(Also known as non-Hodgkin’s lymphoma, NHL, or sometimes just lymphoma) is a cancer that starts in cells of the lymph system, which is part of the body’s immune system. Lymph cells (called lymphocytes) are located mainly in the lymph nodes and other lymphoid tissues (such as the spleen or bone marrow). These will be described in more detail in the section The Lymph System and Lymphoid Tissue.

Other types of cancer — lung or colon cancers, for example — can spread to lymph tissue such as the lymph nodes or bone marrow. But cancers that start in these places and then spread to the lymph tissue are not lymphomas.

There are 2 main types of lymphomas. Hodgkin lymphoma (also known as Hodgkin’s lymphoma, Hodgkin disease, or Hodgkin’s disease) is named after Dr. Thomas Hodgkin, who first described it. Hodgkin disease is discussed in a separate American Cancer Society document. All other types of lymphoma are called non-Hodgkin lymphomas.

These 2 types of lymphoma can usually be distinguished from each other by looking at the cancer cells under a microscope. In some cases, sensitive lab tests may be needed to tell them apart.

The Lymph System and Lymphoid Tissue

To understand what lymphoma is, it helps to know about the body’s lymph system.

The lymph system (also known as the lymphatic system) is composed mainly of lymphoid tissue, lymph vessels, and fluid called lymph (a clear fluid containing waste products and excess fluid from tissues). Lymphoid tissue is formed by several types of immune system cells that work together to help the body fight infections. Lymphoid tissue is found in many places throughout the body (described below).

Lymphocytes

Most of the cells found in lymphoid tissue are lymphocytes, a type of white blood cell. The 2 main types of lymphocytes are B lymphocytes (B cells) and T lymphocytes (T cells). Both types can develop into lymphoma cells, but B-cell lymphomas are much more common than T-cell lymphomas in the United States.

Normal T cells and B cells do different jobs within the immune system.

B cells normally help protect the body against germs (bacteria or viruses) by making proteins called antibodies. The antibodies attach to the bacteria or viruses and attract other immune system cells that surround and digest the antibody-coated germs. Antibodies also attract certain blood proteins that can kill bacteria.

There are several types of T cells, each with a specialized job. Some normal T cells help protect the body against viruses, fungi, and some bacteria. They recognize specific substances found in virus-infected cells and destroy these cells. T cells can also release substances called cytokines that attract certain other types of white blood cells, which then digest the infected cells. T cells are also thought to destroy some types of cancer cells, as well as the cells of transplanted organs. Some types of T cells play a role in either boosting or slowing the activity of other immune system cells.

Lab tests identify B cells and T cells by certain substances on their surfaces. Some substances are found only on B cells, and others are found only on T cells. There are also several stages of B-cell and T-cell development (or maturation) that can be recognized by these lab tests.

This information is helpful because each type of lymphoma tends to resemble a particular subtype of normal lymphocytes at a certain level of development. Determining the type of lymphoma a person has is the first step in considering treatment options.

Organs That Contain Lymphoid Tissue

Because lymphoid tissue is in many parts of the body, lymphomas can start almost anywhere. The major sites of lymphoid tissue are:

Lymph nodes: Lymph nodes are bean-sized organs located throughout the body and connected by a system of lymphatic vessels. These vessels are like veins, except that instead of carrying blood, they carry lymph and immune system cells traveling between lymph nodes and other tissues.

Lymph nodes get bigger when they fight infection. Lymph nodes that grow in reaction to infection are called reactive nodes or hyperplastic nodes and are often tender to the touch. An enlarged lymph node is not usually a sign of a serious problem. Enlarged lymph nodes in the neck are often felt in people with sore throats or colds. But a large lymph node is also the most common sign of lymphoma. Lymph node enlargement is discussed more in the section, “How Is Non-Hodgkin Lymphoma Diagnosed?”

Spleen: The spleen is located under the lower part of the rib cage on the left side of the body. An average adult spleen weighs about 5 ounces. The spleen makes lymphocytes and other immune system cells to help fight infection. It also stores healthy blood cells and filters out damaged blood cells, bacteria, and cell waste.

Thymus gland: The thymus gland lies behind the upper part of the breastbone and in front of the heart. Before birth, the thymus plays a vital role in development of T lymphocytes. The thymus gland’s size (about 1 ounce) and function diminish over the first 20 years of life. Despite this, the thymus continues to be active in immune system function throughout life.

Adenoids and tonsils: These are collections of lymphoid tissue located at the back of the throat. They help make antibodies against germs that are breathed in or swallowed. They are easy to see when they become enlarged during an infection or if they become cancerous.

Digestive tract: The stomach and intestinal tract as well as many other organs also contain lymphoid tissue.

Bone marrow: The bone marrow (the soft inner part of bones) makes red blood cells, blood platelets, and white blood cells. Red blood cells carry oxygen from the lungs to the rest of the body. Platelets plug up small holes in blood vessels caused by cuts or scrapes. White blood cells’ main job is fighting infections. The 2 main types of white blood cells are granulocytes and lymphocytes. Bone marrow lymphocytes are primarily B cells. Lymphomas sometimes start from bone marrow lymphocytes.

Types of Non-Hodgkin Lymphoma

Classifying non-Hodgkin lymphoma can be quite confusing (even for many doctors) because there are so many types (around 30) and because several different systems have been used. The most recent system is the World Health Organization (WHO) classification. The WHO system uses the appearance of the lymphoma cells, the chromosome features of the cells, and the presence of certain chemicals on the surface of the cells. (Older systems classified lymphomas based only on their appearance under a microscope.)

This overview classifies the most common lymphomas according to whether they are B-cell or T-cell lymphomas and lists them by how common they are. Some rarer forms of non-Hodgkin lymphoma are not discussed here.

B-Cell Lymphomas

B-cell lymphomas make up most (about 85%) of non-Hodgkin lymphomas in the United States.

