What Screening Tests Are Available For Colon Cancer?

Screening for colorectal cancer involves special tests performed on people who have no symptoms of a particular illness.

Good screening tests are:

• Safe
• Relatively inexpensive
• Proven effective in detecting the disease at an early stage and reducing the death rate from that disease

Current screening tests for colorectal cancer meet these four requirements and include:

• Digital rectal exam
• Fecal occult blood test (FOBT)
• Flexible sigmoidoscopy
• Colonoscopy

Digital Rectal Exam

During a digital rectal examination (DRE) the doctor inserts a gloved, lubricated finger into the rectum to check for abnormalities. This is a routine part of a physical examination and commonly used to screen for colorectal cancer.

This test is effective in detecting rectal cancer; however, doctors are able to detect only 7 to 10 percent of colorectal cancers since most of the colon cannot be felt by the examiner's finger. The goal of colorectal cancer screening is to detect the cancer before it grows large enough to be felt during such an exam.

By itself, the digital rectal exam is not considered an ideal screening test for colorectal cancer, but rather is used along with other screening tests.

Fecal Occult Blood Test (FOBT)

The fecal occult blood test (FOBT), also called the stool blood test or the guaiac test, is used to detect tiny amounts of blood in a stool sample. This test detects small amounts of blood in the stool that would not be visible.

Stool samples are smeared onto special cards and dropped off at the doctor's office or a laboratory. This is done because tumors may bleed on one day and not the next; therefore, blood may be present in stool on one day and not the next. When colorectal cancer is present, the blood may be dark, or mixed with stool, but you often can't see it. For this reason, the FOBT is important.

Need To Know: Blood in the stool does not always mean you have colorectal cancer. Other causes include: Bleeding ulcers Inflammation of the stomach or gastritis Inflammatory bowel disease (IBD) Hemorrhoids If fecal blood is found, additional tests are done to rule out cancer. Cancer can still be present if the FOBT is negative. This can happen if there was no bleeding when the test was performed. The results may come back negative but cancer is present. This is known as a false negative test.

Flexible Sigmoidoscopy Procedure

During a sigmoidoscopy procedure the doctor inserts a soft flexible, fiberoptic scope into the anus. The walls of the rectum and sigmoid portion of the colon are checked for tumors. A flexible sigmoidoscopy procedure may detect:

• About half of all colon tumors
• Nearly all rectal tumors

If doctors discover a growth or tumor during this procedure, a biopsy will be performed. During a biopsy, a small tissue sample is removed and then prepared for examination under a microscope. The biopsy procedure does not hurt.

Colonoscopy

A colonoscopy is similar to a sigmoidoscopy but is a more thorough examination of the entire colon. Patients receive medications that help them relax during the procedure. A flexible scope with a tiny camera attached is gently guided from the anus through the colon. Looking at the images provided by the camera on a monitor, the doctor examines the inside of the colon for any signs of inflammation, disease, or polyps. During the procedure, the doctor can take a sample of any suspicious areas for further testing, and can remove any polyps that are discovered.

How-To Information: Colon Cancer Screening Guidelines Seventy to 80 percent of all colon cancers occur in adults without known risk factors. The American Cancer Society guidelines recommend adults should begin colon cancer screening by age 50 years, either with: Annual stool occult blood stool tests, sigmoidoscopy, and digital rectal exam every five years, or Colonoscopy and digital rectal exam every 10 years, or Double-contrast barium enema and DRE every five to 10 years. Some experts recommend beginning blood stool tests and a digital rectal exam at age 40. For those who undergo periodic evaluation of the entire colon, no annual FOBT is needed. Those at higher-than-average risk for colon cancer should consult their doctor to begin screening at an earlier age. Their doctors will probably recommend more thorough screening tests, including a colonoscopy or barium enema rather than sigmoidoscopy. People are considered at higher-than-average risk if they have Had colon polyps removed Relatives who developed the disease Inherited colon cancer syndrome A family history of this syndrome

What Are The Symptoms Of Colon Cancer?

The symptoms of colon cancer can be confused with those of a number of digestive disorders. Having one or more of these symptoms does not mean you have cancer. In all cases, people with the following symptoms should contact their doctor:

• Bleeding from the rectum. Sometimes blood can be seen on the toilet tissue or in the toilet bowl after a bowel movement. Other things can cause rectal bleeding other than cancer, but rectal bleeding should never be ignored.

• Changes in bowel habits. These are not usually caused by cancer; however, be sure to discuss such changes with a doctor. If diarrhea or constipation lasts for more than two weeks or bowel habits go back and forth between diarrhea and constipation, or if the stool is unusually narrow, consultation should be made with a doctor.

• Pain in the abdomen or rectum. Discomfort or dull, vague, or sharp pain in the abdomen or rectum may have a number of possible causes. It does not mean that cancer is present but you should make an appointment with your physician.

• A feeling that a bowel movement cannot be completed.

• Unexplained weight loss, unusually low red blood cell counts or anemia, paleness, fatigue, or a yellowish coloring of the skin or whites of the eyes.

Need To Know:

There are many common causes for bleeding from the rectumh such as:

• Hemorrhoids may produce bright red blood from the anus.
• Diverticulosis, in which tiny "pockets" in the wall of the intestine can form and bleed when inflamed or irritated.

Always get checked by a doctor to determine the cause of rectal bleeding and to obtain treatment for the underlying cause of bleeding.

What Are The Symptoms Of Colon Cancer?

The symptoms of colon cancer can be confused with those of a number of digestive disorders. Having one or more of these symptoms does not mean you have cancer. In all cases, people with the following symptoms should contact their doctor:

• Bleeding from the rectum. Sometimes blood can be seen on the toilet tissue or in the toilet bowl after a bowel movement. Other things can cause rectal bleeding other than cancer, but rectal bleeding should never be ignored.
• Changes in bowel habits. These are not usually caused by cancer; however, be sure to discuss such changes with a doctor. If diarrhea or constipation lasts for more than two weeks or bowel habits go back and forth between diarrhea and constipation, or if the stool is unusually narrow, consultation should be made with a doctor.
• Pain in the abdomen or rectum. Discomfort or dull, vague, or sharp pain in the abdomen or rectum may have a number of possible causes. It does not mean that cancer is present but you should make an appointment with your physician.
• A feeling that a bowel movement cannot be completed.
• Unexplained weight loss, unusually low red blood cell counts or anemia, paleness, fatigue, or a yellowish coloring of the skin or whites of the eyes.

