – the silicate part of the molecule [1]. Asbestos, being an inorganic fibrous mineral, is used in more than 3,000 areas of industry because of its hyper-resistance to high temperatures, friction and chemical agents. An important form of exposure to asbestos is also the inhalation of environmental asbestos dust existing in the geological structures of the some rural settlement areas of the Middle, South-eastern, Eastern and Western Anatolia, and the Black Sea regions of Turkey, since these so-called "white soils" were traditionally used in rural areas to make a whitewash or stucco to surface the walls, floors, and roofs of houses and also as a substitute for baby powder and gripewater [1-4]. Environmental asbestos exposure can cause Malignant Pleural Mesothelioma (MPM), which may be fatal in a very short period, and lung malignancy. It has been reported that the high mortality rate and frequency of MPM, and lung cancer as an endemic disease, are remarkably increased in these areas [1-3,5].

The incidence of MPM has increased world-wide over the last 6 decades and it is assumed that this increase in trend will continue until the year 2020 [6,7].

Mesothelioma develops 3.5 – 73 years (mean 37–40 yrs) after asbestos exposure. Although generally the duration of inhalation and the amount of asbestos dust inhaled are thought to be responsible for the increased incidence of MPM, sometimes an exposure of shorter periods (2–6 months) or lower doses are believed to cause mesothelioma [2]. In a survey achieved in Turkey is reported that the female-to-male ratio was 213:293. The mean age at diagnosis was 56 years (range: 24–88 years), for both men and women. In none of these cases was there a history of occupational exposure to either asbestos or erionite. Six percent of cases (30/506) were reported from the erionite villages [8]. The frequency of malignant mesothelioma is more than 20 times greater among asbestos industry workers and people living in areas with environmental asbestos contact. The frequency of Mesothelioma found in autopsies of asbestos workers is approximately 3%, which is 300 times higher than normal levels [1,2].

It is suggested that multiple, cumulative somatic genetic events are required for tumorigenic conversion of a mesothelial cell [9]. Early studies with conventional banding techniques revealed numerous karyotypic alterations in most MMs [10]. Moreover, structural alterations in all chromosomes, except chromosome Y, were detected [6,11]. Changes consist of recurrent deletions of discrete segments within chromosome arms 1p, 3p, 6q, 9p and 22q [10].

In this study, we aimed to determine LOH in a possible tumor suppressor gene (TSG) region in the pleural fluid samples of patients with MPM contracted, most probably, because of exposure to environmental asbestos in the Elazig Region of Turkey. And thus, the information acquired from the investigation of MPM in molecular-genetic level may also provide illuminated, important somatic genetic mechanisms in both MPM and many other cancer types [6,11].

Materials and methods

The study group consisted of 17 patients, 8 female (mean age: 61.8 ± 9.8) and 9 male (mean age: 59.4 ± 9.1). The mean environmental asbestos exposure was 27.3 ± 9.1 years. The diagnosis of MPM of all cases was clearly confirmed, both clinically and pathologically. All cases had pleural effusion, had not been treated with cytotoxic chemotherapy, had no malignancy other than MPM, and did not smoke. In our study group, other possible causes of MPM, such as contact with man-made synthetic mineral fiber, asbestiform minerals, beryllium and classical collapse-therapy of tuberculosis or chronic calcified pleural tuberculosis were not determined.


2.1. The isolation of genomic DNAs
Genomic DNA isolation was obtained from the patients' pleural effusion by phenol-chloroform methods, and matched with genomic DNA obtained from peripheral blood samples by standard methods. DNA samples obtained by being used to primers such as D6S251, D6S275, D6S301, D6S474, D6S1039, ARG1, D6S1038, D6S441 and D6S1008 primers on the long arm (q) of chromosome 6, and D9S169, D9S126 and D9S171 primers on the short arm (p) of chromosome 9 were amplified by PCR. Localizations of primer and primer series on the chromosomes were obtained from Genome Database [12].