Diffuse Large B-cell Lymphoma

This is one of the more common types of non-Hodgkin lymphoma in the United States, accounting for about 1 out of every 3 cases. The cells are fairly large when viewed under the microscope.

Diffuse large B-cell lymphoma DLBCL can affect any age group but occurs mostly in older people (the average age of most patients is mid-60s). The usual symptoms are a quickly growing mass in an internal lymph node, such as in the chest or abdomen or in a lymph node that you can feel, for example, in the neck or armpit. Although this lymphoma usually starts in lymph nodes, it can grow in other areas such as the intestines, bone, and even the brain or spinal cord.

About 1 out of 3 of these lymphomas is confined to one part of the body (localized). When it is localized, this type of lymphoma is considered to be more curable than when it has spread to other parts of the body. Genetic tests have shown that there are different subtypes of DLBCL, even though they look the same under the microscope. These subtypes seem to have different outlooks (prognoses) and responses to treatment.

This is a fast growing lymphoma, but it often responds well to treatment with chemotherapy. Overall, about 3 out of 4 people will have no signs of disease after initial treatment, and about half of all people with this lymphoma are cured with therapy.

Follicular Lymphoma

About 1 out of 4 lymphomas in the United States are follicular lymphomas. The term follicular is used because the cells tend to grow in a circular, or nodular, pattern in lymph nodes.

The average age for people with this lymphoma is about 60. It is rare in very young people. Most of the time, this lymphoma occurs in many lymph node sites in the body, as well as in the bone marrow. In about 10% of cases, it only involves lymph nodes in one part of the body.

Although it is usually not considered curable by standard treatment, this is often a very slow-growing lymphoma, and the 5-year survival rate (the percentage of people surviving at least 5 years) is around 60% to 70%. Often these lymphomas are not treated when they are first diagnosed if the patient has no symptoms of the disease. Over time, out of 3 follicular lymphomas about 1 changes (transforms) into a fast-growing diffuse B-cell lymphoma.

Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma

These related diseases account for about 1 out of 4 lymphomas. The same type of cell (known as a small lymphocyte) is involved in both chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). The only difference is where the cancer occurs. In CLL it is mostly in the blood and bone marrow; in SLL, it is mainly in the lymph nodes.

Both are slow-growing diseases, although CLL, which is much more common, tends to grow slower. CLL and SLL are not considered curable with standard treatments, but depending on the stage and growth rate of the disease, most patients can live longer than 10 years. Occasionally over time, these slow-growing lymphomas transform into a more aggressive type of lymphoma.

For more detailed information, see the American Cancer Society document, Leukemia — Chronic Lymphocytic.

Mantle Cell Lymphoma

Only about 5% of lymphomas are of this type. The cells are small to medium.

Men are affected most often. The average age of patients is in the early 60s. The lymphoma is usually widespread when it is diagnosed, involving lymph nodes, bone marrow, and, very often, the spleen.

Although this isn’t a very fast growing lymphoma, it is hard to treat. Only about 1 in 5 patients survive at least 5 years. Newer, more aggressive treatments may be more effective than those used in the past, which may help improve the survival rates of patients now being diagnosed.

Marginal Zone B-cell Lymphomas

Marginal zone lymphomas account for about 4% of lymphomas. The cells in these lymphomas look small under the microscope. There are 3 main types of marginal zone lymphomas.

Extranodal marginal zone B-cell lymphomas (also known as mucosa-associated lymphoid tissue lymphomas): These lymphomas start in places other than the lymph nodes (hence the name “extranodal”)and are the most common type. Most mucosa-associated lymphoid tissue (MALT) lymphomas arise in the stomach and are thought to be related to an infection by the bacteria Helicobacter pylori, which is also the cause of stomach ulcers. Other possible sites of MALT lymphomas include the lung, skin, thyroid, salivary glands, and tissues surrounding the eye. Usually it is confined to the area where it begins and is not widespread. Many of these other MALT lymphomas have also been linked to infections with bacteria or viruses.

The average age of patients with this lymphoma is about 60. It is a slow-growing lymphoma and is often curable in its early stages. Doctors often use antibiotics as the first treatment for this type of lymphoma, especially MALT lymphoma of the stomach, as they may get rid of the Helicobacter pylori infection.

Nodal marginal zone B-cell lymphoma: This is a rare disease, found mainly in older women. Mostly lymph nodes are involved, although the cells can also sometimes be found in the bone marrow.

This tends to be a slow-growing lymphoma (although not usually as slow as MALT lymphoma), and many patients are cured if they are diagnosed in the early stages.

Splenic marginal zone B-cell lymphoma: This is a rare lymphoma. Most often the lymphoma is found only in the spleen and bone marrow.

Patients are often elderly and male and suffer from fatigue and discomfort caused by an enlarged spleen. Because the disease is slow-growing, treatment may not be needed unless the symptoms become troublesome.

Primary Mediastinal B-cell Lymphoma

This type accounts for about 2% of all lymphomas. The cells are large and resemble those of diffuse large B-cell lymphomas.

This lymphoma starts in the mediastinum (the area around the heart and behind the chest bone). It usually is localized at the beginning and rarely involves the bone marrow. It can cause trouble breathing because it often presses on the windpipe (trachea) leading into the lungs. It can also block the superior vena cava (the large vein that returns blood to the heart from the arms and head). This can cause the arms and face to swell.

About 2 out of 3 people with this lymphoma are women. Most are young — in their 30s. It is a fast growing lymphoma but it is treatable. About half of patients can be cured.

Burkitt Lymphoma

This type makes up about 1% to 2% of all lymphomas. It is named after the doctor who first described this disease in African children and young adults. The cells are medium sized. Another kind of lymphoma, called Burkitt-like lymphoma, has slightly larger cells. Because this second kind of lymphoma is hard to tell apart from Burkitt lymphoma, the WHO classification combines them.

This is a very fast-growing lymphoma. In the African variety, it often starts as tumors of the jaws or other facial bones. In the more common types seen in the United States, the lymphoma usually starts in the abdomen, where it forms a large tumor mass. It can also start in the ovaries, testes, or other organs, and can spread to the brain and spinal fluid.

