Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is the second most common type of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children. 

Normally, the body produces bone marrow stem cells (immature cells) that develop into mature blood cells. There are 3 types of mature blood cells:

• Red blood cells that carry oxygen and other materials to all tissues of the body.
• White blood cells that fight infection and disease.
• Platelets that help prevent bleeding by causing blood clots to form.

In CLL, too many stem cells develop into a type of white blood cell called lymphocytes. There are 3 types of lymphocytes:

• B lymphocytes that make antibodies to help fight infection.
• T lymphocytes that help B lymphocytes make antibodies to fight infection.
• Natural killer cells that attack cells with cancer or a virus.

The lymphocytes in CLL are not able to fight infection very well. Also, as the amount of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may result in infection, anemia, and easy bleeding. 

Older age can affect the risk of developing chronic lymphocytic leukemia.
Risk factors for CLL include the following:

• Being middle-aged or older, male, or white.
• A family history of CLL or cancer of the lymph system.
• Having relatives who are Russian Jews or Eastern European Jews.

Possible signs of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
Usually CLL does not cause any symptoms and is found during a routine blood test. Sometimes symptoms occur that may be caused by CLL or by other conditions. A doctor should be consulted if any of the following problems occur:

• Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin
• Tiredness that does not go away.
• Pain or fullness below the ribs.
• Fever and infection.
• Weight loss (unexplained).

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
The following tests and procedures may be used:

Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient's health habits and past illnesses and treatments will also be taken.

Complete blood count: A procedure in which a sample of blood is drawn and checked for the following:
-The number of red blood cells, white blood cells, and platelets.
-The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
-The portion of the sample made up of red blood cells.

Cytogenetic analysis: A test in which a sample of blood or bone marrow is looked at under a microscope to find out if there are changes in the structure or number of chromosomes in the lymphocytes.

Immunophenotyping: A test in which the cells in a sample of blood or bone marrow are looked at under a microscope to find out if malignant lymphocytes (cancer) began from the B lymphocytes or the T lymphocytes.

Bone marrow biopsy and aspiration: The removal of a small piece of bone and bone marrow by inserting a needle into the hipbone or breastbone. A pathologist views the sample under a microscope to look for abnormal cells.

Certain factors affect treatment options and prognosis (chance of recovery).
Treatment options depend on:

• The stage of the disease.
• Red blood cell, white blood cell, and platelet blood counts.
• Whether there are symptoms, such as fever, chills, or weight loss.
• Whether the liver, spleen, or lymph nodes are larger than normal.
• The response to initial treatment.
• Whether the CLL has recurred (come back).

The prognosis (chance of recovery) depends on:

• Whether there is a change in the DNA and the type of change, if there is one.
• Whether lymphocytes are spread throughout the bone marrow.
• The stage of the disease.
• Whether the CLL gets better with treatment or has recurred (come back).
• Whether the CLL progresses to lymphoma or prolymphocytic leukemia
• The patient's general health.

After chronic lymphocytic leukemia has been diagnosed, tests are done to find out how far the cancer has spread in the blood and bone marrow.
Staging is the process used to find out how far the cancer has spread. It is important to know the stage of the disease in order to plan the best treatment. The following tests may be used in the staging process:

Bone marrow biopsy and aspiration: The removal of a small piece of bone and bone marrow by inserting a needle into the hipbone or breastbone. A pathologist views the sample under a microscope to look for abnormal cells.

Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body, such as the lymph nodes.

MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain and spinal cord. This procedure is also called nuclear magnetic resonance imaging (NMRI).

CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that produces it.

Antiglobulin test: A test in which a sample of blood is looked at under a microscope to find out if there are any antibodies on the surface of red blood cells or platelets. These antibodies may react with and destroy the red blood cells and platelets. This test is also called a Coomb's test.

The following stages are used for chronic lymphocytic leukemia:

Stage 0
In stage 0 chronic lymphocytic leukemia, there are too many lymphocytes in the blood, but there are no other symptoms of leukemia. Stage 0 chronic lymphocytic leukemia is indolent (slow-growing).

Stage I
In stage I chronic lymphocytic leukemia, there are too many lymphocytes in the blood and the lymph nodes are larger than normal.

Stage II
In stage II chronic lymphocytic leukemia, there are too many lymphocytes in the blood, the liver or spleen is larger than normal, and the lymph nodes may be larger than normal.

Stage III
In stage III chronic lymphocytic leukemia, there are too many lymphocytes in the blood and there are too few red blood cells (anemia). The lymph nodes, liver, or spleen may be larger than normal.

Stage IV
In stage IV chronic lymphocytic leukemia, there are too many lymphocytes in the blood and too few platelets (thrombocytopenia). The lymph nodes, liver, or spleen may be larger than normal and there may be too few red blood cells (anemia).