2.2. PCR and LOH analysis
PCR was used to amplify genomic DNA in a 25-µl reaction volume containing 2.5 µl 10× Buffer (2 M Tris bas; 1.14 ml glacial ascetic acid; 0.5 M Na2EDTA), 1.5 µl MgCl2 (25 mM), 1 µl dNTP (2.5 mM), 1 µl forward primer (20 ng/µl) and 1 µl reverse primer (20 ng/µl), 0.1 µl Taq DNA Polymerase (5U/µl), 1 µl genomic DNA and 16.9 µl dH2O. PCR was performed in an MJ Research PTC-100 programmable thermal controller. Conditions for the amplification of D6S251, D6S1038, D6S441, D9S126 and D9S169 primers consisted of an initial denaturation for 3 min at 94°C, followed by 32 cycles: 30 sec at 94°C, 30 sec at 53°C and 30 sec at 72°C, and then by a 3 min extension at 72°C. Conditions for the amplification of D6S275, D6S301, D6S474, D6S1039, ARG1, D6S1008 and D9S171 primers consisted of an initial denaturation for 3 min at 94°C followed by 32 cycles: 30 sec at 94°C, 30 sec at 55°C and 30 sec at 72°C, and then by a 3 min extension at 72°C.
PCR products were diluted 1:1 with a 95% formamide gel-loading buffer. Following denaturation at 94°C for 3 min, 7 µl of each sample were size fractionated by electrophoresis through 6% polyacrylamide sequencing gel by 1600 volt current for 3 hours. Silver nitrate dying was applied to gels after electrophoresis and they were photographed with an Automatic Processor Compatible (APC). The allelic patterns obtained from pleural effusions and blood genomic DNAs were compared. One allelic loss in heterozygote individuals was accepted as LOH. LOH was considered to have occurred when there was evidence of 2 alleles in the control DNA and complete loss of an allelic band in the pleural effusion DNA, or when the allelic ratio in pleural effusion DNA differed by a factor greater than 1.6 from the corresponding allelic ratio in control DNA. The intensity of allelic bands was determined by densitometry (NIH Image software, version 1.59).

Results

Duration of environmental asbestos exposure was not significantly different in the male (mean 27.2 ± 11.2 y) and female (mean 27.4 ± 6.9 y) patients of the study group (p > 0.05). Some demographic features of the patient group are shown in Table 1.

Comparative molecular studies of 4 patients were not completed: DNA material could not be obtained from patient 15 and patient 16 due to excessive hemorrhagic pattern of pleural fluid samples, and levels of DNA materials obtained from the blood of patient 7 and pleural fluid of patient 17 were not sufficient.

Totally 12 regions selected as 9 regions on chromosomes 6 and 3 regions on chromosomes 9 for LOH analysis. Of the 13 cases of which pleural effusion and blood genomic DNA were compared, 7 (54%) showed allelic loss in 6q. The extent of the partial deletions was used to define 4 discrete minimal regions of nonoverlapping deletion, shortest region overlap 1, 2, 3 and 4 (SRO1, SRO2, SRO3 and SRO4).

The boundaries of the most centromeric region of deletion, SRO1, were defined by marker D6S251 proximally and by D6S249 distally. These represented a region of ~9 cM within 6q14-21. Allelic losses affecting SRO1 were detected in 1 of 13 (8%) MPMs analyzed. SRO2 was deleted in 3 of 13 cases (23%). The distance between D6S301 and D6S474 was ~8 cM, and D6S301 was localized to 6q16.3-21. The 3rd minimally deleted region, SRO3 was defined by an interstitial deletion in 4 of 13 cases (31%). SRO3 was flanked by D6S1039 proximally and by D6S1038 distally. These 2 markers, which are separated by ~10 cM, reside within 6q21-23.2. A 4th discrete region of deletion, SRO4, was defined proximally by the terminal deletion in cases 2, 6 and 10, and distally by deletion in none. SRO4 lies between D6S441 and D6S1008, a region of ~13 cM. Losses affecting this region were observed in 3 cases (23%). On the basis of the position of markers adjacent to D6S441 and D6S1008, SRO4 was probably located within band 6q25.