Close to 90% of patients are male, and the average age is about 30. Although this is a fast-growing lymphoma, over half of patients can be cured by intensive chemotherapy.

Lymphoplasmacytic Lymphoma (Waldenstrom Macroglobulinemia)

This type is not common, accounting for 1% to 2% of lymphomas. The cells are small and found mainly in the bone marrow, lymph nodes, and spleen.

Most of the time the lymphoma cells make an antibody called immunoglobulin M (IgM), which is a very large protein. This antibody circulates in the blood in large amounts, and causes the liquid part of the blood to thicken, like syrup. This can lead to decreased blood flow to many organs, which can cause problems with vision (because of poor circulation in blood vessels in the back of the eyes) and neurological problems (such as headache, dizziness, and confusion) caused by poor blood flow within the brain. Other symptoms can include feeling tired and weak, and a tendency to bleed easily.

This lymphoma is slow growing. Although it isn’t usually considered to be curable, most patients live longer than 5 years.

For more information, see the American Cancer Society document, Waldenstrom Macroglobulinemia.

Hairy Cell Leukemia

Despite the name, this is sometimes considered to be a type of lymphoma. This disease is rare — about 1,000 people in the United States are diagnosed with this type each year. The cells are small B lymphocytes with projections around them that give them a “hairy” appearance. They are typically found in the bone marrow and spleen and circulating in the blood.

Patients tend to be older in general. Hairy cell leukemia is slow-growing, and some patients may never need treatment. An enlarging spleen or dropping blood counts (due to cancer cells invading the bone marrow) are the usual reasons to begin treatment, which is highly effective. Hairy cell leukemia is also described in the separate American Cancer Society document, Leukemia–Chronic Lymphocytic.

Primary Central Nervous System Lymphoma

This lymphoma usually involves the brain (called primary brain lymphoma), but it may also be found in the spinal cord and in tissues around the spinal cord and the eye. Over time, it tends to become widespread in the central nervous system. Although this was a rare tumor in the past, it has become more common in patients with acquired immune deficiency syndrome (AIDS). Most people develop headache and confusion. They can also have vision problems, paralysis of some facial muscles, and even seizures in some cases.

The outlook for people with this condition has always been thought to be fairly poor, but about 30% to 50% of people can live at least 5 years with today’s treatments.

T-Cell Lymphomas

T-cell lymphomas represent less than 15% of non-Hodgkin lymphomas in the United States.

Precursor T-lymphoblastic Lymphoma/Leukemia

This disease accounts for about 1% of all lymphomas. It can be considered either a lymphoma or leukemia, depending on how much of the bone marrow is involved (leukemias have more bone marrow involvement). The cancer cells are small-to-medium immature T-cells.

It often starts in the thymus gland (where many T cells are made) and can develop into a large tumor in the mediastinum (the area around the heart and behind the breast bone). This can cause trouble breathing if it presses on the windpipe (trachea) leading into the lungs. It can also block the superior vena cava (the large vein that returns blood to the heart from the arms and head), which can cause the arms and face to swell.

Patients are most often young adults, with males being affected more often than females.

This lymphoma is fast-growing, but if it hasn’t spread to the bone marrow when it is first diagnosed, the chance of cure with chemotherapy is quite good. Once it is in the bone marrow, only about 40% to 50% of patients can be cured.

Peripheral T-cell Lymphomas

These lymphomas develop from more mature forms of T cells. There are several kinds of peripheral T-cell lymphomas, which in total account for about 5% of all lymphomas.

—      Cutaneous T-cell lymphomas (mycosis fungoides, Sezary syndrome): These T-cell lymphomas start in the skin. They are described in the American Cancer Society document, Lymphoma of the Skin. 

—      Angioimmunoblastic T-cell lymphoma: This lymphoma tends to occur in the lymph nodes and may affect the spleen or liver. Patients usually have fever, weight loss, and skin rashes and often develop infections. This lymphoma often progresses quickly, although some patients get better with cortisone-like drugs (corticosteroids) such as prednisone and/or chemotherapy. But it’s not clear that this lymphoma can be cured, and intensive chemotherapy with a stem cell transplant is often used. 

—      Extranodal natural killer/T-cell lymphoma, nasal type: This type often involves the upper airway passages, such as the nose and upper throat, but it can also invade the skin and digestive tract. It is much more common in parts of Asia and South America. All ages can be affected. If the lymphoma is localized to the nasal passages, it can often be cured by chemotherapy and radiotherapy. But if it is widespread, then only a few patients are cured by very aggressive chemotherapy. 

—      Enteropathy type T-cell lymphoma: This lymphoma occurs in people with sensitivity to gluten, the main protein in wheat flour. The disease, called gluten-sensitive enteropathy, can progress to this lymphoma, which typically invades the walls of the intestines. Once it occurs, the patient’s outlook is usually poor because of damage to the intestines. 

—      Subcutaneous panniculitis-like T-cell lymphoma: This rare lymphoma invades the deep layers of the skin, where it causes nodules to form. It is described further in the American Cancer Society document, Lymphoma of the Skin.  

—      Anaplastic large cell lymphoma: About 1% to 2% of lymphomas are of this type. The cells appear large under the microscope. The type of lymphoma is more common in young people, but it does occur in patients in their 50s and 60s. It usually starts in lymph nodes and can also spread to skin. There is also a form that begins in the skin. Although this type of lymphoma appears to be fast-growing, chemotherapy often works well. Many patients with this lymphoma are cured. 

—      Peripheral T-cell lymphoma, unspecified: This name is given to T-cell lymphomas that don’t readily fit into any of the groups above. The tumor cells can be small or large. Most patients are in their 60s. As a group, these lymphomas tend to be widespread and grow quickly. Some cases respond well to chemotherapy, although few patients survive beyond 5 years.