Need To Know: There are many common causes for bleeding from the rectum such as: Hemorrhoids may produce bright red blood from the anus. Diverticulosis, in which tiny "pockets" in the wall of the intestine can form and bleed when inflamed or irritated. Always get checked by a doctor to determine the cause of rectal bleeding and to obtain treatment for the underlying cause of bleeding.

What Causes Colon Cancer?

There are several causes for colorectal cancer as well as factors that place certain individuals at increased risk for the disease. There are known genetic and environmental factors.

People at risk for colorectal cancer:

• The biggest risk factor is age. Colon cancer is rare in those under 40 years. The rate of colorectal cancer detection begins to increase after age 40. Most colorectal cancer is diagnosed in those over 60 years.

• Have a mother, father, sister, or brother who developed colorectal cancer or polyps. When more than one family member has had colorectal cancer, the risk to other members may be three-to-four times higher of developing the disease. This higher risk may be due to an inherited gene.

• Have history of benign growths, such as polyps, that have been surgically removed.

• Have a prior history of colon or rectal cancer.

• Have disease or condition linked with increased risk.

• Have a diet high in fat and low in fiber.

Need To Know: Who is at risk for inherited forms of colorectal cancer? People whose relatives developed colorectal cancer before age 60. Those with relatives who have other forms of cancer, particularly breast or ovarian cancer. Those with a family history of stomach, abdominal, bowel, bone, or liver cancer. In the past, colorectal cancer was misdiagnosed as stomach, abdominal, or bowel cancer, or, in later stages, the cancer may have spread to the bone or liver. Distant relatives, such as cousins, aunts, uncles, etc., who develop colorectal cancer may raise the risk of colorectal cancer for other distant family members. The relative increase in risk is not as high as in those who have first-degree relatives, such as parents or siblings with colorectal cancer.

Having certain diseases or conditions may place people at increased risk for colorectal cancer. These include

• Chronic ulcerative colitis, an inflammatory condition of the colon. People in this risk category have long-term disease, most for ten years or more.
• Crohn's disease, which is an inflammatory disease of the gastrointestinal tract. This disease may increase colorectal cancer risk, although not as much ulcerative colitis.
• A history of breast, uterine, or ovarian cancer in women.
• Inherited a specific colorectal cancer syndrome. Those with an inherited syndromes may develop colorectal cancer at a much younger age, in their 30s or even younger.

Inherited Colon Cancer Syndromes

Inherited colon cancer syndromes is a name given to a group of different types of colon cancer found to be directly inherited, or passed down from one generation to the next. Over the past several years, genetic forms of colon cancer have been identified and genetic tests developed.

Need To Know: Genetic forms of colon cancer represent a smaller percentage of all colon cancer cases. However, those with a strong family history of colon cancer may consider talking to a genetic counselor. Those at high risk may choose to undergo screening at an earlier age.

There are two basic forms of colon cancers recognized as having a genetic basis:

• Familial adenomatous polyposis (FAP) is a rare genetic disorder of the colon characterized by the development of hundreds of polyps on the inner walls of the colon. People with FAP are at a higher risk for developing colon cancer at an early age (in their early 30s).

  The treatment of choice is to have an operation to remove the diseased colon to avoid the eventual development of colon cancer. This operation can be done without the need for a colostomy.

• Hereditary nonpolyposis colon cancer (HNPCC) is a form of colon cancer that runs in certain families. HNPCC is divided into two types:
  • Type I: People with this form of HNPCC can develop colon cancer before age 50.
  • Type II: People with this disorder are not only at higher risk for colon cancer before age 50 but are also at high risk for uterine, ovarian, thyroid, bladder, and other cancers.

Nice To Know: Reliable blood tests can now determine if a person has certain genes responsible for inherited colon cancer. Inherited colon cancer makes up about 20 percent of colon cancer cases.

Gastrointestinal Carcinoid Tumors

Gastrointestinal carcinoid tumors are a rare form of cancer affecting the intestinal tract, including the stomach, small intestine, appendix, colon, or rectum. Carcinoid tumors do not usually cause major, recognizable symptoms and can take years to develop. In most cases, these tumors are accidentally discovered during abdominal surgery. These tumors secrete hormones - groups of chemicals released into the bloodstream that have an effect elsewhere in the body.

In some people, carcinoid tumors may cause symptoms known as "carcinoid syndrome":

• Facial swelling with redness or flushing
• Wheezing
• Diarrhea

Carcinoid syndrome symptoms usually occur only if the cancer spreads to the liver.

Treatment for carcinoid syndrome depends on the stage of the disease and the person's overall health. Treatment may include surgery, radiation therapy, or chemotherapy.

What Is Colon Cancer?

Colon cancer is a common type of malignancy (cancer) in which there is uncontrolled growth of the cells that line the inside of the colon or rectum. Colon cancer is also called colorectal cancer.

• The colon, also known as the large intestine, is the last part of the digestive tract.
• The rectum is the very end of the large intestine that opens at the anus.

Understanding Cancer

The body is made up of different types of cells that normally divide and multiply in an orderly way. These new cells replace older cells. This process of cell birth and renewal occurs constantly in the body.

Cancer or malignant growths occur when:

• Some cells in the body begin to multiply in an uncontrolled manner.
• The body's natural defenses, such as certain parts of the immune system, cannot stop uncontrolled cell division.
• These abnormal cells become greater and greater in number.
• In some types of cancer, including colon cancer, the uncontrolled cell growth forms a mass, also called a tumor.

Some tumors are benign, which means that they are not cancerous. Cancerous or malignant tumors grow out of control and can invade, replace, and destroy normal cells near the tumor. In some cases, cancer cells spread to other areas of the body.

There are two kinds of growths that occur in the colon:

• noncancerous growths, such as polyps.
• Malignant or cancerous growths. Colon cancer usually begins with the growth of benign growths such as polyps.

Most types of colorectal cancer are adenocarcinomas. This means that the cancer cells are formed from abnormal gland cells that line the inner surface of an organ. The prefix "adeno" means "gland." In colorectal cancer, the abnormal growth begins to form in the inner lining of the large bowel.

Nice To Know: Other forms of color cancer may occur, but are not nearly as common as adenocarcinomas. Tumors that begin in connective tissue, such as sarcomas Tumors that begin in the lymphatic system, such lymphomas Rare cancers such as carcinoids and gastrointestinal stromal tumors.

