Cancer

Cancer is a disease characterized by a population of cells that grow and divide without respect to normal limits, invade and destroy adjacent tissues, and may spread to distant anatomic sites through a process called metastasis. These malignant properties of cancers differentiate them from benign tumors, which are self-limited in their growth and do not invade or metastasize (although some benign tumor types are capable of becoming malignant). Cancer may affect people at all ages, but risk for the more common varieties tends to increase with age.[1] Cancer causes about 13% of all deaths.[2]

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. Complex interactions between carcinogens and the host genome may explain why only some develop cancer after exposure to a known carcinogen. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly being recognized as important.

Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are often activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are often inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Cancer is usually classified according to the tissue from which the cancerous cells originate, as well as the normal cell type they most resemble. These are location and histology, respectively. A definitive diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.

Nomenclature
The following closely related terms may be used to designate abnormal growths:

Neoplasm: a scientific term which refers to an abnormal proliferation of genetically altered cells.
Malignant neoplasm: synonymous with cancer.
Tumor: broadly defined, can be any swelling or mass. However, the vast majority of entities referred to as 'tumors' in common usage are in fact neoplasms. Specifically, a tumor is a solid neoplasm; some neoplasms, such as cancers of the blood, are not solid.
Benign tumor: a tumor (solid neoplasm) that has self-limiting growth and does not invade other tissues nor metastasize. Usually not cancerous.
Pre-malignancy: A non-invasive neoplasm that may not form an obvious mass, but has the potential to progress to cancer if left untreated. Pre-malignant neoplasms may show distinctive microscopic changes such as dysplasia or atypia.
Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. Examples of general categories include:

Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
Lymphoma and leukemia: Malignancies derived from hematopoetic (blood-forming) cells
Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).
Blastic tumor: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.
Malignant tumors are usually named using the Latin or Greek root of the organ of origin as a prefix and the above category name as the suffix. For instance, a malignant tumor of the liver is called hepatocarcinoma; a malignant tumor of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.

Benign tumors are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). However, some cancers also use this prefix for historical reasons, examples being melanoma and seminoma.


Adult cancers
In the U.S. and other developed countries, cancer is presently responsible for about 25% of all deaths.[3] On a yearly basis, 0.5% of the population is diagnosed with cancer. The statistics below are for adults in the United States, and will vary substantially in other countries:

Male Female
most common cause of death[3] most common cause of death[3]
prostate cancer (33%) lung cancer (31%) breast cancer (32%) lung cancer (27%)
lung cancer (13%) prostate cancer (10%) lung cancer (12%) breast cancer (15%)
colorectal cancer (10%) colorectal cancer (10%) colorectal cancer (11%) colorectal cancer (10%)
bladder cancer (7%) pancreatic cancer (5%) endometrial cancer (6%) ovarian cancer (6%)
cutaneous melanoma (5%) leukemia (4%) non-Hodgkin lymphoma (4%) pancreatic cancer (6%)


Childhood cancers
Cancer can also occur in young children and adolescents, but it is rare. Some studies have concluded that pediatric cancers, especially leukemia, are on an upward trend.[4][5]

The age of peak incidence of cancer in children occurs during the first year of life. Leukemia (usually ALL) is the most common infant malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms' tumor, lymphomas, rhabdomyosarcoma (arising from muscle), retinoblastoma, osteosarcoma and Ewing's sarcoma.[3] Teratoma is the most common tumor in this age group, but most teratomas are surgically removed while they are still benign.

Female and male infants have essentially the same overall cancer incidence rates, but white infants have substantially higher cancer rates than black infants for most cancer types. Relative survival for infants is very good for neuroblastoma, Wilms' tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.


Signs and symptoms
Roughly, cancer symptoms can be divided into three groups:

Local symptoms: unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice.
Symptoms of metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.
Systemic symptoms: weight loss, poor appetite and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.
Every symptom in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.


Diagnosis
Most cancers are initially recognized either because signs or symptoms appear or through screening. Neither of these lead to a definitive diagnosis, which usually requires the opinion of a pathologist.


Investigation

Chest x-ray showing lung cancer in the left lung.People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.


Biopsy
A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must be confirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained from a biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctor's office. Biopsies of other organs are performed under anesthesia and require surgery in an operating room.

