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(written by Honna, the first administrator of the ped-onc listserve, in the late 1990s)
- What are N-myc and tumor suppressor genes?
- What is the Shimada index?
- What are other important factors when determining prognosis?
- What is VMA?
- What is LDH?
- What is Horner's Syndrome?
- What is opsoclonus/myoclonus?
- What is the MRP gene?
- What are monoclonal antibodies?
- How can you tell if a therapy is questionable?
- How can I ensure my child receives adequate nutrition?
- What role does the National Cancer Institute play in research funding?
- How important is long term follow-up care?
- What are those "hot spots" showing up on my child's bone scans that the doctor calls "growth plates"?
- Can an adult have neuroblastoma?
- What is the difference between a bone marrow transplant and a stem cell transplant?
- What can you tell me about accutane?
The "N" that you see before the "myc", means that it is a "normal" oncogene (it is not found to mutate, such as those oncogenes that start with C, like C-myc). With N-myc, the change is amplification. Tumor suppressor genes control protooncogenes. You've probably been reading a lot about p53 in the newspapers this past year. The job of the p53 gene is to control cell division in cells that have damaged DNA. It is supposed to stop these cells from dividing until the damaged DNA can be repaired. These damaged cells can be cancerous, so that's one reason why the gene is so important. Some people have mutations of this tumor suppressing gene, and it has been implicated in many different forms of cancer.
So, we've got two different things we're looking at here. There are the protooncogenes (for example N-myc which codes for a protein that promotes cell division), and we have tumor suppressor genes (for example the p53 gene product), which code for proteins that inhibit cell division. It is believed that a tumor suppressor gene for neuroblastoma lies on chromosome bands 11q13-23. Also, deletion of subbands of 1p36 is found in 35-40% of neuroblastomas, and is also thought to involve loss of a neuroblastoma suppressor gene. Other chromosomes are also being studied.
The Shimada index is a histopathologic classification system, widely used for neuroblastoma, developed by H. Shimada. Using the Shimada criteria, kids with neuroblastoma can be grouped into a favorable or unfavorable category. It's based on the presence or absence of cell stroma, the degree of differentiation, and the mitosis-karyorrhexis index. Another researcher, Joshi, has simplified Shimada's classification system. Now both these researchers, along with others, are working to combine the predictive abilities of both into a simple and comprehensive system.
Histology refers to the actual tumor pathology. The best method for classifying histology is the Shimada index. It reads:
- stroma rich, all ages, no nodular pattern
- stroma poor, age 1.5-5 yr, differentiated, MKI < 100
- stroma poor, age <1.5 yr, MKI < 200
- stroma rich, all ages, nodular pattern
- stroma poor, age >5 yr
- stroma poor, age 1.5-5 yr, undifferentiated
- stroma poor, age < 1.5 yr, MKI > 200
MKI is the mitosis-karyorrhexis index (number of mitoses and karyorrhexis per 5,000 cells)
Besides histology, there are other factors that are important when determining prognostic significance. Of course, the age at diagnosis is important, with children under the age of 1 year having the best overall prognosis. Here are some other important factors:
- neuron-specific enolase: normal level (1- 100 ng/ml) > abnormal (> 100 ng/ml)
- ferritin level: normal level (0- 150 ng/ml) > abnormal (> 150 ng/ml)
- VMA/HVA ratio: high (> 1) > low (< 1)
- stage: I or II or IVs > III > IV
- site of primary tumor: neck/ posterior mediastinum/ pelvis > abdominal primaries
- gallium uptake by tumor: absent > present
- n-myc amplification: 1 n-myc copy > greater than 1 n-myc copy
- P-glycoprotein levels in tumor cells at dx: expression before treatment may be of some prognostic significance.
- expression of neural growth factor receptor (TRK) gene: high levels of messenger RNA of TRK gene in tumor cells strongly predicts good outcome.
- lower LDH levels (< 1500 u/ml) > high LDH levels (> 1500 u/ml)
- Ha-ras p21 expression: aggressive tumors have low expression of Ha-ras p51. High Ha-ras p21 correlates with better disease-free survival.
- chromosome 1p deletion is associated with poor survival.
Catecholamines are produced by a part of the adrenal gland, called the medulla (the central part of the gland, as opposed to the cortex, which is the outer area). The 2 main catecholamine hormones are called adrenaline (or epinephrine) and noradrenaline (or norepinephrine). They can be tested in the blood, but most often are measured in the urine, along with their metabolic end products, VMA (vanillylmandelic acid) and HVA (homovanillic acid). The majority (not all!) of neuroblastoma's produce the catecholamine metabolites, VMA and HVA. So, testing the urine is very often done to detect disease. It's also used as an indictor for response to treatment. For example, a child newly dx with neuroblastoma with higher than normal levels (remember, these metabolites are normally found in the urine, anyway) of VMA, would be expected to see the levels drop back towards normal values as s/he begins to respond to therapy. About 5-10 percent of neuroblastoma's do not produce elevated VMA and HVA.