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There is a good book that has come out in October, 2005 An Illustrated Guide to Skin Lymphomas, Cerroni, Gatter, Kerl, 2nd. Ed, that devoted most of chapter 4 to LyP.

Okay, I know you are wondering about the lymphoma cancer link. Most papers on LyP suggest that 10-20% of LyP patients go on to develop an associated CTCL (cutaneous t cell lymphoma).  My advice to you is not to dwell on what might or might not happen in the future. Try to live a healthy lifestyle and think positive (some doctors and patients believe that stress increases the amount of lesions). If you do develop symptoms of lymphoma (swollen lymph nodes, fever, unexplained weight loss, night sweats) contact your doctor.

If you have LyP (as verified by your doctor’s diagnosis and a biopsy slide and report from pathology), I would strongly recommend that you join the Lymphomatoid Papulosis Central Registry at Beth Israel Hospital in Boston, MA.

In my biased opinion, if anyone is going to find a cure for this condition, it will be hematopathologist Marshall E. Kadin and his colleagues. (On March 1, 1999, Dr. Kadin wrote in an e-mail: There are two LyP funds. One is at my hospital and the other is in Fargo, North Dakota, organized by Warren Macaulay, the man who first described LyP.  His fund is supporting a research project in my lab to look for a possible virus in LyP. We are making the first rigorous investigation of this possibility and should know the answer within a year). You can e-mail Dr. Kadin at mkadin@caregroup.harvard.edu to get more information about joining the registry or to learn about his LyP clinical trials.

I was unable to locate an online support group for folks with LyP, so I started an electronic mailing loop in September 1998. This allowed folks to submit group posts to “discuss” what’s happening in our lives and the medical research community in regard to this disorder. We have now switched over to a mailing list, which makes it easier for folks to post to our discussion group. If you (or a family member) has LyP and would like to join a wonderful group of folks from around the world.

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Phase I/II Clinical Trial Results

John P. Leonard¹, Morton Coleman¹, Jamie C. Ketas¹, Amy Chadburn², Richard Furman¹, Michael W. Schuster¹, Eric J. Feldman¹, Michelle Ashe¹, Stephen J. Schuster³, William A. Wegener⁴, Hans J. Hansen⁴, Heather Ziccardi⁴, Michael Eschenberg⁵, Urte Gayko⁵, Scott Z. Fields⁶, Alessandra Cesano⁵ and David M. Goldenberg^4,7

¹ Division of Hematology and Oncology and ² Department of Pathology, Center for Lymphoma and Myeloma, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York; ³ University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania; ⁴ Immunomedics, Inc., Morris Plains, New Jersey; ⁵ Amgen Inc., Thousand Oaks, California; ⁶ Eisai Medical Research, Teaneck, New Jersey; and ⁷ Center for Molecular Medicine and Immunology, Garden State Cancer Center, Belleville, New Jersey

ABSTRACT

Purpose: We conducted a single-center, dose-escalation study evaluating the safety, pharmacokinetics, and efficacy of epratuzumab, an anti-CD22 humanized monoclonal antibody, in patients with aggressive non-Hodgkin’s lymphoma.

Experimental Design: Epratuzumab was administered once weekly for 4 weeks at 120-1000-mg/m² doses to 56 patients [most (n = 35) with diffuse large B-cell lymphoma].

Results: Patients were heavily pretreated (median, 4 prior therapies), 25% received prior high-dose chemotherapy with stem cell transplant, and 84% had bulky disease (5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Most (95%) infusions were completed within 1 h. The mean serum half-life was 23.9 days. Across all dose levels and histologies, objective responses (ORs) were observed in five patients (10%; 95% confidence interval, 3–21%), including three complete responses. In patients with diffuse large B-cell lymphoma, 15% had ORs. Overall, 11 (20%) patients experienced some tumor mass reduction. Median duration of OR was 26.3 weeks, and median time to progression for responders was 35 weeks. Two responses are ongoing at 34 months, including one rituximab-refractory patient.

Conclusions: These data demonstrate that epratuzumab has a good safety profile and exerts antitumor activity in aggressive non-Hodgkin’s lymphoma at doses of 240 mg/m², thus warranting further evaluation in this clinical setting.

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Cancer is a disease of cells. It is an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).

Cancer is also called malignancy. A cancerous growth or tumor is sometimes referred to as a malignant growth or tumor. A non-malignant growth or tumor is referred to as benign. Benign tumors are not cancer.

Cancer is not one disease. It is a group of more than 100 different and distinctive diseases. Cancer is NOT contagious.

Cancer can involve any tissue of the body and have many different forms in each body area. Most cancers are named for the type of cell or organ in which they start. If a cancer spreads (metastasizes), the new tumor bears the same name as the original (primary) tumor.

Cancer is the Latin word for crab. The ancients used the word to mean a malignancy, doubtless because of the crab-like tenacity a malignant tumor sometimes seems to show in grasping the tissues it invades. Cancer may also be called malignancy, a malignant tumor, or a neoplasm (literally, a new growth).

What are the most common types of cancer?

The frequency of a particular cancer may depend on gender.

The list of common cancers includes cancers that are diagnosed with the greatest frequency in the United States. Cancer incidence statistics from the American Cancer Society and other resources were used to create the list. To qualify as a common cancer, the estimated annual incidence for 2006 had to be 30,000 cases or more.

The most common type of cancer on the list is non-melanoma skin cancer, with more than 1,000,000 new cases expected in the United States in 2006. Non-melanoma skin cancers represent about half of all cancers diagnosed in the US.

The cancer on the list with the lowest incidence is thyroid cancer. The estimated number of new cases of thyroid cancer for 2006 is 30,180.

Because colon and rectal cancers are often referred to as “colorectal cancers,” these two cancer types were combined for the list. For 2006, the estimated number of new cases of colon cancer is 106,680, and the estimated number of new cases of rectal cancer is 41,930. These numbers are slightly larger than those estimated for 2005.