The tissue diagnosis indicates the type of cell that is proliferating, its histological grade and other features of the tumor. Together, this information is useful to evaluate the prognosis of this patient and choose the best treatment. Cytogenetics and immunohistochemistry may provide information about future behavior of the cancer (prognosis) and best treatment.


Treatment
Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development.

Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.

Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases.


Surgery
In theory, cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.

Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.

In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy.

Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.


Radiation therapy
Main article: Radiation therapy
Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.

Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.


Chemotherapy
Main article: Chemotherapy
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.

Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.

The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation. Alternatively, hematopoeitic stem cells may be transplanted from a matched unrelated donor (MUD).


Targeted therapies
Main article: Targeted therapy
Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib and gefitinib.

Monoclonal antibody therapy is another strategy in which the theraputic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin®) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.

Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to this peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.


Immunotherapy
Main article: Cancer immunotherapy
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells.

Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation" from a genetically non-identical donor) can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.


Hormonal therapy
Main article: Hormonal therapy (oncology)
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.


Symptom control
Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. Although all practicing doctors have the therapeutic skills to control pain, nausea, vomiting, diarrhea, hemorrhage and other common problems in cancer patients, the multidisciplinary specialty of palliative care has arisen specifically in response to the symptom control needs of this group of patients.

Pain medication, such as morphine and oxycodone, and antiemetics, drugs to suppress nausea and vomiting, are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.

Chronic pain due to cancer is almost always associated with continuing tissue damage due to the disease process or the treatment (i.e. surgery, radiation, chemotherapy). Although there is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, these are not usually the predominant etiologic factors in patients with cancer pain. Furthermore, many patients with severe pain associated with cancer are nearing the end of their lives and palliative therapies are required. Issues such as social stigma of using opioids, work and functional status, and health care consumption are not likely to be important in the overall case management. Hence, the typical strategy for cancer pain management is to get the patient as comfortable as possible using opioids and other medications, surgery, and physical measures. Doctors have been reluctant to prescribe narcotics for pain in terminal cancer patients, for fear of contributing to addiction or suppressing respiratory function. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients.


Complementary and alternative
Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine. Oncology, the study of human cancer, has a long history of incorporating unconventional or botanical treatments into mainstream cancer therapy. Some examples of this phenomenon include the chemotherapy agent paclitaxel, which is derived from the bark of the Pacific Yew tree, and ATRA, all-trans retinoic acid, a derivative of Vitamin A that induces cures in an aggressive leukemia known as acute promyelocytic leukemia. Many "complementary" and "alternative" medicines for cancer have not been studied using the scientific method, such as in well-designed clinical trials, or they have only been studied in preclinical (animal or in-vitro) laboratory studies. Many times, "complementary" and "alternative" medicines are supported by marketing materials and "testimonials" from users of the substances. Frequently, when these treatments are subjected to rigorous scientific testing, they are found not to work. A recent example was reported at the 2007 annual meeting of the American Society of Clinial Oncology: a Phase III clinical trial comparing shark cartilage extract to placebo in non-small cell lung cancer demonstrated no benefit of the shark cartilage extract, AE-491. [6]

"Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine. A study of CAM use in patients with cancer in the July 2000 issue of the Journal of Clinical Oncology found that 69 percent of 453 cancer patients had used at least one CAM therapy as part of their cancer treatment.[7]

Some complementary measures include botanical medicine, such as an NIH trial currently underway testing mistletoe extract combined with chemotherapy for the treatment of solid tumors, acupuncture for managing chemotherapy-associated nausea and vomiting and in controlling pain associated with surgery, psychological approaches such as "imaging" or meditation to aid in pain relief or improve mood.[7]

A wide range of alternative treatments have been offered for cancer over the last century. The appeal of alternative cures arises from the daunting risks, costs, or potential side effects of many conventional treatments, or in the limited prospect for cure. No alternative therapies have been shown in any scientific study to effectively treat cancer.


Treatment trials
Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.

A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.

Patients who take part may be helped personally by the treatment(s) they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. Of course, there is no guarantee that a new treatment being tested or a standard treatment will produce good results. New treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit.


Prognosis
Cancer has a reputation for being a deadly disease. While this certainly applies to certain particular types, the truths behind the historical connotations of cancer are increasingly being overturned by advances in medical care. Some types of cancer have a prognosis that is substantially better than nonmalignant diseases such as heart failure and stroke.