If a polyp develops and is not removed, it may become cancerous. Once a cancer develops it begins to invade the intestinal wall and may spread to nearby lymph nodes. Lymph nodes are part of the lymphatic system, which carries special filtered fluids throughout the body. Through the lymphatic system, cancer cells may also be carried to areas of the body far away the original tumor.

This process of cancer cells traveling to other parts of the body is known as metastasis. The spread of cancer may also occur via the blood stream. Colon and rectal cancers that metastasize through the blood stream will travel first to the liver. There the cancerous cells may continue to grow and develop new tumors. As these new tumors continue to grow and spread further, the function of vital organs, such as the liver, may deteriorate.

About The Digestive System

The digestive system receives food, breaks it down into smaller, useful nutrients, absorbs these nutrients into the bloodstream, and eliminates the remaining waste from the body.

The digestive system is made up of

• The esophagus
• The stomach
• The small intestine
• The large intestine, also known as the colon

The colon has several parts:

• Ascending colon - Beginning in the lower right abdomen and continuing up the right side.
• Transverse colon - Beginning at the upper right side of the abdomen and continuing across to the left side of the abdomen.
• Descending colon - From the left upper abdomen straight down to the left lower side.
• Sigmoid colon - An S-shaped section that leads downward into the pelvic cavity.
• Rectum - The last six or so inches of the colon, ending at the anus.

Facts About Colon Cancer About 150,000 new cases of colorectal (colon and rectal) cancer are diagnosed each year in the U.S., making it the second most common type of cancer and the second leading cause of cancer death in the U.S. One-third of all colorectal cancers are found in the rectum; the rest are found in other parts of the colon. Screening for colorectal cancer should begin at the age of 40 in healthy adults. Seventy to 80 percent of colorectal cancer cases occur in adults without specific risk factors. Widespread screening for colorectal cancer could save up to many lives each year. Early detection reduces the probability of major surgery and increases chances of cure. Risk increases after age 40. Both men and women are equally at risk for colorectal cancer. In the U.S. the death rate for colorectal cancer is declining. This may be due to a higher rate of screening for the disease. Colon cancer may affect any racial or ethnic group; however, some studies suggest that Americans of northern European heritage have a higher-than-average risk of colon cancer.

Pituitary gland tumours

This information is about tumours of the pituitary gland. Although pituitary tumours are classified as brain tumours they have very few similarities to other types of brain tumour.

Much of our general information about brain tumours will not be appropriate for people with pituitary tumours, although you may still wish to read it.

The pituitary gland

The pituitary gland is a small oval-shaped gland found at the base of the brain (see diagram below), below the optic nerve (the nerve which leads to and from the eye).

The pituitary gland produces hormones which control and regulate the other glands in the body. These glands release hormones that are responsible for the body’s growth and metabolism.

The pituitary gland is divided into two parts: the anterior (front) and posterior (back).

The anterior pituitary produces six hormones:

• growth hormone which controls growth
• prolactin which stimulates the production of breast milk after childbirth
• ACTH (adrenocorticotrophic hormone) which stimulates the production of hormones from the adrenal glands
• TSH (thyroid-stimulating hormone) which stimulates the production of hormones from the thyroid gland
• FSH (follicle-stimulating hormone) and LH (leuteinising hormone) which stimulate the ovaries in women and the testes in men.

The posterior pituitary produces:

• ADH (anti-diuretic hormone) which reduces the amount of urine produced by the kidneys
• oxytocin which stimulates the contraction of the womb during childbirth and the production of milk for breastfeeding.

Side view of the head

Pituitary tumours

Cells within the brain normally grow in an orderly and controlled way, but if for some reason this order is disrupted, the cells continue to divide and form a lump or tumour.

A tumour may be either benign or malignant. Although a benign tumour can continue to grow, the cells do not spread from the original site. In a malignant tumour, the cells can invade and destroy surrounding tissue and may spread to other parts of the brain.

Tumours affecting the whole of the central nervous system (CNS), which is made up of the brain and spinal cord, are fairly rare.

About 4500 new brain tumours are diagnosed each year in the UK. Pituitary tumours are one of the most common types and make up nearly one in 10 (10%) of all brain tumours. They are most commonly found in young or middle-aged adults.

Almost all tumours of the pituitary gland are benign and do not spread. They are sometimes called adenomas.

Pituitary tumours are either secreting (producing hormones) or non-secreting tumours (not producing hormones). Secreting tumours can release excess amounts of any of the pituitary hormones, and are named after the hormone that is being over-produced, for example, a prolactin-secreting tumour.

Causes of a pituitary tumour

As with most brain tumours, the cause of pituitary tumours is unknown. Research is being carried out into possible causes.

Signs and symptoms

Signs and symptoms of pituitary tumours are caused either by direct pressure from the tumour itself, or by a change in the normal hormone levels. As the tumour grows, it puts pressure on the optic nerve (which leads to the eye) and this often causes headaches and sight problems.

Symptoms caused by a change in hormone levels usually take a long time to develop.

Prolactin-secreting tumours are the most common type of secreting tumour. Women with this type of tumour may notice that their monthly periods stop and they may also produce small amounts of breast milk. Symptoms in men may include impotence (loss of the ability to have an erection).

Infertility (inability to have children) is common in both men and women and the tumour may be discovered during routine tests for infertility.

Symptoms of other secreting tumours will relate to the hormones that are released.

Growth hormone-secreting tumours Excess production of growth hormones can cause a condition called giantism. This leads to abnormal growth that is known as acromegaly. This causes enlargement of the hands, feet, lower jaw and brows, and can also lead to high blood pressure and diabetes.

TSH-secreting tumours A tumour that releases too much TSH causes a disruption in the body’s normal metabolism. However, these tumours are extremely rare.

ACTH-secreting tumours Over-production of ACTH can produce a number of symptoms, including Cushing’s syndrome, which is characterised by a round face (known as moon-face), weight gain, increased facial hair in women, and mental changes such as depression.

Other anterior pituitary tumours Tumours that secrete FSH or LH are very rare and are likely to cause infertility.

Posterior pituitary tumours Tumours in the posterior pituitary are very rare and disturbances in this area are more likely to be caused by pressure being applied to the area from the surrounding tissues.