Kidney cancer can be divided into two major groups, renal parenchyma cancers and renal pelvis cancers. Approximately 82 percent of kidney cancers develop in the renal parenchyma,2 and nearly all of these cancers are renal cell cancers. The estimated number of new cases of renal cell cancer for 2006 is 31,890.

Leukemia as a cancer type includes acute lymphoblastic (or lymphoid) leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous (or myeloid) leukemia, and other forms of leukemia. It is estimated that more than 35,000 new cases of leukemia will be diagnosed in the United States in 2006, with acute myeloid leukemia being the most common type (approximately 12,000 new cases). The total number of new leukemia cases estimated for 2006 is slightly larger than the number estimated for 2005.

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Stromal cell-derived factor-1 (CXCL12/SDF-1) is a chemokine involved in development and trafficking of B cells and hematopoietic progenitors. Recent evidences also suggest CXCL12/SDF-1 involvement in breast cancer cell pseudopodia formation and in invasive breast cancer metastasis . The responses of hematopoietic, B, and breast cancer cells to CXCL12/SDF-1 appear to be mediated by its receptor CXCR4. CXCL12/SDF-1 seems to play a relevant role also in some B-cell malignancies. In fact, CXCL12/SDF-1 enhances migration of follicular NHL³ cells , and the CXCR4-CXCL12/SDF-1 circuitry appears to be crucial for migration of chronic lymphocytic leukemia  and acute lymphoblastic leukemia B cells .

In the present study, we evaluated a panel of malignant lymphoid cell lines and primary NHL cells, and found CXCR4 expression in the large majority of malignant cells. CXCR4 neutralization by monoclonal antibodies had profound in vitro effects on NHL cells including inhibition of transendothelial/stromal migration, enhanced apoptosis, decreased proliferation, and inhibition of pseudopodia formation. In preclinical models, CXCR4 neutralization demonstrated remarkable efficacy in either tumor challenge and therapy trials in the absence of overt short- or long-term toxicity. Furthermore, CXCR4 neutralization increased the number of lymphoma cells circulating 24 h after i.v. injection, suggesting a crucial role of CXCR4 in tumor cell extravasation. Taken together, our data indicate that the CXCR4-CXCL12/SDF-1 circuitry may be an useful target for NHL therapy.

Cells and Cell Lines.

We evaluated a panel of 12 malignant lymphoid cell lines and 19 primary NHL cells. NHL cell lines were Namalwa (Burkitt’s NHL), HS-Sultan (Burkitt’s NHL), DoHH2 (transformed follicular NHL), Granta-519 (mantle cell NHL), and RAP1-EIO (T cell-rich B-cell NHL) from patients with B-cell NHL; L363 from a patient with plasma cell leukemia; Karpas 299 from a patient with T-cell NHL; Jurkat, CEM, and MOLT-4 from patients with T-cell leukemia-NHL; and JJN3 and IM9 from patients with multiple myeloma. After informed consent, primary NHL cells were collected from the bone marrow or peripheral blood of 19 NHL patients (purity >87%). Diagnoses were diffuse large B-cell NHL (n = 3), mantle cell NHL (n = 5), follicular NHL (n = 4), peripheral blood T-cell NHL (n = 2), lymphocytic NHL (n = 3), and marginal zone NHL (n = 2). Cells were cultured in RPMI-10% FBS with the exception of the Granta-519 (DMEM-10% FBS) cell line.

Detection of Chemokine Receptors and CXCL12/SDF-1 mRNA.

CXCR1, 2, 3, and 4, and CCR1, 2, 3, 4, and 5 mRNA expression was evaluated by multiplex RT-PCR. Total RNA was isolated from cell lines and primary cells by QIAamp RNA kit (Quiagen, Hilden, Germany), and treated with a reverse transcriptase enzyme (SuperScript II; Life Technologies, Inc., Gaithersburg, MD). The cDNA generated following this approach was amplified by multiplex PCR using commercially available kits Cytoexpress hCXCR and hCCR (Biosource, Camarillo, CA) according to manufacturer’s instructions. PCR-amplified products were stained with ethidium bromide and evaluated by 2% agarose-gel electrophoresis. The Quantikine colorimetric assay (R&D, Minneapolis, MN) was used according to manufacturer’s instructions for quantitative evaluation of CXCL12/SDF-1 mRNA. Positive controls (Cytoexpress) and reagents to generate a calibrator curve (Quantikine) were obtained by manufacturers, and the appropriate null control reactions always remained negative.

Flow Cytometry Studies

The expression of CXCR4 on the surface of cell lines and primary NHL cells was evaluated by four-color flow cytometry using a FACScalibur (BD, Mountain View, CA), anti-CD45, -CD19, -, -, and -CXCR4 monoclonal antibodies (BD), annexin V, and 7AAD to depict apoptotic or dead cells as described previously .

In Vitro Studies

Sodium azide-free monoclonal antibodies anti-CXCR4 (clones MAB171 from R&D and 12G5 from BDPharMingen, San Diego, CA) and polyclonal anti-SDF-1 (R&D) were used to neutralize the CXCR4-CXCL12/SDF-1 circuitry. Appropriate irrelevant antibodies (sodium azide-free 2007OD and anti-CD19; BDPharMingen) were used as control in vitro and in vivo. After 5-h culture in RPMI-10% FBS at 37°C, the extent of cell proliferation was evaluated by a standard MTT assay (Sigma, St. Louis, MO) and by cell proliferation reagent WST-1 (Boehringer Mannheim, Mannheim, Germany; Ref. 8 ), and cell viability measured by flow cytometry. Apoptosis was investigated by flow cytometry and commercially available multiplex RT-PCR kits (Biosource) able to detect caspases, Fas, FasL, FLICE, FADD, and TRADD.