Progressive and disseminated malignant disease has a substantial impact on a cancer patient's quality of life, and many cancer treatments (such as chemotherapy) may have severe side-effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care solutions may include permanent or "respite" hospice nursing.

Cancer patients, for the first time in the history of oncology, are visibly returning to the athletic arena and workplace. Patients are living longer with either quiescent persistent disease or even complete, durable remissions. The stories of Lance Armstrong, who won the Tour de France after treatment for metastatic testicular cancer, or Tony Snow, who was working as the White House Press Secretary as of June, 2007 despite relapsed colon cancer, continue to be an inspiration to cancer patients everywhere.


Emotional impact
Many local organizations offer a variety of practical and support services to people with cancer. Support can take the form of support groups, counseling, advice, financial assistance, transportation to and from treatment, films or information about cancer. Neighborhood organizations, local health care providers, or area hospitals may have resources or services available.

While some people are reluctant to seek counseling, studies show that having someone to talk to reduces stress and helps people both mentally and physically. Counseling can also provide emotional support to cancer patients and help them better understand their illness. Different types of counseling include individual, group, family, self-help (sometimes called peer counseling), bereavement, patient-to-patient, and sexuality.

Many governmental and charitable organizations have been established to help patients cope with cancer. These organizations often are involved in cancer prevention, cancer treatment, and cancer research. Examples include: American Cancer Society, National Comprehensive Cancer Network, Lance Armstrong Foundation, BC Cancer Agency, Macmillan Cancer Relief , the Terry Fox Foundation, Cancer Research UK, Cancer Research Foundation, Canadian Cancer Society, International Agency for Research on Cancer, The Cancer Council Australia and the National Cancer Institute (US).


Causes
Main article: Carcinogenesis
Cancer is a diverse class of diseases which differ widely in their causes and biology. The common thread in all known cancers is the acquisition of abnormalities in the genetic material of the cancer cell and its progeny. Research into the pathogenesis of cancer can be divided into three broad areas of focus. The first area of research focuses on the agents and events which cause or facilitate genetic changes in cells destined to become cancer. Second, it is important to uncover the precise nature of the genetic damage, and the genes which are affected by it. The third focus is on the consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events, leading to further progression of the cancer.


Chemical carcinogens
Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer and bladder cancer. Prolonged exposure to asbestos fibers is associated with mesothelioma.

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagens. Such chemicals are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes (see aneuploidy above).


The incidence of lung cancer is highly correlated with smoking. Source:NIH.Decades of research have demonstrated the strong association between tobacco use and cancers of many sites, making it perhaps the most important human carcinogen. Hundreds of epidemiological studies have confirmed this association. Further support comes from the fact that lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men.


Ionizing radiation
Sources of ionizing radiation, such as radon gas, can cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.


Infectious diseases
Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage.[8] The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming viruses, which already carry the viral oncogene.

Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.

Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the US FDA approved a human papilloma virus vaccine, called Gardasil®. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US CDC Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11-12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.

In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer.[9]


Hormonal imbalances
Some hormones can act in a similar manner to non-mutagenic carcinogens in that they may stimulate excessive cell growth. A well-established example is the role of hyperestrogenic states in promoting endometrial cancer.


Immune system dysfunction
HIV is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer. AIDS-defining illnesses have long included these diagnoses. The increased incidence of malignancies in HIV patients points to the breakdown of immune surveillance as a possible etiology of cancer.[10] Certain other immune deficiency states (e.g. common variable immunodeficiency and IgA deficiency) are also associated with increased risk of malignancy.[11]


Heredity
Most forms of cancer are "sporadic", and have no basis in heredity. There are, however, a number of recognised syndromes of cancer with a hereditary component, often a defective tumor suppressor allele. Famous examples are:

certain inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft-tissue sarcoma, brain tumors) due to mutations of p53
Turcot syndrome (brain tumors and colonic polyposis)
Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
Hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
Retinoblastoma, when occurring in young children, is due to a hereditary mutation in the retinoblastoma gene.
Down syndrome patients, who have an extra chromosome 21, are known to develop malignancies such as leukemia and testicular cancer, though the reasons for this difference are not well understood.