LDH stands for lactate dehydrogenase. It's another prognostic variable used for neuroblastoma. LDH is an enzyme found in many body organs and in red blood cells, which when damaged or diseased, release the enzyme into the blood serum. LDH can be measured in the blood or in the urine (as well as a few other places). It's a frequently done test with neuroblastomas because increased levels can indicate the presence of cancer or certain other diseases.
Horner's Syndrome is sometimes associated with neuroblastoma. It occurs when there is some type of damage or interruption of the nerve to the eye (a sympathetic nerve). One of the signs of Horner's Syndrome is a drooping eye lid (called ptosis). The pupil of the eye will be small (called miosis) and it will not get bigger, as it should, when the lighting of the room is darkened. Sometimes the side of face (the side with the affected eye) will not be able to produce sweat (called anhidrosis) and the eyeball may move back into the socket (called enophthalmos). Oftentimes, when Horner's Syndrome occurs, it has been after some sort of neck surgery.
This is a rare syndrome that can occur with neuroblastoma. It is sometimes referred to as "dancing eyes- dancing feet syndrome", because of its symptoms. Opsoclonus is characterized by spontaneous and chaotic movement of the eyes. Myoclonus is involuntary and sudden movement of the trunk and extremities.
The N-myc gene, mapped to chromosome 2p24, is only one of many prognostic indicators for neuroblastoma. An interesting study that was published in NEJM January 25, 1996 -- Volume 334, Number 4, showed that overexpression of the gene for the multidrug-resistance-associated protein (MRP) correlates with N-myc oncogene amplification. The MRP gene has been linked with resistance to chemotherapeutic agents (multidrug resistance) in vitro. I can remember reading about this in the newspapers. The work was done in Australia, and I was lucky enough to have a friend who lived there that sent it to me. Researchers are working on drugs to block the effects of the MRP gene.
P-glycoprotein lives in the cell membrane. It actually has a "pump type" effect, coiling back and forth across the layer of the membrane approximately 12 times. As an example, adriamycin attacks the nucleus of a drug sensitive cell and interferes with cell division. These pumps can actually "spit the chemo drug out" before it has a chance to do its job. (greatly simplified, of course). That's why treatment for various cancers, neuroblastoma included, use combination chemotherapy approaches.
The NCI currently has about 4 active protocols using monoclonal antibodies that kids with neuroblastoma may qualify for. Mostly phase I and II clinical trials.
It is called "monoclonal antibodies", because they are made by the identical offspring of a single, cloned antibody producing cell. A mouse is injected with a specific antigen which causes the production of antibodies against it. These antibodies are isolated from the mouse's spleen. The monoclonal antibodies are made by attaching single antibody-forming cells to tumor cells grown in culture.
I thought it might be a good idea to review some tips to keep in mind when considering alternative therapies. You are bound to come across the "snake oil salesman" during your neuroblastoma experience. These are people without morals that prey on those dealing with cancers and other chronic illnesses. They can be very shrewd. Often, they will take scientific data from reputable institutions, and skew it to fit their purposes. Aloe vera is a prime example of this. They know that a lot of people have strong religious convictions, so often they will throw in bible quotes to catch your attention. They try to capitalize on your overwhelming desire to help your child get well again, by insinuating that "if you really cared, you would buy this product because it's sure to work."
Here are some ideas and tips to keep in mind when you come across such therapies, or when you are approached by someone who says they can "fix everything".
- Have their findings been published in any major medical journals?
- Have they presented their studies to other scientists for verification?
- Is the key to their treatment's efficacy a secret?
- Do they push the fact that their treatments have no side effects?
- Do they provide only anecdotal evidence to show how it works?
- Do they claim that they have been persecuted by the medical community?
- Are you being encouraged to discard conventional therapy for their "proven" cure?
It's important that you never start your child on any form of therapy without first discussing it with his/her oncologist. Even vitamin therapy should be discussed first before starting. It is possible that what you are giving your child can interfere with the conventional therapy they are receiving. Better to be safe than sorry and always check first.
Bottom line is that if you should receive any mail from anyone claiming they have the cure, or an effective treatment that offers no side effects, buyer beware. There's always a price attached, and it may end up costing you more than your bank account.