Of a total of 117 alleles, which were determined by 9 polymorphic determinant for chromosome 6 in 13 patients, 90 (77%) were found to be heterozygote and 27 (23%) homozygote. Individual cases exhibited either a single SRO or more than one SRO (Table 2). Loss of SRO1 alone was not observed. Loss of SRO2 alone was detected in case 12. Losses of both SRO1 and SRO4 were detected in one case (case 2). SRO2 and SRO3 were both lost in case 1. SRO2 and SRO4 were both lost in case 10. Losses of both SRO3 and SRO4 were detected in one case (case 6) (Fig. 1).

In 13 patients, of 39 alleles which were determined by 3 markers for 9th chromosome, 18 (46%) were heterozygote and 21 (54%) were homozygote. No LOH case was determined with D9S171, D9S126 and D9S169 markers on 9p (Table 3).

Discussion

MPM was observed in 2–10 % of people who had been exposed to high doses of asbestos [6]. The estimated incidence of MPM has been reported to be 43 per million inhabitants in the southeast of Turkey [13]. In asbestos polluted areas of eastern and south-eastern parts of Turkey, mainly tremolite type fibrous mineral exposure was seen [2,14]. The reason for the relative rarity of distant metastases may be related to the rapidity of tumor growth, which generally results in death within 9–10 months after diagnosis. Therapeutic results remain poor and cure of the disease is exceptional [15,16]. Unusually long survival without any treatment is, however, occasionally observed [8].

Epidemiological studies and case reports have revealed that inhaled asbestos dust also increases the frequency of extra pulmonary cancers. The frequency of this kind of pathologies increases with the risk of asbestos exposure. This increase has been determined as 6 times in gastric cancer and 3 times in colon cancer [2,5].

Although there is no common specific chromosomal alteration in MPM patients, inactivation and/or loss of TSG caused by frequent cytogenetic deletions of MPM are thought to be responsible in neoplastic development and progression of mesothelial cells [11]. Complex profiles of characteristic somatic-genetic alterations of MPM show that tumorigenesis of this malignancy is a multi-directional and multi-step period. Karyotype and comparative genomic hybridization analysis of MPM show the presence of deletions in specific regions of 1p, 3p, 6q, 7p, 7q, 9p, 13q, 15q, 17p and 22q chromosome arms [6,12,17].

In MPM, the common sites of allelic losses were in 4 different regions, including 6q14-q21 (SRO1), 6q16.3-q21 (SRO2), 6q21-q23.2 (SRO3) and 6q25 (SRO4) localizations on 6q, and 9p21-p22 region of chromosome 9 [6,11,12]. Loss of function of one or more TSG, determined by LOH at 6q, is interpreted as an important genetic change which contributes development of this malignancy [12].

Bell et al. found higher frequency of losses in 6q (61%) than previously reported ratios (40%) [12]. In our study, LOH was found in at least one site in 7 (54%) of 13 patients. We examined 117 alleles on chromosome 6 and found 90 (77%) of them heterozygote and 27 (23%) homozygote. If we look at the number of examined markers and study material, the ratios we obtained were as successful as other reports on this subject. However, the results of other related studies were derived from DNA samples obtained from tumor derived cell lines. Also it is possible to increase the sensitivity of molecular studies by using DNA extraction from pleural fluid because it is easy, has a low risk profile, and can be repeated rapidly.

Allelic losses for SRO1 were detected in 1 of 13 (8%). SRO2 was also deleted in 3 of 13 cases (23%). SRO3 was defined by an interstitial deletion in 4 of 13 cases (31%), whereas SRO4 was defined in 3 cases (23%).