Other causes
A few types of cancer in non-humans have been found to be caused by the tumor cells themselves. This phenomenon is seen in Sticker's sarcoma, also known as canine transmissible venereal tumor.[12] The closest known analogue to this in humans is individuals who have developed cancer from tumors hiding inside organ transplants.


Pathophysiology

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to tranform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.

There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. Aneuploidy, the presence of an abnormal number of chromomes, is one genomic change which is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Epigenetic changes are changes which do not affect chromosomal number or DNA sequence, but which can be passed on through generations of cell division, and thus may play a role in cancer. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations.


Oncogenes
Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to effect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.

One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.[13] Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.[14]


Tumor suppressor genes
Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor gene, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.

The Warburg effect is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway. [15]

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.[16]

Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.[17]


Cancer cell biology

Tissue can be organized in a continuous spectrum from normal to cancer.Often, the multiple genetic changes which result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimuli, such as a hormonal imbalance or chronic irritation.

The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.


Clonal evolution
The process of malignancy can be explained from an evolutionary perspective. Millions of years of biological evolution insure that the cellular metabolic changes that enable cancer to grow occur only very rarely. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. Cancer cells undergo a process analogous to natural selection, in that the few cells with new genetic changes that enhance their survival continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are outcompeted. This process is called clonal evolution. Tumors often continue to evolve in response to chemotherapy treatments, and on occasion aberrant cells may acquire resistance to particular anti-cancer pharmaceuticals.


Biological properties of cancer cells
Malignant tumor cells acquire distinct biological properties:

evading apoptosis
unlimited growth potential (immortalitization) due to overabundance of telomerase
self-sufficiency of growth factors
insensitivity to anti-growth factors
increased cell division rate
altered ability to differentiate
no ability for contact inhibition
ability to invade neighbouring tissues
ability to build metastases at distant sites
ability to promote blood vessel growth (angiogenesis)

Prevention
Cancer prevention is defined as active measures to decrease the incidence of cancer. This can be accomplished by avoiding carcinogens or altering their metabolism, pursuing a lifestyle or diet that modifies cancer-causing factors and/or medical intervention (chemoprevention, treatment of pre-malignant lesions). The epidemiological concept of "prevention" is usually defined as either primary prevention, for people who have not been diagnosed with a particular disease, or secondary prevention, aimed at reducing recurrence or complications of a previously diagnosed illness.

Observational epidemiological studies that show associations between risk factors and specific cancers mostly serve to generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials then test whether hypotheses generated by epidemiological trials and laboratory research actually result in reduced cancer incidence and mortality. In many cases, findings from observational epidemiological studies are not confirmed by randomized controlled trials.


Modifiable ("lifestyle") risk factors
Examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (although 20% of women with lung cancer have never smoked, versus 10% of men[18]), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption may contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexually transmitted diseases, the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures.

See alcohol and cancer for more on that topic.


Diet
The consensus on diet and cancer is that obesity increases the risk of developing cancer. Particular dietary practices often explain differences in cancer incidence in different countries (e.g. gastric cancer is more common in Japan, while colon cancer is more common in the United States). Studies have shown that immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.[19] Whether reductions obesity in a population also reduces cancer incidence is unknown.

Despite frequent reports of particular substances (including foods) having a beneficial or detrimental effect on cancer risk, few of these have an established link to cancer. These reports are often based on studies in cultured cell media or animals. Public health recommendations cannot be made on the basis of these studies until they have been validated in an observational (or occasionally a prospective interventional) trial in humans.

Proposed dietary interventions for primary cancer risk reduction generally gain support from epidemiological association studies. Examples of such studies include reports that reduced meat consumption is associated with decreased risk of colon cancer,[20] and reports that consumption of coffee is associated with a reduced risk of liver cancer.[21] Studies have linked consumption of grilled meat to an increased risk of stomach cancer,[22], colon cancer,[23] breast cancer [24] , and pancreatic cancer, [25] a phenomenon which could be due to the presence of carcinogens such as benzopyrene in foods cooked at high temperatures.

A 2005 secondary prevention study showed that consumption of a plant-based diet and lifestyle changes resulted in a reduction in cancer markers in a group of men with prostate cancer who were using no conventional treatments at the time.[26] These results were amplified by a 2006 study in which over 2,400 women were studied, half randomly assigned to a normal diet, the other half assigned to a diet containing less than 20% calories from fat. The women on the low fat diet were found to have a markedly lower risk of breast cancer recurrence, in the interim report of December, 2006[27].