We used an approach similar to Burger et al. and Poznansky et al. with slight modifications to study the effect of CXCR4 neutralization in NHL cell transendothelial/stromal migration in transwell (diameter, 6.5 mm; pore, 5 µm; Costar, Cambridge, MA) culture. A layer consisting of 2 x 10⁴ human microvascular endothelial cells (Cascade Biologics, Portland, OR) or bone marrow-derived stromal cell lines L87/4 and L88/5  was seeded in the upper chamber and cultured for 48 h in RPMI-10% FBS. A total of 2 x 10⁵ Namalwa NHL cells were preincubated for 30 min in 100 µl migration buffer containing different concentrations of neutralizing anti-CXCR4 monoclonal antibodies or control antibodies. Cells were seeded in the upper chambers coated with endothelial or stromal cells. After 30-min incubation at 4°C, chambers were transferred to wells containing medium with or without CXCL12/SDF-1 (125 ng/ml; R&D) as a chemoattractant and incubated for 2 h at 37°C. Cells that migrated to the lower chamber were counted in triplicates by flow cytometry.

Pseudopodia formation in Namalwa and Granta 519 cells was evaluated as described by Muller et al.  . Cells were incubated at 37°C in RPMI supplemented with 125 ng/ml CXCL12/SDF-1 (or CX₃CL1/fractalkine as negative control) in the presence of anti-CXCR4, anti-CD19, or control (irrelevant) antibodies. After a 20-min culture, cells were fixed by paraformaldehyde, and pseudopodia formation was observed and enumerated by microscopy.

In Vivo Studies

CXCR4- and CXCL12/SDF-1 neutralization were evaluated in a model of human NHL generated in our laboratory by transplanting Namalwa cells in NOD/SCID mice (11 , 12) . This NHL cell line was found to be the most aggressive one in terms of efficiency of engraftment, speed of engraftment, and tumor size in a panel of lymphoid malignant cell lines tested in i.p. (11 , 12) or s.c. (13) xenotransplants. To generate a disease similar to human high-grade B-cell NHL, we transplanted NOD/SCID mice i.p. rather than s.c., and Namalwa cells generated measurable i.p. tumors in the injection site in 100% of injected animals. Tumor volume was measured by calipers and the formula [width² x length x 0.52] applied for approximating the volume of a spheroid (12) .

In a first tumor-challenge trial, 2 x 10⁵ Namalwa cells were preincubated with 10 µg of sodium azide-free anti-CXCR4, anti-CXCL12/SDF-1, or control antibodies before i.p. injection (n = 6/study group). In a second tumor-challenge trial, mice were injected i.v. with 2 x 10⁵ Namalwa cells preincubated with 10 µg of sodium azide-free anti-CXCR4, anti-CXCL12/SDF-1, or control antibodies (n = 12/study group). In both tumor-challenge trials, tumor cells were washed before injection.

To investigate the therapeutic potential of CXCR4-neutralization, mice injected i.p. with 2 x 10⁵ Namalwa cells (not preincubated by anti-CXCR4) were treated in a site different from tumor injection with 3 weekly i.p. injections of 100 µg of sodium azide-free anti-CXCR4 or control antibodies. Animals (n = 12/study group, in two replicate trials involving a total of 12 treated animals and 12 controls) were treated on days 3, 10, and 17 after tumor injection.

Tumor-bearing mice were sacrificed by CO₂ inhalation, and tumor engraftment confirmed by histology, immunohistochemistry, and flow cytometry. Tumor weight was evaluated after complete removal of the i.p. tumor bulk. For histology and immunohistochemistry evaluation, tumor samples were fixed in 10% formalin and embedded in paraffin. Sections (4 µm-thick) were stained with H&E and Giemsa for conventional histology. For immunohistochemistry, sections were immunostained with the anti-CD10 and -CD20 monoclonal antibodies by DAKO (Glostrup, Denmark). In flow cytometry, tumor expression of human CD19 and CD20 antigens was evaluated by BD monoclonal antibodies.

In separate studies (n = 6), Namalwa cell extravasation was evaluated in vivo injecting NOD/SCID mice i.v. with 2 x 10⁵ Namalwa cells preincubated with 10 µg of sodium azide-free anti-CXCR4 or control antibodies. Mice were sacrificed 24 h after injection, and the frequency and viability of Namalwa cells circulating in the peripheral blood evaluated by flow cytometry. A minimum of 100,000 circulating cells were evaluated.

All of the procedures involving animals were done in accordance with national and international laws and policies.

Statistical Analysis

Statistical comparisons were performed using the t test and ANOVA when data were normally distributed, and the nonparametric analyses of Spearman and Mann-Whitney when data were not normally distributed. All of the Ps were two-sided and considered statistically significant at <0.05.

Expression of CXCR4, Other Chemokine Receptors, and CXCL12/SDF-1 in NHL Cells

Strong CXCR4 mRNA expression was found in 10 of 12 lines and in 18 of 19 primary NHL cells, respectively. As indicated in Table 1 , other chemokine receptors were less frequently expressed in cell lines and primary NHL cells. Flow cytometry studies confirmed CXCR4 expression in all of the RT-PCR-positive NHL lines and in primary cells, and indicated high levels of CXCR4 expression when compared with other normal lymphoid cells

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Woburn, Mass. I just woke up one morning and found a large lymph node under my right arm,” said Daniel Sabbatelli. “I didn’t think much of it at the time and neither did my doctor.” Back in 2003, not even the characters in “House” would think of linking Protopic Ointment to a lymphoma.

Lymphoma is a broad term encompassing a variety of cancers of the lymphatic system.

The two main groups of lymphoma are Hodgkin’s Disease (characterized by the growth of Reed-Sternberg cells in the cancer) and the Non-Hodgkin’s Lymphomas. In 2005, about 56,390 Americans were expected to be diagnosed with non-Hodgkin’s lymphoma while more than 7,000 new cases of Hodgkin’s disease will be diagnosed in the US this year. Both forms of lymphoma are a serious condition.

“In 2000 I had dermatitis on my face so my dermatologist prescribed Protopic ointment (tacrolimus). It certainly helped the symptoms - mainly itching and inflammation - but it wasn’t intended to cure an allergic reaction that caused the dermatitis in the first place,” says Daniel. He used it sporadically for the next few years, applying the cream daily for a few days until the rash cleared up. Then it would reappear a few days later. This went on for a few years.