The most common symptom of a problem in the posterior pituitary is a condition called diabetes insipidus (not the same as the more common diabetes mellitus). The main symptom of diabetes insipidus is being very thirsty and passing large amounts of very weak urine.

Tests and investigations

In order to plan your treatment, it is important to find out as much as possible about the type, position and size of the tumour. This is done through a number of tests and investigations.

Pituitary tumours are often discovered during a blood test. If high levels of pituitary hormones are found in your blood, your doctor may arrange for you to have a CT scan or MRI scan. The scans will normally be able to confirm whether a pituitary tumour is present or not.

CT (computerised tomography) scan A CT scan takes a series of x-rays which build up a three-dimensional picture of the inside of the body. The scan is painless but takes from 10–30 minutes. CT scans use a small amount of radiation, which will be very unlikely to harm you and will not harm anyone you come into contact with. You will be asked not to eat or drink for at least four hours before the scan.

Most people who have a CT scan are given a drink or injection to allow particular areas to be seen more clearly. This may make you feel hot all over. Before having the injection or drink, it is important to tell the person doing this test if you are allergic to iodine or have asthma.

MRI (magnetic resonance imaging) scan This test is similar to a CT scan, but uses magnetism instead of x-rays to build up a detailed picture of areas of your body. During the scan you will be asked to lie very still on the couch inside a long tube for about 30 minutes. It is painless but can be uncomfortable, and some people feel a bit claustrophobic during the scan. It is also noisy, but you will be given earplugs or headphones.

Some people are given an injection of dye into a vein in the arm, but this usually does not cause any discomfort.

Eye tests By examining your eyes, your doctor can detect pressure on the optic nerve, which may indicate that a tumour is present. A simple test may also be done to check your visual fields (range of vision).

Treatment

Your treatment will usually be planned by a team of specialists known as a multidisciplinary team (MDT). The team will usually include a doctor who operates on the brain (neurosurgeon), a doctor who specialises in treating illnesses of the brain (neurologist), a specialist nurse and possibly other health professionals, such as a physiotherapist or a dietitian.

Consent

Before you have any treatment, your doctor will give you full information about what the treatment involves and explain the aims of the treatment to you. They will usually ask you to sign a form saying that you give your permission (consent) for the hospital staff to give you the treatment. No medical treatment can be given without your consent.

Benefits and disadvantages of treatment

Treatment can be given for different reasons and the potential benefits will vary depending upon the individual situation. If you have been offered treatment that aims to cure your cancer, deciding whether to have the treatment may not be difficult. However, if a cure is not possible and the treatment is to control the cancer for a period of time, it may be more difficult to decide whether to go ahead.

If you feel that you can’t make a decision about the treatment when it is first explained to you, you can always ask for more time to decide.

You are free to choose not to have the treatment and the staff can explain what may happen if you do not have it. You don’t have to give a reason for not wanting to have treatment, but it can be helpful to let the staff know your concerns so that they can give you the best advice.

Surgery

Surgery is the most common treatment for most pituitary tumours. The aim of surgery is to remove the tumour and leave at least some of the normal pituitary gland behind. This is not always possible, and in some cases the whole gland needs to be removed.

Surgery is usually carried out by making a small cut on the inside of the roof of the nose, or by making a small opening under the upper lip, to be able to reach the pituitary gland. This makes recovery after surgery much quicker than other operations for brain tumours. Your doctor will explain the operation to you in more detail beforehand.

Drug treatment

Some prolactin-secreting tumours can be treated with a drug called bromocriptine, which reduces the production of prolactin.

If the whole pituitary gland is removed, drugs will have to be taken to replace the hormones that are normally produced (hormone replacement).

Radiotherapy

Radiotherapy treatment uses high‑energy rays to destroy abnormal cells, and is an extremely effective and safe form of treatment, which is often used following pituitary surgery for all types of tumour.

Follow-up

Treatment of pituitary tumours is usually very successful, although many people will have to continue taking hormone replacements, sometimes for the rest of their lives. Regular check-ups at an endocrinology clinic, where your hormone levels will be monitored, are likely and may continue for several years.

Your feelings

You may find the idea of a tumour affecting your brain extremely frightening. The brain controls the body, and not being in control is something that can be very worrying. You may experience many different emotions, including anxiety and fear. These are all normal reactions, and are part of the process many people go through in trying to come to terms with their condition.

Many people find it helpful to talk things over with their doctor or nurse, or with one of our support service nurses. Close friends and family members can also offer support.

Via: http://www.cancerbackup.org.uk

Tumours of the parathyroid glands

The endocrine system

The thyroid gland and the parathyroid glands are part of the endocrine system. Although they are close to each other and have similar names, they have very different functions.

The parathyroid glands

There are four parathyroid glands, which are attached to the thyroid gland, in the front of the neck.

The parathyroid glands are small, but their function is very important: they maintain the correct levels of calcium in the body. Calcium plays an essential role in controlling muscle and nerve function.

Position of the parathyroid glands

Parathyroid tumours

Parathyroid tumours can be non-cancerous (benign) or cancerous (malignant). Most tumours of the parathyroid gland are benign. This information discusses the malignant endocrine tumours of the parathyroid glands. Cancer of the parathyroid gland is extremely rare.

A tumour of the parathyroid gland may cause the overproduction of the hormone that controls the level of calcium in the body. The hormone is called parathyroid hormone (PTH), or parathormone.

Causes of parathyroid gland cancer

The exact cause of parathyroid tumours is not fully understood, but we do know that the risk of developing it increases in people affected by a condition known as multiple endocrine neoplasia 1 (MEN1). This is a rare condition that is caused by a faulty gene; it can be passed on from one generation to another (inherited).

Cancer of the parathyroid glands has also been linked to exposure to radiation.

Signs and symptoms

Some people with a parathyroid tumour may feel a lump or swelling in their neck, but this is not common.

If parathyroid hormone is being overproduced, it may cause some of the following symptoms:

• high levels of calcium in the blood (hypercalcaemia)
• muscle weakness
• pain in the bones
• vomiting
• loss of appetite/weight loss
• constipation
• difficulty sleeping
• feeling run down and tired
• inflammation of the pancreas
• stomach ulcer
• kidney stones
• feeling nervous
• thin bones (osteoporosis).

Some people may only have one or two of these symptoms. These symptoms may also be caused by other conditions not related to parathyroid tumours.

Diagnosis

Before a diagnosis can be made, your doctor will ask you about your past medical conditions, including any symptoms that you have.