Vitamins
The concept that cancer can be prevented through vitamin supplementation stems from early observations correlating human disease with vitamin deficiency, such as pernicious anemia with vitamin B12 deficiency, and scurvy with Vitamin C deficiency. This has largely not been proven to be the case with cancer, and vitamin supplementation is largely not proving effective in preventing cancer. The cancer-fighting components of food are also proving to be more numerous and varied than previously understood, so patients are increasingly being advised to consume fresh, unprocessed fruits and vegetables for maximal health benefits.[28]

The Canadian Cancer Society has advised Canadians that the intake of vitamin D has shown a reduction of cancers by close to 60%,[29], and at least one study has shown a specific benefit for this vitamin in preventing colon cancer.[30]

Vitamin D and its protective effect against cancer has been contrasted with the risk of malignancy from sun exposure. Since exposure to the sun enhances natural human production of Vitamin D, some cancer researchers have argued that the potential deleterious malignant effects of sun exposure are far outweighed by the cancer-preventing effects of extra Vitamin D synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that 23,800 premature cancer deaths occur in the US annually due to insufficient UVB exposure (apparently via vitamin D deficiency).[31] This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun exposure might be beneficial. Another research group[32][33] estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.

The case of beta-carotene provides an example of the importance of randomized clinical trials. Epidemiologists studying both diet and serum levels observed that high levels of beta-carotene, a precursor to vitamin A, were associated with a protective effect, reducing the risk of cancer. This effect was particularly strong in lung cancer. This hypothesis led to a series of large randomized clinical trials conducted in both Finland and the United States (CARET study) during the 1980s and 1990s. This study provided about 80,000 smokers or former smokers with daily supplements of beta-carotene or placebos. Contrary to expectation, these tests found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality. In fact, the risk of lung cancer was slightly, but not significantly, increased by beta-carotene, leading to an early termination of the study.[34]

Results reported in JAMA in 2007 indicate that folic acid supplementation is not effective in preventing colon cancer, and folate consumers may be more likely to form colon polyps.[35]


Chemoprevention
The concept that medications could be used to prevent cancer is an attractive one, and many high-quality clinical trials support the use of such chemoprevention in defined circumstances.

Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. A recent study reported that the selective estrogen receptor modulator raloxifene has similar benefits to tamoxifen in preventing breast cancer in high-risk women, with a more favorable side effect profile.[36]

Raloxifene is a SERM like tamoxifen; it has been shown (in the STAR trial) to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. In this trial, which studied almost 20,000 women, raloxifene had fewer side effects than tamoxifen, though it did permit more DCIS to form.[36]

Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors.[37] The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients[38] and in the general population.[39][40] In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.


Genetic testing
Genetic testing for high-risk individuals is already available for certain cancer-related genetic mutations. Carriers of genetic mutations that increase risk for cancer incidence can undergo enhanced surveillance, chemoprevention, or risk-reducing surgery. Early identification of inherited genetic risk for cancer, along with cancer-preventing interventions such as surgery or enhanced surveillance, can be lifesaving for high-risk individuals.

Gene Cancer types Availability
BRCA1, BRCA2 Breast, ovarian, pancreatic Commercially available for clinical specimens
MLH1, MSH2, MSH6, PMS1, PMS2 Colon, uterine, small bowel, stomach, urinary tract Commercially available for clinical specimens


Vaccination
Considerable research effort is now devoted to the development of vaccines to prevent infection by oncogenic infectious agents, as well as to mount an immune response against cancer-specific epitopes) and to potential venues for gene therapy for individuals with genetic mutations or polymorphisms that put them at high risk of cancer.

As reported above, a preventive human papillomavirus vaccine exists that targets certain sexually transmitted strains of human papillomavirus that are associated with the development of cervical cancer and genital warts. The only two HPV vaccines currently on the market are Gardasil and Cervarix.


Screening
Cancer screening is an attempt to detect unsuspected cancers in an asymptomatic population. Screening tests suitable for large numbers of healthy people must be relatively affordable, safe, noninvasive procedures with acceptably low rates of false positive results. If signs of cancer are detected, more definitive and invasive follow up tests are performed to confirm the diagnosis.