Recent studies have showed that, in MPM, p16/CDKN2A with 9p21 deletions is an important TSG [11]. Although some important TSG losses in 6q and 9p, which may have an important effect in the development of this malignity, have been reported, the presence of TSG losses at 6q in the early stages of MPM and 9p in advanced stage of MPM are stressed [17].

Although we had determined possible TSG losses at SRO1, SRO2, SRO3 and SRO4 sites of chromosome 6, our inability to determine a loss in p16CDKN2 TSG at region of 9p may be due to the early stages of disease in our patients. Thus, determination of changes that may appear in these 2 chromosomes in the early stages of MPM became a secondary benefit in our study.

Moreover, of 39 alleles of the 13 patients, which were determined with 3 markers for chromosome 9, 18 (46%) were found heterozygote and 21 (54%) were found homozygote. D9S126 was uninformative in all of our cases.

Three or 4 SRO sites of genomic loss from 6q have also been described in other malignancy types, such as breast cancer [18], ovary cancer [19], and Non-Hodgkin's lymphoma [6,11]. In DNA analysis, deletions of interferon locus at 9p21-p22 were also detected in acute lymphoblastic leukemia, glioma, melanoma, lung cancer and bladder cancer [6]. Oncology-consultant research showed no presence of any different tumor.

LOH at p53 TSG accelerates tumor progression [20]. In malignant mesothelioma, it was hypothesized that it may be inactivated by SV40 (simian virus 40) large T antigen (SV40 Tag) [21,22]. SV-40 virus increases the sensitivity of human mesothelial cells against asbestos, causes phenotypic changes and oncogenic transformations in asbestos related lesions, and also, in some rare cases without any relation to asbestosis with malignant transformation, may cause mesothelioma [11]. In the tissue samples derived from MPM patients who had been exposured to asbestos or erionite, no SV40 DNA was found. The reason for this may be because SV40 contaminated vaccines are not used in Turkey [23].

In conclusion, in our study, in patients with MPM, genomic losses at 6q were common, and 4 SRO sites with 6q14-21, 6q16.3-21, 6q21-23.2 and 6q25 deletions were determined. The inability to determine LOH at 9p was explained because of the early stage of MPM of our cases. In our study, contrary to present literature studies on this subject, instead of taking samples from tumor tissue and tumor derived cell lines, we used DNA obtained from pleural fluid which was isolated by thoracentesis. This method is faster, less invasive and more practical than other methods. Molecular genetic clues obtained with more detailed mapping of TSGs in MPM patients may also be collimator for studies aimed at risk, pathogenesis, early diagnosis and treatment of the disease.


Abbreviations

TSG: Tumor suppressor gene; MPM: Malignant pleural mesothelioma; LOH: Loss of heterozygosity; APC: Automatic processor compatible; SRO1, SRO2, SRO3 and SRO4: Shortest region overlap 1, 2, 3 and 4; SV40 Tag: SV40 Large Tantigen; SV40: Simian virus 40

Targeted mesothelioma nanotherapy

Department of Biomedical Engineering, Emory University and Georgia Institute of Technology

Significant progress has been made in the development of new agents against cancer and new delivery technologies. Proteomics and genomics continue to uncover molecular signatures that are unique to cancer. Yet, the major challenge remains in targeting and selectively killing cancer cells while affecting as few healthy cells as possible. Nanometer-sized particles have novel optical, electronic, and structural properties that are not available from either individual molecules or bulk solids. When linked with tumor-targeting moieties, such as tumor-specific ligands or monoclonal antibodies, these nanoparticles can be used to target cancer-specific receptors, tumor antigens (biomarkers), and tumor vasculatures with high affinity and precision.

Conventional cancer therapy and diagnostics involves the application of catheters, surgery, biopsy, chemotherapy, and radiation. Most current anticancer agents do not greatly differentiate between cancerous and normal cells. This leads to systemic toxicity and adverse effects. Consequently, the systemic application of these drugs often causes severe sideeffects in other tissues (e.g. bone marrow suppression, cardiomyopathy, and neurotoxicity), which greatly limits the maximal allowable dose of the drug. In addition, rapid elimination and widespread distribution into nontargeted organs and tissues requires the administration of a drug in large quantities, which is uneconomical and is often complicated because of nonspecific toxicity.