A number of tests will be done. These may include any of the following:

Blood and urine tests Samples of blood and urine are taken to look for the presence of certain hormones. A sample of urine may be collected over a 24 hour period. Sometimes it is necessary to fast (not eat) overnight before having certain blood tests.

Parathyroid scan This scan can identify the size and position of the parathyroid glands, and how well they are working. A slightly radioactive substance is injected into a vein in your arm. The scan shows how much of the substance is taken up by the parathyroid glands, and identifies any abnormal areas.

X-rays and scans A combination of x-rays and scans will be taken to find where the tumour is, and if it has spread.

Ultrasound scan Sound waves are used to make up a picture of the neck area. Once you are lying comfortably on your back, a gel is spread over your neck. A small device like a microphone, which produces sound waves, is then passed over the area.

CT (computerised tomography) scan This is a series of x-rays, which builds up a three‑dimensional picture of the inside of the body. The scan is painless. It takes about 30 minutes.

MRI (magnetic resonance imaging) scan This uses magnetism instead of x-rays to form a series of cross-sectional pictures of the inside of the body. During the scan you will be asked to lie very still on a couch inside a metal cylinder. The test can take up to an hour and is completely painless. If you don't like enclosed spaces, you may find the machine claustrophobic. The machine is also quite noisy, but you will be given earplugs or headphones to wear.

PET (Positron emission tomography) scan This is a new type of scan and is occasionally used for this type of tumour. A PET scan uses low-dose radioactive sugar to measure the activity of cells in different parts of the body. Areas of tumour are usually more active than surrounding tissue, and show up on the scan. If you need a PET scan, you might have to travel to a specialist centre to get one.

Biopsy A small sample of cells is taken from the tumour to be examined under a microscope. A local or general anaesthetic may be given.

Treatment

Surgery

If the tumour is contained in one area (localised), or if there has been only limited spread, surgery is usually the first choice of treatment. If it is possible to remove the tumour completely, no other treatment may be necessary.

Surgery usually involves removing all of the parathyroid gland and part, or all, of the nearest half of the thyroid gland, and some surrounding tissue. After the operation, the calcium levels in the body can go up and down. Your doctors will monitor your calcium level by taking regular blood tests.

Usually, this type of surgery is done under a general anaesthetic and requires a short stay in hospital. Sometimes it is possible to remove the affected parathyroid gland using keyhole surgery, under a local anaesthetic. However, the effectiveness of this technique is still being investigated in research trials.

Radiotherapy

This is the use of high-energy rays. Radiotherapy can be given after surgery, with the aim of reducing the risk of the cancer coming back. It may also be given If your cancer comes back some time after the initial surgery, or if it has spread to another part of the body.

Chemotherapy

This uses anti-cancer (cytotoxic) drugs to destroy cancer cells. Chemotherapy is occasionally used for parathyroid cancer that has come back after initial treatment, or has spread to other parts of the body.

Bisphosphonates

Medicines known as bisphosphonates can be given to reduce high levels of calcium in the blood (hypercalcaemia).

Calcimimetic agents

These are medicines that are used to control some of the symptoms associated with an overproduction of parathyroid hormone (PTH) and hypercalcaemia.

Clinical trials

Research into treatments for parathyroid cancer is ongoing and advances are being made. Cancer doctors use clinical trials to assess new treatments. Before any trial is allowed to take place it must have been approved by an ethics committee, which will have checked whether the trial is in the interest of patients.

You may be asked to take part in a clinical trial. Your doctor must discuss the treatment with you so that you have a full understanding of the trial and what it involves. You may decide not to take part, or to withdraw from a trial, at any stage. You will then receive the best standard treatment available.

Your feelings

You may have many different emotions including anger, resentment, guilt, anxiety and fear. These are all normal reactions, and are part of the process many people go through in trying to come to terms with their illness.

Each individual has their own way of coping with difficult situations; some people find it helpful to talk to friends or family, while others prefer to seek help from people outside their situation. Some people prefer to keep their feelings to themselves. There is no right or wrong way to cope; but help is there if you need it. You may wish to contact our cancer support service for information about counselling in your area.

Via: http://www.cancerbackup.org.uk

Carcinoid tumours

This information is about a rare type of cancer called a carcinoid tumour. We hope that it will answer any questions that you may have. If you have any further questions you can ask your doctor or nurse at the hospital where you are having your treatment.

Carcinoid tumours

A carcinoid tumour, sometimes referred to as simply 'carcinoid', is a tumour of the neuroendocrine system. The neuroendocrine system is a network of glands that produce particular hormones and send them into the bloodstream to affect the function of different organs in the body.

Most carcinoid tumours are found in the appendix or the small bowel (intestine). Less commonly, they may arise in the lung or the pancreas. Rarely, they may arise in other parts of the body.

Carcinoid tumours often grow slowly and it may be several years before any symptoms appear and the tumour is diagnosed.

Causes of a carcinoid tumour

This is a rare type of tumour. Approximately 1200 new carcinoid tumours are diagnosed each year in the UK. Men and women are affected equally and carcinoid is usually found in adults over the age of 30. As with many other forms of cancer, the exact cause is unknown.

Signs and symptoms

The type of symptoms will depend on where the tumour started, where it may have spread to, and whether it produces a hormone known as serotonin. If a carcinoid tumour starts in the appendix it does not usually spread to other parts of the body and does not produce serotonin. As a result there are very few symptoms and it is often discovered by chance when the appendix is removed for another reason.

Carcinoid syndrome

If a carcinoid tumour starts outside the appendix, and particularly if it spreads to the liver, it will often produce serotonin and cause symptoms known as carcinoid syndrome. Symptoms include:

• diarrhoea
• flushing of the skin
• wheezing (similar to asthma)
• loss of appetite
• weight loss

It may be possible to reduce the symptoms of carcinoid syndrome by avoiding substances or conditions that cause flushing, such as alcohol and stress.

How it is diagnosed

Before your doctor can make a firm diagnosis of a carcinoid tumour a number of tests will have to be done.

Urine test When serotonin is broken down in the liver, it is excreted as a chemical called 5HIAA in the urine. Your urine will be collected over a 24-hour period to check whether there are raised levels of 5HIAA.

Blood tests may be taken to check serotonin levels.

The doctor may also carry out a number of tests to find out whether the cancer has spread.

X-rays and scans These may be taken to show if there has been any spread of the tumour.