Screening for cancer can lead to earlier diagnosis in specific cases. Early diagnosis may lead to extended life, but may also falsely prolong the lead time to death through lead time bias or length time bias.

A number of different screening tests have been developed for different malignancies. Breast cancer screening can be done by breast self-examination, though this approach was discredited by a 2005 study in over 300,000 Chinese women. Screening for breast cancer with mammograms has been shown to reduce the average stage of diagnosis of breast cancer in a population. Stage of diagnosis in a country has been shown to decrease within ten years of introduction of mammographic screening programs. Colorectal cancer can be detected through fecal occult blood testing and colonoscopy, which reduces both colon cancer incidence and mortality, presumably through the detection and removal of pre-malignant polyps. Similarly, cervical cytology testing (using the Pap smear) leads to the identification and excision of precancerous lesions. Over time, such testing has been followed by a dramatic reduction of cervical cancer incidence and mortality. Testicular self-examination is recommended for men beginning at the age of 15 years to detect testicular cancer. Prostate cancer can be screened using a digital rectal exam along with prostate specific antigen (PSA) blood testing, though some authorities (such as the US Preventive Services Task Force) recommend against routinely screening all men.

Screening for cancer is controversial in cases when it is not yet known if the test actually saves lives. The controversy arises when it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example: when screening for prostate cancer, the PSA test may detect small cancers that would never become life threatening, but once detected will lead to treatment. This situation, called overdiagnosis, puts men at risk for complications from unnecessary treatment such as surgery or radiation. Follow up procedures used to diagnose prostate cancer (prostate biopsy) may cause side effects, including bleeding and infection. Prostate cancer treatment may cause incontinence (inability to control urine flow) and erectile dysfunction (erections inadequate for intercourse). Similarly, for breast cancer, there have recently been criticisms that breast screening programs in some countries cause more problems than they solve. This is because screening of women in the general population will result in a large number of women with false positive results which require extensive follow-up investigations to exclude cancer, leading to having a high number-to-treat (or number-to-screen) to prevent or catch a single case of breast cancer early.

Cervical cancer screening via the Pap smear has the best cost-benefit profile of all the forms of cancer screening from a public health perspective as, being largely caused by a virus, it has clear risk factors (sexual contact), and the natural progression of cervical cancer is that it normally spreads slowly over a number of years therefore giving more time for the screening program to catch it early. Moreover, the test itself is easy to perform and relatively cheap.

For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake cancer screening.

Use of medical imaging to search for cancer in people without clear symptoms is similarly marred with problems. There is a significant risk of detection of what has been recently called an incidentaloma - a benign lesion that may be interpreted as a malignancy and be subjected to potentially dangerous investigations. Recent studies of CT scan-based screening for lung cancer in smokers have had equivocal results, and systematic screening is not recommended as of July 2007. Randomized clinical trials of plain-film chest xrays to screen for lung cancer in smokers have shown no benefit for this approach.

Canine cancer detection has shown promise, but is still in the early stages of research.


Epidemiology

The risk of cancer rises with ageCancer epidemiology is the study of the incidence of cancer as a way to infer possible trends and causes. The first such cause of cancer was identified by British surgeon Percivall Pott, who discovered in 1775 that cancer of the scrotum was a common disease among chimney sweeps. The work of other individual physicians led to various insights, but when physicians started working together they could make firmer conclusions.

A founding paper of this discipline was the work of Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health. Her ground-breaking work on cancer epidemiology was carried on by Richard Doll and Austin Bradford Hill, who published "Lung Cancer and Other Causes of Death In Relation to Smoking. A Second Report on the Mortality of British Doctors" followed in 1956 (otherwise known as the British doctors study). Richard Doll left the London Medical Research Center (MRC), to start the Oxford unit for Cancer epidemiology in 1968. With the use of computers, the unit was the first to compile large amounts of cancer data. Modern epidemiological methods are closely linked to current concepts of disease and public health policy. Over the past 50 years, great efforts have been spent on gathering data across medical practise, hospital, provincial, state, and even country boundaries, as a way to study the interdependence of environmental and cultural factors on cancer incidence.