Refractory Chronic Lymphocytic Leukemia
Refractory chronic lymphocytic leukemia is cancer that does not get better with treatment.

There are different types of treatment for patients with chronic lymphocytic leukemia.
Different types of treatment are available for patients with chronic lymphocytic leukemia. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. Before starting treatment, patients may want to think about taking part in a clinical trial. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the "standard" treatment, the new treatment may become the standard treatment.

Four types of standard treatment are used:

Watchful waiting
Watchful waiting is closely monitoring a patient's condition without giving any treatment until symptoms appear or change. This is also called observation. During this time, problems caused by the disease, such as infection, are treated.

Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly in the spinal column, a body cavity such as the abdomen, or an organ, the drugs mainly affect cancer cells in those areas. The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Surgery
Splenectomy is surgery to remove the spleen.

Other types of treatment are being tested in clinical trials. These include the following:
Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances in the body that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells or block their growth. Monoclonal antibodies are given by infusion. They may be used alone or to deliver drugs, toxins, or radioactive material directly to cancer cells.

Chemotherapy with stem cell transplantation
Stem cell transplantation is a method of giving chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor, frozen, and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. Over time, these reinfused stem cells grow into (and restore) the body's blood cells.

Treatment Options by Stage

Stage 0 Chronic Lymphocytic Leukemia
Treatment of stage 0 chronic lymphocytic leukemia is usually watchful waiting.

Stage I Chronic Lymphocytic Leukemia
Treatment of stage I chronic lymphocytic leukemia may include the following:

• Watchful waiting when there are few or no symptoms.
• Chemotherapy with 1 or more drugs, with or without steroids.
• Low-dose external radiation therapy to areas of the body where cancer is found, such as the spleen or lymph nodes.
• A clinical trial of monoclonal antibodies.
• A clinical trial of chemotherapy with stem cell transplantation.

Stage II Chronic Lymphocytic Leukemia
Treatment of stage II chronic lymphocytic leukemia may include the following:

• Watchful waiting when there are few or no symptoms.
• Chemotherapy with 1 or more drugs, with or without steroids.
• Low-dose external radiation therapy to areas of the body where cancer is found, such as the spleen or lymph nodes.
• Radiation therapy to the spleen as palliative therapy to relieve symptoms and improve quality of life.
• A clinical trial of monoclonal antibodies.
• A clinical trial of chemotherapy with stem cell transplantation.

Stage III Chronic Lymphocytic Leukemia
Treatment of stage III chronic lymphocytic leukemia may include the following:

• Watchful waiting when there are few or no symptoms.
• Chemotherapy with 1 or more drugs, with or without steroids.
• Splenectomy
• Radiation therapy to the spleen as palliative therapy to relieve symptoms and improve quality of life.
• A clinical trial of monoclonal antibodies.
• A clinical trial of chemotherapy with stem cell transplantation.

Stage IV Chronic Lymphocytic Leukemia
Treatment of stage IV chronic lymphocytic leukemia may include the following:

• Watchful waiting.
• Chemotherapy with 1 or more drugs, with or without steroids.
• Splenectomy.
• Radiation therapy to the spleen as palliative therapy to relieve symptoms and improve quality of life.
• A clinical trial of monoclonal antibodies.
• A clinical trial of chemotherapy with stem cell transplantation.

Treatment Options for Refractory Chronic Lymphocytic Leukemia
Treatment of refractory chronic lymphocytic leukemia may include the following:

• A clinical trial of chemotherapy with stem cell transplantation.
• A clinical trial of a new treatment.

Cancer Glossary Terms

abdomen (AB-do-men)
The area of the body that contains the pancreas, stomach, intestine, liver, gallbladder, and other organs.

abnormal 
Not normal. In referring to a lesion or growth, may be cancerous or premalignant (likely to become cancer). 

anemia (a-NEE-mee-a)
A condition in which the number of red blood cells is below normal.

antibody (AN-tih-BOD-ee)
A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. 

B lymphocyte
A white blood cell that makes antibodies and is an important part of the immune system. B lymphocytes come from bone marrow. Also called B cell. 

blood chemistry study
A procedure in which a sample of blood is examined to measure the amounts of certain substances made in the body. An abnormal amount of a substance can be a sign of disease in the organ or tissue that produces it.

bone marrow
The soft, sponge-like tissue in the center of most large bones. It produces white blood cells, red blood cells, and platelets.

bone marrow aspiration (as-per-AY-shun)
The removal of a small sample of bone marrow (usually from the hip) through a needle for examination under a microscope.

bone marrow biopsy (BY-op-see)
The removal of a sample of tissue from the bone marrow with a needle for examination under a microscope. 

cancer
A term for diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Lymphoma is cancer that begins in the cells of the immune system.