Chest x-ray This will show whether there has been any spread to the lungs.

Ultrasound scan A simple, painless scan which uses sound waves to form a picture of the inside of the abdomen.

CT (computerised tomography) scan A CT scan takes a series of x-rays to build up a three-dimensional picture of the inside of the body. The scan is painless but takes longer than an x-ray (about 30 minutes). It may be used to find where the cancer started (the primary tumour) or to check for any spread of the disease (secondaries or metastases).

MRI (magnetic resonance imaging) scan This scan uses magnetism instead of x-rays to form a series of cross-sectional pictures of the inside of the body. During the scan you will be asked to lie very still on a couch inside a metal cylinder. The test can take up to an hour and is completely painless, although the machine is quite noisy. If you don’t like enclosed spaces you may find the machine claustrophobic.

Octreotide scan An octreotide scan examines how several of your internal organs are working. Octreotide is a substance that is absorbed by carcinoid cells. It can show where a cancer started and any areas that it has spread to. The scan is done in the nuclear medicine department and takes place over three consecutive days.

On the first day you will go to the department twice. In the morning you will have an injection in your arm. You are then usually free to stay in or leave the hospital. In the afternoon you will have a scan taken using a gamma camera. The scan takes about an hour and during this time you will lie still on a bed. On the following two afternoons pictures will again be taken for up to one and a half hours.

123MIBG scan A drug called 123MIBG may be used to show up the site of a carcinoid tumour. 123MIBG is a mildly radioactive drug that is absorbed by carcinoid cells. The scan takes place over two consecutive days in the nuclear medicine department.

On the first day you will go to the department twice. In the morning you will be given an injection in the arm. You are then usually free to stay or leave the hospital. You will go back to the department in the afternoon to have a scan with a gamma camera lasting for about an hour. The following morning you will have further pictures taken for about one and a quarter hours. At this point you may be given a further injection of 123MIBG.

Biopsy A small sample of cells is taken from the tumour to be examined under a microscope. Depending on which part of the body is affected, a local or general anaesthetic is given.

Treatment

The treatment for a carcinoid tumour depends on a number of factors including your general health and the size and position of the tumour. The results of your tests will enable your doctor to discuss the best type of treatment with you.

Surgery

If the tumour is contained in one area (localised), or if there has been only limited spread (regional), surgery is usually the first choice of treatment. If it is possible to remove the tumour completely no other treatment may be necessary.

If the tumour has spread to other parts of the body (metastatic) but there are only one or two areas – for example, in the liver – surgery may still be possible because of the slow growth of the tumour.

Chemotherapy

Chemotherapy is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It may sometimes be used to treat carcinoid tumours that have spread, with the intention of reducing the tumour and the secretion of serotonin, and of prolonging a good quality of life.

Interferon

Another type of drug treatment for the symptoms of carcinoid tumours is interferon, which is a biological therapy. Interferon is given as an injection under the skin. At first it can cause flu-like symptoms such as chills, fever, aching joints and tiredness, but these usually disappear.

Radiotherapy

For this treatment, high-energy rays are used to destroy cancer cells. Radiotherapy is usually given to treat symptoms, such as pain, which may occur if the tumour has spread to the bones.

Hepatic artery embolisation

This treatment may be used to slow down the growth of secondary liver tumours (metastases) by reducing the blood supply to the liver. Sometimes it is combined with chemotherapy. The procedure usually requires an anaesthetic, and you will probably have to stay in hospital overnight. You may feel unwell and your temperature may be raised for a few days afterwards.

131MIBG

Another drug, 131MIBG, may be used to reduce the number of carcinoid cells and the symptoms of carcinoid syndrome. It gives a dose of radiotherapy to the carcinoid cells, and is known as targeted radiotherapy. This treatment can be given as a drink or as an injection into the vein.

Radio-labelled octreotide

Octreotide is absorbed by carcinoid cells. A small dose of radioactivity can be attached to it. This treatment is given as an injection into a vein in the arm. Again, it can reduce the number of carcinoid cells.

Radiofrequency ablation

This may be used in some situations where the tumour is affecting the liver. It uses laser or radiowaves (microwaves) to destroy the cancer cells by heating them to high temperatures. A sedative drug is given to make the person feel drowsy and a local anaesthetic is used to numb the skin of the abdomen. A fine needle is then inserted through the skin over the liver and into the centre of the tumour. Powerful laser light or radiowaves are then passed through the needle and into the tumour, which heats the cancer cells and destroys them.

Treatments for carcinoid syndrome

Somatostatin analogues

Carcinoid syndrome can be treated with drugs known as somatostatin analogues. These work by reducing the production of hormones by the tumour, and can help to reduce the flushing and diarrhoea.

The somatostatin analogue octreotide (Sandostatin®) is given as a short-acting injection under the skin up to three times a day. Most people are taught how to give the injection themselves.

Other somatostatin analogues are given as longer-acting injections into the muscle (intramuscular) between 7 and 28 days apart, depending on the drug that is used and the response. Commonly used drugs are octreotide (Sandostatin Lar®) and lanreotide (Somatuline® LA, Somatuline Autogel®).

Clinical trials

Research into treatments for carcinoid tumours is ongoing and advances are being made. Cancer doctors use clinical trials to assess new treatments.

You may be asked to take part in a clinical trial. Your doctor must discuss the treatment with you, so that you have a full understanding of the trial and what it means to take part.

Your feelings

During your diagnosis and treatment you are likely to experience a number of different emotions, from shock and disbelief to fear and anger. At times these emotions can be overwhelming and hard to control. It is quite natural, and important, to be able to express them. Everyone has their own ways of coping with difficult situations; some people find it helpful to talk to friends or family, while others prefer to seek help from people outside their situation. Others prefer to keep their feelings to themselves. There is no right or wrong way to cope, but help is available if you need it.

References

This section has been compiled using information from a number of reliable sources, including:

• Oxford Textbook of Oncology (2nd edition). Souhami et al. Oxford University Press, 2002.
• Gastrointestinal Oncology: Principles and Practice. Kelsen et al. Lippincott Williams and Wilkins, 2002.
• The Textbook of Uncommon Cancers (2nd edition). Raghavan et al. Wiley, 1999.

For further references, please see the general bibliography.