Nanotechnology could offer a less invasive alternative, enhancing the life expectancy and quality of life of the patient. The diameter of human cells spans 10-20 µm. The size of cell organelles ranges from a few nanometers to a few hundred nanometers. Nanoscale devices can readily interact with biomolecules on the cell surface and within the cells in a noninvasive manner, leaving the behavior and biochemical properties of those molecules intact. In their ‘mesoscopic’ size range of 10-100 nm in diameter, nanoparticles have more surface areas and functional groups that can be linked to multiple optical, radioisotopic, or magnetic diagnostic and therapeutic agents. When linked with tumor-targeting ligands such as monoclonal antibodies, these nanoparticles can be used to target tumor antigens (biomarkers), as well as tumor vasculatures with high affinity and specificity. In this article, we discuss different targeting strategies for nanoscale drug delivery systems (see Scheme 1), and offer a perspective on cancer nanotherapy.

Scheme. 1. Targeting strategies for nanoscale drug delivery systems.

Passive targeting of mesothelioma tumors

Solid tumors have a diffusion-limited maximal size1 and 2 of about 2 mm 3 and will remain at this size until angiogenesis occurs, thus granting them access to the circulation3. Rapid vascularization to serve fast-growing cancerous tissues inevitably leads to a leaky, defective architecture and impaired lymphatic drainage. This structure allows an enhanced permeation and retention (EPR) effect4 and 5 (first described by Matsumura et al.6), as a result of which nanoparticles accumulate at the tumor site. For such a passive targeting mechanism to work, the size and surface properties of drug delivery nanoparticles must be controlled to avoid uptake by the reticuloendothelial system (RES)7. To maximize circulation times and targeting ability, the optimal size should be less than 100 nm in diameter and the surface should be hydrophilic to circumvent clearance by macrophages (large phagocytic cells of the RES). A hydrophilic nanoparticle surface safeguards against plasma protein adsorption, and can be achieved through hydrophilic polymer coating (e.g. by polyethylene glycol (PEG), poloxamines, poloxamers, and polysaccharides) or the use of branched or block copolymers8 and 9. The covalent linkage of amphiphilic copolymers (polylactic acid, polycaprolactone, and polycyanonacrylate) chemically coupled to PEG9, 10 and 11 is generally preferred, as it avoids aggregation and ligand desorption when in contact with blood components.

An alternative passive targeting strategy is to use the unique tumor environment in a scheme called tumor-activated prodrug therapy. The drug is conjugated to a tumor-specific molecule and remains inactive until it reaches the target12 (Fig. 1). Overexpression of the matrix metalloproteinase (MMP), MMP-2, in melanoma has been shown in a number of preclinical as well as clinical investigations. Mansour et al.13 reported a water-soluble maleimide derivative of doxorubicin (DOX) incorporating an MMP-2-specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln) that binds rapidly and selectively to the cysteine-34 position of circulating albumin. The albumin-doxorubicin conjugate is cleaved efficiently and specifically by MMP-2, releasing a doxorubicin tetrapeptide (Ile-Ala-Gly-Gln-DOX) and subsequently doxorubicin. pH and redox potential have also been explored as drug-release triggers at the tumor site14.

Fig. 1. Tumor-activated prodrug delivery and targeting. The anticancer agent is conjugated to a biocompatible polymer via an ester bond. The linkage is hydrolyzed by cancer-specific enzymes, or by high or low pH, at the tumor site, at which time the nanoparticle releases the drug.

Yet another passive targeting method is the direct local delivery of anticancer agents to tumors. This approach has the obvious advantage of excluding the drug from the systemic circulation. However, administration can be highly invasive, as it involves injections or surgical procedures. For some tumors that are difficult to access, such as lung cancers, the technique is nearly impossible to use.