The biggest problem facing cancer epidemiology today is the changing concept of "cancer incidence". For example, a breast cancer tumor with a very slow growth rate may be found with a mammogram at 50 years, while the same tumor may have been found as a noteworthy 'lump' at 70 years, depending on the specific growth factors affecting that particular patient's case. As diagnostic tools improve, this has a direct impact on the epidemiological data.

In some Western countries, such as the USA,[3] and the UK[41] cancer is overtaking cardiovascular disease as the leading cause of death. In many Third World countries cancer incidence (insofar as this can be measured) appears much lower, most likely because of the higher death rates due to infectious disease or injury. With the increased control over malaria and tuberculosis in some Third World countries, incidence of cancer is expected to rise; this is termed the epidemiologic transition in epidemiological terminology.

Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighboring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various Third World countries, lung cancer incidence has increased in a parallel fashion.


History
Today, the Greek term carcinoma is the medical term for a malignant tumor derived from epithelial cells. It is Celsus who translated carcinos into the Latin cancer, also meaning crab. Galen used "oncos" to describe all tumours, the root for the modern word oncology.[42]


Breast cancer in a mastectomy specimen (top). The cancerous tumour (pale yellow) resembles the figure of a crab, giving the disease its name.Hippocrates described several kinds of cancers. He called benign tumours oncos, Greek for swelling, and malignant tumours carcinos, Greek for crab or crayfish. This name probably comes from the appearance of the cut surface of a solid malignant tumour, with a roundish hard center surrounded by pointy projections, vaguely resembling the shape of a crab (see photo). He later added the suffix -oma, Greek for swelling, giving the name carcinoma. Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient's humor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but humor-theory based treatment remained popular until the 19th century with the discovery of cells.

Though treatment remained the same, in the 16th and 17th centuries it became more acceptable for doctors to dissect bodies to discover the cause of death. The German professor Wilhelm Fabry believed that breast cancer was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a follower of Descartes, believed that all disease was the outcome of chemical processes, and that acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer was a poison that slowly spreads, and concluded that it was contagious.[43]

With the widespread use of the microscope in the 18th century, it was discovered that the 'cancer poison' spread from the primary tumor through the lymph nodes to other sites ("metastasis"). This view of the disease was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874 [44]. The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro saw only 2 breast tumor patients out of 60 surviving surgery for two years. In the 19th century, asepsis improved surgical hygiene and as the survival statistics went up, surgical removal of the tumor became the primary treatment for cancer. With the exception of William Coley who in the late 1800s felt that the rate of cure after surgery had been higher before asepsis (and who injected bacteria into tumors with mixed results), cancer treatment became dependent on the individual art of the surgeon at removing a tumor. During the same period, the idea that the body was made up of various tissues, that in turn were made up of millions of cells, laid rest the humor-theories about chemical imbalances in the body. The age of cellular pathology was born.

When Marie Curie and Pierre Curie discovered radiation at the end of the 19th century, they stumbled upon the first effective non-surgical cancer treatment. With radiation came also the first signs of multi-disciplinary approaches to cancer treatment. The surgeon was no longer operating in isolation, but worked together with hospital radiologists to help patients. The complications in communication this brought, along with the necessity of the patient's treatment in a hospital facility rather than at home, also created a parallel process of compiling patient data into hospital files, which in turn led to the first statistical patient studies.

Cancer patient treatment and studies were restricted to individual physicians' practices until World War II, when medical research centers discovered that there were large international differences in disease incidence. This insight drove national public health bodies to make it possible to compile health data across practises and hospitals, a process that many countries do today. The Japanese medical community observed that the bone marrow of bomb victims in Hiroshima and Nagasaki was completely destroyed. They concluded that diseased bone marrow could also be destroyed with radiation, and this led to the discovery of bone marrow transplants for leukemia. Since WWII, trends in cancer treatment are to improve on a micro-level the existing treatment methods, standardize them, and globalize them as a way to find cures through epidemiology and international partnerships.

Mesothelioma

Mesothelioma is a form of cancer that is almost always caused by previous exposure to asbestos. In this disease, malignant cells develop in the mesothelium, a protective lining that covers most of the body's internal organs. Its most common site is the pleura (outer lining of the lungs and chest cavity), but it may also occur in the peritoneum (the lining of the abdominal cavity) or the pericardium (a sac that surrounds the heart).

Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or have been exposed to asbestos dust and fibre in other ways, such as by washing the clothes of a family member who worked with asbestos, or by home renovation using asbestos cement products. Unlike lung cancer, there is no association between mesothelioma and smoking

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

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

These symptoms may be caused by mesothelioma or by other, less serious conditions.

Mesothelioma that affects the pleura can cause these signs and symptoms:

chest wall pain
pleural effusion, or fluid surrounding the lung
shortness of breath
fatigue or anemia
wheezing, hoarseness, or cough
blood in the sputum (fluid) coughed up
In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread, to other parts of the body.

Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:

abdominal pain
ascites, or an abnormal buildup of fluid in the abdomen
a mass in the abdomen
problems with bowel function
weight loss
In severe cases of the disease, the following signs and symptoms may be present:

blood clots in the veins, which may cause thrombophlebitis
disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs
jaundice, or yellowing of the eyes and skin
low blood sugar level
pleural effusion
pulmonary emboli, or blood clots in the arteries of the lungs
severe ascites
A mesothelioma does not usually spread to the bone, brain, or adrenal glands. Pleural tumors are usually found only on one side of the lungs.


[edit] 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 opening 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. However some research indicates that 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.[3]


[edit] Staging
Mesothelioma is described as localized if the cancer is found only on the membrane surface where it originated. It is classified as advanced if it has spread beyond the original membrane surface to other parts of the body, such as the lymph nodes, lungs, chest wall, or abdominal organs.


[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).[4] However, there is now evidence that smaller particles may be more dangerous than the larger fibers.[1][2] 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.[3]

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:

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 fibres 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 is approximately one per 1,000,000. 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.[5] 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 [4]. 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. 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.[6]


[edit] 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.

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.

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.

Environmental Exposure

Incidence of mesothelioma had been found to be higher in populations living near Naturally Occuring Asbestos (NOA)


[edit] Treatment
Treatment of MM using conventional therapies has not proved successful and patients have a median survival time of 6 - 12 months after presentation. The clinical behaviour of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favours 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, either by itself or used in combination with pre- and post-operative adjuvant therapies has proved disappointing. 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. It is not possible to remove the entire mesothelium without killing the patient.


[edit] Radiation
Wikibooks has a book on the topic of
Radiation Oncology/Lung/MesotheliomaFor 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. [7] 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
In February 2004, the United States Food and Drug Administration approved pemetrexed (brand name Alimta) for treatment of malignant pleural mesothelioma. Pemetrexed is given in combination with cisplatin. Folic acid is also used to reduce the side-effects of pemetrexed.


[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.[7] 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] Prevention & Expectations
What can be done to prevent the disease? Since the 1970s, the Environmental Protection Agency and the Occupational Safety and Health Administration have regulated the asbestos industry in the U.S. In the past, asbestos was used as a fire retardant and an insulator. Other products are now used in its place. The controversy involving exposure to different forms of asbestos continues.

There are two major types of asbestos: chrysotile and amphibole. It is thought that exposure to the amphibole form is more likely to cause mesothelioma. However, chrysotile has been used more frequently, hence many mesotheliomas are caused by chrysotile.

Removal is taking place in schools and other public buildings throughout the U.S. The hope is that these measures will greatly reduce the occurrence of this cancer.

What are the long-term effects of the disease? A mesothelioma is a highly aggressive tumor that is generally deadly. Current treatment of malignant mesothelioma is designed to make the person with cancer comfortable. Although long-term survival cannot usually be expected, the case of famed paleontologist Stephen Jay Gould is a noted exception.

What are the risks to others? Mesothelioma is not contagious and cannot be passed from one person to another. The exposure to the asbestos that caused the cancer occurred many years to several decades before the disease appeared. People who live with asbestos workers have a higher risk of getting this cancer.


[edit] Notable people with mesothelioma
Mesothelioma, though rare, has had a number of notable patients. 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.

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 US Marines as a young adult—asbestos was then commonly used to insulate ships' piping—or because of its use as an insulating material in car racing suits.[8] (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.

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"[9] 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 complimentary modalities and has written a book about his experience.


[edit] Legal issues
Main article: asbestos and the law
The first lawsuits against asbestos manufacturers were in 1929. Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898). The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars. The amounts and method of allocating compensation have been the source of many court cases, and government attempts at resolution of existing and future cases.


[edit] 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.[10] 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.[11] 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.