Gastroenteropancreatic tumours (GEPs)

This information is about a rare group of neuroendocrine tumours (NETs) called gastroenteropancreatic tumours (GEPs). We hope that the information will answer any questions that you may have about them. If you have any further questions you can ask your doctor or nurse at the hospital where you are having your treatment.

Neuroendocrine tumours (NETs)

NETs are a rare group of tumours that start in the cells of the neuroendocrine (pronounced new-row-en-doe-crin) system.

The neuroendocrine system is a network of endocrine glands and cells throughout the body. Endocrine glands produce and release hormones that are circulated around the body. The hormones control the levels of particular chemicals and fluids in the body and help us respond to changes in our environment.

Neuroendocrine tumours can be non-cancerous (benign) or cancerous (malignant). This information focuses on the malignant types of neuroendocrine tumours affecting the gastrointestinal tract (the GI tract). The GI tract is the digestive system.

The digestive system

When a tumour develops in part of the neuroendocrine system, it often causes too much of a certain hormone to be produced.

The type of hormone overproduced depends on the type of gland that is affected by the tumour.

Some tumours may not cause an over-production of any hormones and may not cause any obvious symptoms. These are known as non-functioning NETs.

Many of these tumours, even if they appear cancerous under the microscope or have spread, may be very slow-growing and may even appear to stop growing for a long time.

NETs are classified depending on:

• the type of cell in which the tumour starts
• the part of the body affected
• the particular endocrine glands that are involved.

Gastroenteropancreatic tumours

Most gastroenteropancreatic tumours (GEPs) develop in the organs of the digestive system. They usually start in the cells of the stomach (gastro), intestines (entero) and the pancreas.

The different types of GEP are named after cells where they develop. Some of these include:

• insulinomas
• gastrinomas
• glucagonomas
• VIPomas
• somatostatinomas.

Sometimes the primary site (where the cancer started) cannot be found. In this situation, the cancer may be found when it has spread to a different part of the body, such as the liver, and has formed a secondary tumour (metastasis).

Causes

The exact cause of GEPs is unknown. However, the risk of developing one is increased in people with Multiple Endocrine Neoplasia 1 and 2 (MEN 1 and MEN 2). These conditions are usually caused by inherited faulty genes. The affected person may develop tumours in several different endocrine organs. MEN 1 and MEN 2 can affect both males and females. Genetic testing can be carried out for people with a family history of MEN.

Signs and symptoms

The signs and symptoms will depend on where the tumour is in the body, and whether it is producing extra hormones.

Insulinomas

Insulinomas can occur in any part of the pancreas. The pancreas produces insulin, which controls the level of sugar in the blood. When there is an abnormally high level of insulin in the body, this causes a fall in the blood-sugar level (hypoglycaemia).

A low blood-sugar level causes symptoms which can include:

• headaches
• confusion
• trembling and palpitations
• anxiety
• eyesight changes
• possible fits (seizures)
• weakness.

A low blood-sugar level is most likely to occur first thing in the morning, when exercising or after missing a meal. It can often be relieved by eating food or by having sugary drinks.

Gastrinomas

Gastrinomas (gas-trin-oma) often start in the pancreas or the upper part of the small bowel (duodenum). They usually produce too much of the hormone gastrin. Gastrin causes the production of gastric acid. If too much gastric acid is produced, it can lead to ulcers in the stomach, gullet (oesophagus) and the small bowel (small intestine). There may be several ulcers and they tend not to respond well to the usual ulcer medicines in normal doses. This is often called Zollinger-Ellison syndrome.

Common symptoms can include:

• bleeding into the stomach
• perforation of the wall of the stomach or duodenum
• narrowing of part of the bowel (stricture)
• diarrhoea
• steatorhoea (pale, greasy and offensive smelling stools)
• inflammation of the lining of the gullet (oesophagitis).

Glucagonomas

Glucagonomas (glue-ca-gone-oma) occur most often in the pancreas. Glucagonomas usually produce too much of the hormone glucagon. Glucagon is another hormone that controls the level of sugar in the body.

Common symptoms can include:

• anaemia (low level of haemoglobin in the blood)
• weight loss
• diabetes (sugar intolerance)
• a skin rash
• blood clots.

VIPomas

VIPomas usually occur in the pancreas. They can produce too much of a substance called vasoactive intestinal peptide.

Common symptoms can include:

• excessive watery diarrhoea
• low levels of potassium as a result of the diarrhoea
• weakness and tiredness
• nausea and vomiting.

Somatostatinomas

Somatostatinomas (pronounced so-mat-o-stat-tin-oma) are extremely rare tumours that usually occur in the pancreas, duodenum or jejunum (parts of the small intestine).

Common symptoms can include:

• steatorhoea (pale, greasy and offensive smelling stools)
• weight loss
• anaemia (low level of haemoglobin in the blood)
• pain in the affected area
• diarrhoea
• diabetes.

It is important to remember that many of the symptoms of tumours of the neuroendocrine system are the same as the symptoms of other, non-cancerous, conditions.

How GEPs are diagnosed

GEPs can be very difficult to diagnose. Before a diagnosis can be made, your doctor will ask you about your past medical conditions, including any symptoms that you have.

A number of tests will be done. These may include any of the following:

Blood and urine tests Several samples of blood and urine are taken to look for the levels of particular hormones. A sample of urine may be collected over a 24-hour period. Sometimes it is necessary to fast overnight before having certain blood tests. These tests may be repeated to monitor any ongoing changes in hormone levels.

X-rays and scans A combination of x-rays and scans will be taken to find where the tumour is and if it has spread.

Ultrasound of the abdomen This test uses sound waves to make up a picture of the abdomen and surrounding organs. It is done in the hospital scanning department. You will be asked not to eat, and to drink clear fluids only (nothing fizzy or milky) for 4–6 hours before the scan. Once you are lying comfortably on your back, a gel is spread onto your abdomen. A small device like a microphone is then rubbed over the area. The sound waves are converted into a picture using a computer. The test is completely painless and takes about 15–20 minutes.

Endoscopic ultrasound A flexible tube (endoscope) is inserted into the mouth, down the throat, and into the digestive system. An ultrasound is attached to the end of the endoscope. This enables the doctor to examine the digestive system organs more closely.

123MIBG scan A drug called 123MIBG may be used to show up the site of a GEP. 123MIBG is a mildly radioactive drug that is absorbed by GEP cells. The scan takes place over two consecutive days in the nuclear medicine department. On the first day you will go to the department twice. In the morning you will be given an injection in the arm. You are then free to stay or to leave the hospital. You will go back to the department in the afternoon to have a scan with a gamma camera lasting for about an hour. The following morning you will have further pictures taken for about one and a quarter hours. At this point you may be given a further injection.