“Then I discovered this enlarged lymph node. I showed it to a physician friend and he wasn’t too concerned but suggested that I get a CAT Scan. Well, one year later I still hadn’t done anything about it. It hadn’t got any larger and it didn’t bother me; I was going to work, taking care of my kids (I’m a single Dad with three girls) and besides, there really wasn’t enough time in the day.

By 2004 I visited my primary care physician and showed him this lump. He didn’t think it was cancerous but what he couldn’t understand was how it had just appeared one day.

He ordered a CAT scan. This time I paid attention - I lit up like a Christmas tree! I had nodules everywhere, hundreds of them, mostly surrounding my critical organs. I don’t have x-ray vision and had no idea -I had none of the classic cancer signs. The only symptom I noticed was fatigue and I would get out of breath when I exercised. I am 41 years old and consider myself in excellent health; the only medication I have ever taken besides Protopic is aspirin. So this came right out of the blue.

The reality was this: the lymphoma had been there the whole time, maybe for a few years, but was held back by muscle tissue. And now, - like the proverbial finger in the dyke - it couldn’t hold back anymore.

But I am a problem solver so I said, ‘What do we do now, what is the next step?’ My doctor interpreted the scan to be serious and sent me right away to the oncologist and had it removed. Next up, I started chemotherapy treatments.

Of course I lost my hair. I had six treatments, 21 days apart. I consider myself lucky because this lymphoma was only a stage four. My oncologist told me that, if I had waited another six months, I probably wouldn’t have survived. I can’t even imagine what would happen to my family - I’m a single Dad with three girls, from ages 9 to 12.

My treatments were over and about three weeks later I was watching Fox news; there was a trailer at the bottom the screen and it said that the FDA recently black-boxed two popular dermatological type medications - Elidel and Protopic. I was in shock - I finally realized that Protopic had caused my lymphoma!

Then I filled out some form on the FDA website about Protopic but I didn’t hear back from the agency or Fujisawa Pharmaceuticals, the makers of Protopic. I know the company didn’t develop this product to hurt people but it has been a very unpleasant thing to go through and has definitely compromised my health. And I was out of work for one year. I would never have Protopic if I knew that it was an immunosuppressive drug.”

Fujisawa Pharmaceuticals, the maker of Protopic, said its research indicated no increase in the rates of lymphoma or skin cancer in users of the drug, but the FDA has received reports of lymphoma and skin cancer in children and adults treated with Protopic since it approved the drug in December 2000. Since its approval, an estimated 2.1 million patients in the United States and 5.4 million patients worldwide have been treated with Protopic.

In January 2006, the FDA updated the labeling of Elidel® cream and Protopic® ointment. The new labeling includes a boxed warning about a possible risk of cancer and a Medication Guide (FDA-approved patient labeling). Now, Health Canada is advising people who use Elidel® cream and Protopic® ointment about safety information that indicates a potential cancer risk.

The Fujisawa Pharmaceuticals website has now issued a warning: “Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Protopic. Therefore, continuous long-term use of topical calcineurin inhibitors, including Protopic, in any age group should be avoided.”

Protopic Legal Help

If you have used Protopic and subsequently developed skin cancer or lymphoma, a lawyer may be able to help you. Please send your [Protopic] story to an attorney who will evaluate your claim for no charge or obligation.

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A new study on aspartame conducted by the Ramazzini Foundation reveals that aspartame causes a dose-dependent increase in cancers (lymphomas, leukemias and breast cancers) when consumed at levels approaching those consumed by humans in diet soft drinks. Specifically, the study shows (reprinted from the abstract):

a) a significant dose-related increase of malignant tumor-bearing animals in males, in particular in the group treated at 2000 ppm; b) a significant increase of the incidence in lymphomas/leukemias in males treated at 2000 ppm and a significant dose-related increase of the incidence of lymphomas/leukemias in females, in particular in the group treated at 2000 ppm; c) a significant dose-related increase of the incidence of mammary cancer in females, in particular in the group treated at 2000 ppm. Conclusions. The results of this carcinogenicity bioassay not only confirm, but also reinforce the first experimental demonstration of [aspartame’s] multipotential carcinogenicity at a dose level close to the acceptable daily intake (ADI) for humans. Furthermore, the study demonstrates that when lifespan exposure to [aspartame] begins during fetal life, its carcinogenic effects are increased.

The study, entitled “Lifespan Exposure to Low Doses of Aspartame Beginning During Prenatal Life Increases Cancer Effects in Rats” has been accepted for publication in the peer-reviewed journal Environmental Health Perspectives (EHP), the most widely-read environmental science journal in the world.

This is the second study conducted by the Ramizzini Foundation documenting the cancer-causing effects of aspartame in animals. Most sane people, when faced with such evidence, would ask the obvious questions: Could aspartame also cause cancer in humans? Should we review the safety of aspartame just in case?

Shutting down good science to protect profits

Virtually the entire health and medical system in the United States is not interested in these questions. Following the publication of this study, the U.S. Food and Drug Administration issued a statement flatly denying aspartame poses any safety risk whatsoever, rejecting the idea that its safety or approval as a food ingredient should be reviewed at all. Specifically, FDA spokesperson Michael Herndon said, “…the FDA finds no reason to alter its previous conclusion that aspartame is safe as a general purpose sweetener in food.”

In other words, the FDA is not interested in any new science that might challenge a decision it already made. Long live scientific-sounding dogma!

As reported by the CSPI in a recent press release, according to a 1996 report in the Minneapolis Star Tribune, the FDA rejected repeated proposals by NIEHS to test aspartame using more modern methods than were originally used. David Rall, the former director of NIEHS and its National Toxicology Program, said, “any compound that is that widely used needs to be retested with modern methods every once in a while.” The State of California, too, has urged new testing of aspartame. The FDA also rejected NIEHS’s proposal to test acesulfame potassium, which CSPI says was “abysmally tested” by its manufacturer and showed signs of causing cancer in animals.