catheter (KATH-i-ter)
A flexible tube used to deliver fluids into or withdraw fluids from the body. 

cell
The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells.

chemotherapy (kee-mo-THER-a-pee)
Treatment with anticancer drugs. 

chest x-ray
An x-ray of the structures inside the chest. An x-ray is a type of  high-energy radiation that can go through the body and onto film, making pictures of areas inside the chest, which can be used to diagnose disease.

chromosome (KRO-mo-some)
Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes.

chronic lymphocytic leukemia (KRAHN-ik lim-fo-SIT-ik loo-KEE-mee-a) CLL.
A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. 

clinical trial
A type of research study that tests how well new medical treatments or other interventions work in people. Such studies test new methods of screening, prevention, diagnosis, or treatment of a disease. The study may be carried out in a clinic or other medical facility. Also called a clinical study.

complete blood count
CBC. A test to check the number of red blood cells, white blood cells, and platelets in a sample of blood. Also called blood cell count.

CT scan
Computed tomography scan. A series of detailed pictures of areas inside the body taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan.

cytogenetics (SITE-o-juh-NET-iks)
The study of chromosomes and chromosomal abnormalities.

DNA
Deoxyribonucleic acid. The molecules inside cells that carry genetic information and pass it from one generation to the next.

external radiation (ray-dee-AY-shun)
Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external-beam radiation.

family history
A record of a person's current and past illnesses, and those of his or her parents, brothers, sisters, children, and other family members. A family history shows the pattern of certain diseases in a family, and helps to determine risk factors for those and other diseases.

groin
The area where the thigh meets the abdomen.

hemoglobin (HE-muh-GLOW-bun)
The substance inside red blood cells that binds to oxygen and carries it from the lungs to the tissues.

immune system (im-YOON)
The complex group of organs and cells that defends the body against infections and other diseases.

indolent (IN-doe-lint)
A type of cancer that grows slowly. 

infection
Invasion and multiplication of germs in the body. Infections can occur in any part of the body, and can be localized or systemic (spread throughout the body). The germs may be bacteria, viruses, yeast, or fungi. They can cause a fever and other problems, depending on the site of the infection. When the body's natural defense system is strong, it can often fight the germs and prevent infection. Cancer treatment can weaken the natural defense system.

infusion
A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. 

injection
Use of a syringe and needle to push fluids or drugs into the body; often called a "shot."

internal radiation (ray-dee-AY-shun)
A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy.

leukemia (loo-KEE-mee-a)
Cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of blood cells to be produced and enter the blood stream.

liver
A large organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile.

lymph node (limf node)
A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Lymph nodes filter lymph (lymphatic fluid), and they store lymphocytes (white blood cells). They are located along lymphatic vessels. Also called a lymph gland.

lymphatic system (lim-FAT-ik SIS-tem)
The tissues and organs that produce, store, and carry white blood cells that fight infections and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes, and lymphatic vessels (a network of thin tubes that carry lymph and white blood cells). Lymphatic vessels branch, like blood vessels, into all the tissues of the body.

lymphocyte (LIM-fo-site)
A type of white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases.

lymphoma (lim-FO-ma)
Cancer that begins in cells of the immune system. There are two basic categories of lymphomas. One kind is Hodgkin's lymphoma, which is marked by the presence of a type of cell called the Reed-Sternberg cell. The other category is non-Hodgkin's lymphomas, which includes a large, diverse group of cancers of immune system cells. Non-Hodgkin's lymphomas can be further divided into cancers that have an indolent (slowly progressing) course and those that have an aggressive (rapidly progressing) course. These subtypes behave and respond to treatment differently. Both Hodgkin's and non-Hodgkin's lymphomas can occur in children and adults, and prognosis and treatment depend on the stage and the type of cancer.

malignant (ma-LIG-nant)
Cancerous. Malignant tumors can invade and destroy nearby tissue and spread to other parts of the body.

monoclonal antibody (MAH-no-KLO-nul AN-tih-BAH-dee)
A laboratory-produced substance that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor.

MRI
Magnetic resonance imaging (mag-NET-ik REZ-o-nans IM-a-jing). A procedure in which radio waves and a powerful magnet linked to a computer are used to create detailed pictures of areas inside the body. These pictures can show the difference between normal and diseased tissue. MRI makes better images of organs and soft tissue than other scanning techniques, such as CT or X-ray. MRI is especially useful for imaging the brain, spine, the soft tissue of joints, and the inside of bones. Also called nuclear magnetic resonance imaging. 

natural killer cell
NK cell. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called a large granular lymphocyte.

organ
A part of the body that performs a specific function. For example, the heart is an organ.