Active targeting of mesothelioma tumors

Active targeting is usually achieved by conjugating to the nanoparticle a targeting component that provides preferential accumulation of nanoparticles in the tumor-bearing organ, in the tumor itself, individual cancer cells, intracellular organelles, or specific molecules in cancer cells. This approach is based on specific interactions such as lectin-carbohydrate, ligand-receptor, and antibody-antigen.

Lectin-carbohydrate is one of the classic examples for targeted drug delivery. Lectins are proteins of nonimmunological origin that are capable of recognizing and binding to glycoproteins expressed on cell surfaces. Lectin interactions with certain carbohydrates are very specific. Carbohydrate moieties can be used to target drug delivery systems to lectins (direct lectin targeting), and lectins can be used as targeting moieties to target cell surface carbohydrates (reverse lectin targeting). However, drug delivery systems based on lectin-carbohydrate have been developed mainly to target whole organs, which can harm normal cells. Therefore, in most cases, the targeting moiety is directed toward specific receptors or antigens expressed on the plasma membrane or elsewhere at the tumor site.

Multiple drug resistance (MDR), which is a major challenge in chemotherapy, often stems from the overexpression of the plasma membrane P-glycoprotein (Pgp). In general, Pgp acts as an efflux pump to extrude positively charged xenobiotics – including some anticancer drugs – out of the cell. Many tumor cells are resistant to doxorubicin, which is a Pgp substrate. To overcome the resistance, poly(cyanocarylate) nanoparticles have been developed. Adsorption of the nanoparticles onto the plasma membrane and the subsequent release of doxorubicin leads to saturation of Pgp. Furthermore, the negatively charged degradation products of the polymer form an ion pair and neutralize the positive charge of doxorubicin19, enhancing the diffusion of the drug across the plasma membrane. Blagosklonny proposed an approach to selectively kill resistant cancer cells that is based on a temporary increase in the resistance of sensitive cells against certain drugs by specific protectors, such as pharmacological inhibitors of apoptosis. These protectors are pumped out by MDR cells, while increasing the resistance in sensitive cells that do not have active drug efflux pumps. After applying a cytotoxic drug, sensitive cells are protected and survive the exposure, while unprotected MDR counterparts are killed. By abolishing dose-limiting side-effects of chemotherapy, this strategy might provide a means to selectively treat aggressive and resistant cancers. Tsuruo suggested that antibodies to P-glycoprotein overexpressed on multidrug resistant (MDR) cells could make an attractive targeting moiety.

The overexpression of receptors or antigens in many human cancers lends itself to efficient drug uptake via receptor-mediated endocytosis (cellular ingestion) – see Fig. 2. Since glycoproteins cannot remove polymer-drug conjugates that have entered the cells via endocytosis, this active targeting mechanism provides an alternative route for overcoming MDR.

Monday, May 25, 2009

Legal History

The first lawsuit against asbestos manufacturers was brought in 1929. The parties settled that lawsuit, and as part of the agreement, the attorneys agreed not to pursue further cases. It was not until 1960 that an article published by Wagner et al. first officially established mesothelioma as a disease arising from exposure to crocidolite asbestos.[27] The article referred to over 30 case studies of people who had suffered from mesothelioma in South Africa. Some exposures were transient and some were mine workers. In 1962 McNulty reported the first diagnosed case of malignant mesothelioma in an Australian asbestos worker.[28] The worker had worked in the mill at the asbestos mine in Wittenoom from 1948 to 1950.

In the town of Wittenoom, asbestos-containing mine waste was used to cover schoolyards and playgrounds. In 1965 an article in the British Journal of Industrial Medicine established that people who lived in the neighbourhoods of asbestos factories and mines, but did not work in them, had contracted mesothelioma.