Octreotide scan This scan examines how several of your internal organs are working. Octreotide (ock-tree-o-tide) is a substance that is absorbed by GEP cells. It can show where a cancer started and where it has spread. The scan is done in the nuclear medicine department and takes place over three consecutive days. On the first day you will go to the department twice. In the morning you will have an injection in your arm. You are then free to stay in or leave the hospital. In the afternoon you will have a scan taken using a gamma camera. The scan takes about an hour and during this time you will lie still on a bed. On the following two afternoons pictures will be taken for up to one and a half hours.

CT (computerised tomography) scan This is a series of x-rays that builds up a three-dimensional picture of the inside of the body. The scan is painless and takes about 30 minutes. It may be used to find where a tumour started and can also show whether a tumour has spread.

MRI (magnetic resonance imaging) scan This type of scan uses magnetism (not x-rays) to form a series of cross-sectional pictures of the inside of the body. During the scan you will be asked to lie very still on the couch inside a metal cylinder. The test can take up to an hour and is completely painless, although the machine is quite noisy. If you don’t like enclosed spaces you may find the machine claustrophobic.

PET (positron emission tomography) scan A PET scan uses low-dose radioactive sugar to measure the activity of cells in different parts of the body. Areas of cancer are usually more active than normal tissue and show up on the scan. If you need a PET scan you might have to travel to a specialist centre to have one. PET scans are not always routinely carried out as specialists have different opinions as to whether they are more helpful than other investigations.

Biopsy A small sample of cells (a biopsy) is taken from the tumour to be examined under a microscope. The biopsy may be taken using ultrasound or CT scans to make sure that the sample is taken from the tumour. Depending on which part of the body is affected, a local or general anaesthetic is given.

Surgical treatment

Treatment will depend on a number of factors and varies from person to person.

Surgery

If the tumour is contained in one area (localised), or if there has been only limited spread, surgery is usually the first choice of treatment. If it is possible to remove the tumour completely, no other treatment may be necessary.

If the tumour has spread to other parts of the body (metastatic), surgery may still be possible to remove the part of the tumour that is producing too many hormones. This is often referred to as tumour debulking.

If a GEP is blocking an organ, such as the bowel, surgery may be helpful to relieve the blockage (obstruction).

Liver surgery

If the tumour has spread to the liver, surgery can be used to remove the parts of the liver containing the tumour. Very occasionally, a liver transplant may be considered for people with a particularly slow-growing tumour affecting the liver.

Non surgical treatments

Somatostatin analogues

Somatostatin analogues are drugs that have been found to be effective in controlling certain symptoms that GEPs can cause. They work by blocking the release of specific hormones. Commonly used somatostatin analogues are octreotide and lanreotide. Octreotide (Sandostatin®) is given as a short-acting injection under the skin (subcutaneously) up to three times a day. You, or a family member, can be taught to give the injection. Longer-acting injections of octreotide (Sandostatin Lar®) or lanreotide (Somatuline® LA, Somatuline Autogel®) can also be given. These injections are given deep under the skin, from once a week to once every four weeks, depending upon the drug used and the situation.

Chemotherapy

This is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It may sometimes be used to treat GEPs that have spread, to reduce the size of the tumour and lower the levels of hormones they produce. Chemotherapy is often used for GEPs of the pancreas. However, as these may be very slow-growing tumours, your doctor may not think it is appropriate to use chemotherapy if your situation appears to be stable.

Embolisation

Sometimes blocking the blood supply to the tumours can slow down the growth of GEPs. This is called embolisation and is done by putting a temporary tube into the artery that provides the blood supply to the tumour. Then a substance is injected to block the artery. This can be particularly useful for people with slow-growing tumours affecting the liver.

Interferon

Another type of drug treatment for the symptoms of GEPs is interferon, which is a biological therapy. Interferon is given as an injection under the skin. At first it can cause flu-like symptoms such as chills, fever, aching joints and tiredness, but these usually disappear.

Targeted radiotherapy

131MIBG

A drug called 131MIBG may be used to reduce the number of tumour cells and the symptoms of GEP tumours. It gives a dose of radiotherapy to the tumour cells, and is known as targeted radiotherapy. This treatment can be given as a drink or as an injection into the vein.

Radio-labelled octreotide

Octreotide is absorbed by neuroendocrine cells. A small dose of radioactivity can be attached to it. This treatment is given as an injection into a vein in the arm. It can reduce the number of neuroendocrine cells.

If you have targeted radiotherapy, you may need to be in a room by yourself for a few days so that other people around you are not unnecessarily exposed to the radiotherapy.

Radiofrequency ablation

This may be used in some situations where the tumour is affecting the liver. It uses laser or radiowaves (microwaves) to destroy the cancer cells by heating them to high temperatures. A sedative drug is given to make the person feel drowsy and a local anaesthetic used to numb the skin of the abdomen. A fine needle is then inserted through the skin over the liver and into the centre of the tumour. Powerful laser light or radiowaves are then passed through the needle and into the tumour, which heats the cancer cells and destroys them.

Treating symptoms

Sometimes medicines such as antacids will be given to reduce the amounts of acid in the stomach. Other drugs may be used to control your blood sugar or to control diarrhoea.

Clinical trials

Research into treatments for GEP tumours is ongoing and advances are being made. Cancer doctors use clinical trials to assess new treatments.

You may be asked to take part in a clinical trial. Your doctor must discuss the treatment with you so that you have a full understanding of the trial and what it means to take part.

Your feelings

You may have many different emotions including anger, resentment, guilt, anxiety and fear. These are all normal reactions and are part of the process many people go through in trying to come to terms with their illness.

References

This section has been compiled using information from a number of reliable sources, including:

• Oxford Textbook of Oncology (2nd edition). Souhami et al. Oxford University Press, 2002.
• Gastrointestinal Oncology: Principles and Practice. Kelsen et al. Lippincott Williams and Wilkins, Philadelphia, 2002.
• The Textbook of Uncommon Cancers (2nd edition). Raghavan et al. Wiley, 1999.
• Endocrine Tumours. Clark et al. Ontario, BC Decker Inc, 2003.

For further references, please see the general bibliography.