palliative therapy (PAL-ee-yuh-tiv)
Treatment given to relieve the symptoms and reduce the suffering caused by cancer and other life-threatening diseases. Palliative cancer therapies are given together with other cancer treatments, from the time of diagnosis, through treatment, survivorship, recurrent or advanced disease, and at the end of life. 

pathologist (pa-THOL-o-jist)
A doctor who identifies diseases by studying cells and tissues under a microscope.

physical examination
An exam of the body to check for general signs of disease.

platelet (PLAYT-let)
A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called a thrombocyte.

prognosis (prog-NO-sis)
The likely outcome or course of a disease; the chance of recovery or recurrence.

progression
Increase in the size of a tumor or spread of cancer in the body. 

prolymphocytic leukemia
PLL. A type of chronic lymphocyctic leukemia (CLL), in which too many immature white blood cells (prolymphocytes) are found in the blood and bone marrow. PLL usually progresses more rapidly than classic CLL.

protein (PRO-teen)
A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

quality of life
The overall enjoyment of life. Many clinical trials assess the effects of cancer and its treatment on the quality of life. These studies measure aspects of an individual's sense of well-being and ability to carry out various tasks.

radiation (ray-dee-AY-shun)
Energy released in the form of particles or electromagnetic waves. Common sources of radiation include radon gas, cosmic rays from outer space, and medical x-rays.

radiation therapy (ray-dee-AY-shun)
The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy, irradiation, and x-ray therapy.

radioactive (RAY-dee-o-AK-tiv)
Giving off radiation.

radioactive seed
A small, radioactive pellet that is placed in or near a tumor. Cancer cells are killed by the energy given off as the radioactive material decays (breaks down).

recur
To occur again.

red blood cell
RBC. A cell that carries oxygen to all parts of the body. Also called an erythrocyte.

refractory cancer
Cancer that has not responded to treatment.

risk factor
Something that may increase the chance of developing a disease. Some examples of risk factors for cancer include age, a family history of certain cancers, use of tobacco products, certain eating habits, obesity, exposure to radiation or other cancer-causing agents, and certain genetic changes.

spleen
An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach.

splenectomy (splen-EK-toe-mee)
An operation to remove the spleen.

stage
The extent of a cancer within the body. If the cancer has spread, the stage describes how far it has spread from the original site to other parts of the body.

stage 0 chronic lymphocytic leukemia
Too many lymphocytes are in the blood but there are usually no other symptoms of leukemia.

stage I chronic lymphocytic leukemia
The blood has too many lymphocytes, and lymph nodes are swollen.

stage II chronic lymphocytic leukemia
The blood has too many lymphocytes, and the liver or spleen is swollen.

stage III chronic lymphocytic leukemia
There are too many lymphocytes in the blood, and there are too few red blood cells (anemia). Lymph nodes, liver, or spleen may be swollen.

stage IV chronic lymphocytic leukemia
There are too many lymphocytes in the blood and too few platelets. This makes it hard for the blood to clot. Lymph nodes, liver, or spleen may be swollen and there may be too few red blood cells present (anemia).

staging (STAY-jing)
Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. It is important to know the stage of the disease in order to plan the best treatment.

standard therapy
A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research.

stem cell
A cell from which other types of cells can develop.

stem cell transplantation
A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells.

steroid (STAIR-oyd)
A type of drug used to relieve swelling and inflammation. 

stomach
An organ that is part of the digestive system. It helps in the digestion of food by mixing it with digestive juices and churning it into a thin liquid.

symptom
An indication that a person has a condition or disease. Some examples of symptoms are headache, fever, fatigue, nausea, vomiting, and pain.

systemic chemotherapy
Treatment with anticancer drugs that travel through the bloodstream, reaching and affecting cells all over the body.

T cell
One type of white blood cell that attacks virus-infected cells, foreign cells, and cancer cells. T cells also produce a number of substances that regulate the immune response.

thrombocytopenia
A decrease in the number of platelets in the blood that may result in easy bruising and excessive bleeding from wounds or bleeding in mucous membranes and other tissues.

tissue (TISH-oo)
A group or layer of cells that are alike and that work together to perform a specific function.

toxin
A poison produced by certain animals, plants, or bacteria.

virus (VYE-rus)
A microorganism that can infect cells and cause disease.

watchful waiting
Closely monitoring a patient's condition but withholding treatment until symptoms appear or change. Also called observation.

white blood cell
WBC. Refers to a blood cell that does not contain hemoglobin. White blood cells include lymphocytes, neutrophils, eosinophils, macrophages, and mast cells. These cells are made by bone marrow and help the body fight infection and other diseases.

x-ray
A type of high-energy radiation. In low doses, x-rays are used to diagnose diseases by making pictures of the inside of the body. In high doses, x-rays are used to treat cancer.

Source: National Institutes of Health; National Cancer Institute