Despite proof that the dust associated with asbestos mining and milling causes asbestos related disease, mining began at Wittenoom in 1943 and continued until 1966. In 1974 the first public warnings of the dangers of blue asbestos were published in a cover story called "Is this Killer in Your Home?" in Australia's Bulletin magazine. In 1978 the Western Australian Government decided to phase out the town of Wittenoom, following the publication of a Health Dept. booklet, "The Health Hazard at Wittenoom", containing the results of air sampling and an appraisal of worldwide medical information.

By 1979 the first writs for negligence related to Wittenoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the Wittenoom victims.

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.

[edit] Environmental exposures

Incidence of mesothelioma had been found to be higher in populations living near naturally occurring asbestos. For example, in central Cappadocia, Turkey, an unprecedented mesothelioma epidemic caused 50% of all deaths in three small villages — Tuzköy, Karain and Sarıhıdır — found that mesothelioma was causing 50% of all deaths. 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.[13][14]

[edit] Occupational

Exposure to asbestos fibres has been recognised 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.

[edit] Paraoccupational secondary exposure

Family members and others living with asbestos workers have an increased risk of developing mesothelioma, and possibly other asbestos related diseases.[citation needed] 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.

[edit] 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.

[edit] Treatment

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

[edit] 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.

[edit] 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.[15] 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.

[edit] 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.[16] 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.[17]

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.

[edit] 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.

[edit] Heated Intraoperative Intraperitoneal Chemotherapy

A procedure known as heated intraoperative intraperitoneal chemotherapy was developed by Paul Sugarbaker at the Washington Cancer Institute.[18] 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.

[edit] Notable people who died from mesothelioma

Mesothelioma, though rare, has had a number of notable patients. Hamilton Jordan, Chief of Staff for President Jimmy Carter and life long cancer activist, died in 2008. Australian anti-racism activist Bob Bellear died in 2005. British science fiction writer Michael G. Coney, responsible for nearly 100 works also died in 2005. American film and television actor Paul Gleason, perhaps best known for his portrayal of Principal Richard Vernon in the 1985 film The Breakfast Club, died in 2006. Mickie Most, an English record producer, died of mesothelioma in 2003. Paul Rudolph, an American architect known for his cubist building designs, died in 1997.

Bernie Banton was an Australian workers' rights activist, who fought a long battle for compensation from James Hardie after he contracted mesothelioma after working for that company. He claimed James Hardie knew of the dangers of asbestos before he began work with the substance making insulation for power stations. Mesothelioma eventually took his life along with his brothers and hundreds of James Hardie workers. James Hardie made an undisclosed settlement with Banton only when his mesothelioma had reached its final stages and he was expected to have no more than 48hrs to live. Australian Prime Minister Kevin Rudd mentioned Banton's extended struggle in his acceptance speech after winning the 2007 Australian Federal Election.

Steve McQueen was diagnosed with peritoneal mesothelioma on December 22, 1979. He was not offered surgery or chemotherapy because doctors felt the cancer was too advanced. McQueen sought alternative treatments from clinics in Mexico. He died of a heart attack on November 7, 1980, in Juárez, Mexico, following cancer surgery. He may have been exposed to asbestos while serving with the U.S. Marines as a young adult—asbestos was then commonly used to insulate ships' piping—or from its use as an insulating material in car racing suits.[19] (It is also reported that he worked in a shipyard during World War II, where he might have been exposed to asbestos.[citation needed])

United States Congressman Bruce Vento died of mesothelioma in 2000. The Bruce Vento Hopebuilder is awarded yearly by his wife at the MARF Symposium to persons or organizations who have done the most to support mesothelioma research and advocacy.

After a long period of untreated illness and pain, rock and roll musician and songwriter Warren Zevon was diagnosed with inoperable mesothelioma in the fall of 2002. Refusing treatments he believed might incapacitate him, Zevon focused his energies on recording his final album The Wind including the song "Keep Me in Your Heart," which speaks of his failing breath. Zevon died at his home in Los Angeles, California, on September 7, 2003.