Clearly, the FDA only hears what it wants to hear when it comes to protecting the highly profitable aspartame market. Those who have studied a bit of aspartame history know that aspartame was pushed through the FDA by none other than Donald Rumsfeld. Click here to read more articles on aspartame and its dubious history. Since the very beginning, the FDA has done everything in its power to protect the aspartame industry, including denying approval for the natural herbal sweetener stevia as a way to suppress the competition and protect the market for corporate-manufactured chemical sweeteners like aspartame.

CSPI urges re-evaluation of aspartame safety

This latest study on aspartame and cancer caused the CSPI to issue a public press release calling for the FDA to review the study to determine whether aspartame is really safe. CSPI also downgraded its rating on aspartame and is now recommending that everyone should avoid using aspartame.

(For the record, I’ve been recommending people avoid aspartame since I first began writing about nutrition. The toxicity of this chemical sweetener was obvious to me, and in my opinion there is no safe dose of a substance that breaks down into formaldehyde in the human body. In my view, aspartame is an obvious neurotoxin, not to mention its cancer-promoting effects. No one should consume it, and children or expectant mothers should avoid it like a poison.)

Also reported by CSPI: Among those who today called on FDA Commissioner Andrew von Eschenbach to review the new aspartame study are former Occupational Safety and Health Administration officials John Froines (now at UCLA) and Peter F. Infante (now at George Washington University); James Huff, current Associate Director for Chemical Carcinogenesis at the National Institute of Environmental Health Sciences (NIEHS); and Kamal M. Abdo, a toxicologist formerly at the National Toxicology Program of the NIEHS.

Let’s poison America!

With its stubborn refusal to even review the safety record on aspartame, the FDA seems to be shouting out loud, “Let’s poison America!” Of course, the FDA has no intention of initiating anything resembling real scientific scrutiny on aspartame because aspartame was never proven safe in the first place! It was force-fed through the FDA’s approval process based purely on distorted, junk science constructed to win approval for a chemical that would earn billions of dollars for powerful corporations (and the powerful, evil bastards who run them).

And ever since, aspartame has been poisoning Americans each and every day, contributing to seizures, blindness, migraine headaches, vision problems, neurological disorders and possibly even cancers. The fact that no health authority in America is interested in taking a new look at the safety of aspartame is nothing short of astonishing. That is, until you consider the fact that most medical authorities suffer from a severe case of Groupthink and posses no ideas other than the ones spoonfed them by their politically-motivated bosses. It takes real courage to break with the herd and actually state the obvious these days. Most people are satisfied just to go along with whatever the masses say, even if it makes no sense.

Some people call this refusal by the FDA to review aspartame’s safety an “oversight” or “mistake” on the part of the agency. Who are they kidding? I call it a crime against the People of America, because to knowingly allow a dangerous, cancer-causing, nerve-damaging chemical to be used in the national food supply — even while receiving tens of thousands of health complaints from the people consuming aspartame — is nothing less than negligent homicide. It’s a felony, and those responsible for allowing this poison to contaminate America’s food supply are, indeed, unindicted felons who deserve to be arrested and prosecuted for their crimes. (A fitting punishment, as always, would be to force-feed them high doses of aspartame and see what happens. If it’s really as safe as they claim, there’s no harm, is there?)

Anybody with a brain that still functions in this country — and I admit that number is shrinking by the hour — knows that all the pro-aspartame studies upon which the FDA based its previous safety approval were partially or fully funded by the corporations making money from the sale of aspartame. The entire history of aspartame boils down to corruption, influence and profit-mongering.

There is nothing resembling scientific scrutiny in the aspartame debacle. Nearly every decision that has been made about aspartame by government regulators or private industry has been a political decision, not a public safety decision. There is nothing resembling public safety still operating at the Food and Drug Administration anymore.

Add aspartame to the FDA’s Hall of Shame, right alongside Vioxx, Rezulin and the ordered destruction of recipe books that dared to mention the stevia herb as an ingredient. It’s just one more way in which the FDA continues to betray the American people and subject them to life-threatening ingredients that any honest Food and Drug Administration would have banned long ago.

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Hodgkin’s lymphoma is a malignancy (cancer) of lymph tissue found in the lymph nodes, spleen, liver, and bone marrow.

Alternative Names

Lymphoma - Hodgkin’s; Hodgkin’s disease; Cancer - Hodgkin’s lymphoma

Causes

The first sign of this cancer is often an enlarged lymph node which appears without a known cause. The disease can spread to nearby lymph nodes and later may spread to the lungs, liver, or bone marrow.

The cause is not known. Hodgkin’s lymphoma is most common among people 15 to 35 and 50 to 70 years old.

Symptoms

—      Painless swelling of the lymph nodes in the neck, armpits, or groin (swollen glands)

—      Fatigue

—      Fever and chills

—      Night sweats

—      Weight loss

—      Loss of appetite

—      Generalized itching

 

Additional symptoms that may be associated with this disease:

—      Excessive sweating

—      Skin blushing or flushing

—      Neck pain

—      Hair loss

—      Flank pain

—      Clubbing of the fingers or toes

—      Splenomegaly

 

Exams and Tests

The disease may be diagnosed after:

—      A lymph node biopsy

—      A bone marrow biopsy

—      A biopsy of suspected tissue

—      Detection of Reed-Sternberg (Hodgkin’s lymphoma) cells by biopsy

A staging evaluation (tumor staging) may be done to determine the extent of the disease. The following procedures may be done:

—      Physical examination

—      CT scans of the chest, abdomen, and pelvis

—      Bone marrow biopsy

—      Blood chemistry tests

—      PET scan  

In some cases, abdominal surgery to take a piece of the liver and remove the spleen may be needed. However, because the other tests are now so good at detecting the spread of Hodgkin’s lymphoma, this surgery is usually unnecessary.

Hodgkin’s lymphoma may change the results of the following tests:

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