Christie Hennessy, the influential Irish singer-songwriter, died of mesothelioma in 2007, and had stridently refused to accept the prognosis in the weeks before his death.[20] His mesothelioma has been attributed to his younger years spent working on building sites in London.[21][22]

Bob Miner, one of the founders of Software Development Labs, the forerunner of Oracle Corporation died of mesothelioma in 1994.

Scottish Labour MP John William MacDougall died of mesothelioma on August 13, 2008, after fighting the disease for two years.[23]

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

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

[edit] Notable people who have lived for some time with mesothelioma

Although life expectancy with this disease is typically limited, there are notable survivors. In July 1982, Stephen Jay Gould was diagnosed with peritoneal mesothelioma. After his diagnosis, Gould wrote the "The Median Isn't the Message"[24] for Discover magazine, in which he argued that statistics such as median survival are just useful abstractions, not destiny. Gould lived for another twenty years eventually succumbing to metastatic adenocarcinoma of the lung, not mesothelioma.

Author Paul Kraus was diagnosed with mesothelioma in June 1997 following an umbilical hernia operation. His prognosis was "a few months." He continues to survive using a variety of integrative and complementary modalities and has written a book about his experience.

[edit] Legal issues

The first lawsuits against asbestos manufacturers were in 1929. Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898). Today, you may see a commercial stating something like, "Mesothelioma is a rare type of cancer caused by asbestos particles. Asbestos particles can be found in lumberyards, shipyards or any of the heating or automotive industries." The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars.[25] The amounts and method of allocating compensation have been the source of many court cases, reaching up to the United States Supreme Court, and government attempts at resolution of existing and future cases. However, to date, Congress has failed to enact significant asbestos reforms.[26]

Diagnosis

Diagnosing mesothelioma is often difficult, because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient's medical history. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytology if this fluid is aspirated with a syringe. For pleural fluid this is done by a pleural tap or chest drain, in ascites with an paracentesis or ascitic drain and in a pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure).

If cytology is positive or a plaque is regarded as suspicious, a biopsy is needed to confirm a diagnosis of mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples.

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

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

[edit] Screening

There is no universally agreed protocol for screening people who have been exposed to asbestos. Screening tests might diagnose mesothelioma earlier than conventional methods thus improving the survival prospects for patients. The serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma. The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening.[4] Doctors have begun testing the Mesomark assay which measures levels of soluble mesothelin-related proteins (SMRPs) released by diseased mesothelioma cells.[5]

[edit] Staging

Mesothelioma is described as localized if the cancer is found only on the membrane surface where it originated. It is classified as early (stages I or II) if localized to a single organ surface, usually the lining of the lungs or kidney. Advanced classification is defined (stages III or IV) if it has spread beyond the original membrane surface to other parts of the body.

[edit] Pathophysiology

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

Pleural contamination with asbestos or other mineral fibres has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers).[6] However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System. Dr. Fein has treated several patients for "World Trade Center syndrome" or respiratory ailments from brief exposures of only a day or two near the collapsed buildings.[7]

Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibres. It has been suggested that in humans, transport of fibres to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localised lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumour.

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

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

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

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.

[edit] Epidemiology

[edit] Incidence

Although reported incidence rates have increased in the past 20 years, mesothelioma is still a relatively rare cancer. The incidence rate is approximately one per 1,000,000. The highest incidence is found in Britain, Australia and Belgium: 30 per 1,000,000 per year.[8] 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.[9] 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.[10] 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.

[edit] Risk factors

Working with asbestos is the major risk factor for mesothelioma.[11] A history of asbestos exposure exists in almost all cases. However, mesothelioma has been reported in some individuals without any known exposure to asbestos. In rare cases, mesothelioma has also been associated with irradiation, intrapleural thorium dioxide (Thorotrast), and inhalation of other fibrous silicates, such as erionite.

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

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

Some studies suggest that simian virus 40 (SV40) may act as a cofactor in the development of mesothelioma.[12]

[edit] Exposure