We all know that maintaining good nutrition is crucial in the fight against cancer. Problem is how do we overcome the issues that often go hand in hand with cancer therapy? What do we do when our child has absolutely no appetite, they refuse to eat because they say the food "tastes weird", or if they have other problems that prevent them from eating, such as mouth sores? Maybe they're afraid to eat because they think they will just throw it all back up again. Definitely not a pleasant experience. :-(
Sometimes, when all else fails, the child requires intervention and TPN is given. Some kids require an NG tube and are fed in this manner. Sometimes we can modify diets to get the necessary nutrition they need. Our bodies need proteins, minerals, fats, carbohydrates and vitamins to survive. It's even more critical that they receive these nutrients when they are sick, as the body is fighting a disease in addition to the damage caused by the treatments required. Proper nutrition helps repair that damage, it aids our immune system and makes us feel stronger. Actually, while our children are fighting cancer, they will need even more of these nutrients than a healthy child would require. Protein is used to repair damaged tissue, but if we don't take in enough, it will be used for energy first, and there might not be any left over to fix the damage caused by treatment or the disease. Diet should be considered as part of the total treatment plan.
Here are some ideas to help you deal with some of the more common problems.
- Weight loss: Encourage foods that are high in protein and calories. If your child won't sit for a full meal, try offering several small meals throughout the day. Consider using some of the products available that pack a lot of calories into a small size, such as sustecal and ensure. Fortify milk by using whole milk, and adding a small amount of powdered milk to it.
- Nausea and vomiting: An anti-emetic may be needed to control nausea and vomiting. Foods that are at room temperature are generally tolerated better than those that are hot or cold. Try some relaxation techniques, such as deep breathing before eating. Serve small frequent meals. If the smell is what's making them sick, try not to prepare the food while the child is around. Sometimes just the aroma can turn them off.
- Taste blindness: Try serving foods that are colorful and "fun" to look at. Instead of just a plain peanut butter sandwich, why not make a face on it before serving. Go wild with this one. Sometimes the crazier it looks, the more apt they will be to give it a try.
I think that often not enough emphasis is placed on nutrition when it comes to children receiving treatment for cancer. One of the best things you can do for your child is to set up a meeting with the hospital's dietician and work out a plan of action for your child.
The NCI (part of NIH) is the federal government's main agency for cancer research and training. One of the many things that NCI does is to support and coordinate research projects conducted by universities, hospitals, research foundations, and businesses throughout the country and abroad through research grants and cooperative agreements. Many hospitals get funding for clinical trials from NCI through Cancer Center Support Grants (CCSGs). For an institution to be considered for a CCSG, they have to meet certain criteria, including specific minimum levels of "peer reviewed, funded research projects."
I think that long term follow up should be continued for as long as the group that provided care for your child is able to make contact with you. Many issues need to be considered when looking at the long term consequences of cancer treatment. Altered bone growth is one of the most common. Cardiopulmonary toxicity can be an issue, too. Most children with neuroblastoma are familiar with adriamycin. Effects from this anthracycline can be seen many years later.
Children treated for cancer as a child are also at a somewhat higher risk of secondary malignancies than the general population.
What are those "hot spots" showing up on my child's bone scans that the doctor calls "growth plates"?
The growth plates are the areas of the skeleton where tissue comprised of cartilage is being made into bone. The skeleton of the fetus in the womb is made up mostly of cartilage. As pregnancy continues, bone develops, but even when the child is born, there are still areas that are a cartilage/bone combo (the growth plates). In the long bones, such as the arms and legs, there are growth plates at each end. Growth plates are areas of intense activity until the child reaches mid to late teens, or in other words, until they stop growing. At this point the bones are said to have fused. It's because of the activity taking place in these areas that growth plates will generally appear as a hot spot on an mIBG scan. Areas of healing bone (for example, in the case of a fracture), will also show up as a hot spot.
Yes. However, less than 10 percent of all neuroblastomas are diagnosed in patients older than 10, so it is very rare to find in an adult. Adult neuroblastoma tends to have a slower rate of growth than in the pediatric population. Primary sites of disease are similar between both children and adults. Neuroblastoma in the adult is generally more resistant to chemotherapy. Treatment is aggressive and will often include surgery, chemotherapy, radiation therapy, and autologous bone marrow transplantation. Biologic characteristics between adults and children with neuroblastoma are often different. For example, many adults will not have elevations in urinary catecholamines, and most will not have MYCN amplification.
The difference between bone marrow and stem cell transplantation lies not so much in the actual transplant as with the method used to harvest cells for the procedure. Regardless of which method is used for harvesting, the oncologist is looking for "pluripotent stem cells," sometimes referred to as "the mother of all cells."
Pluripotent stem cells are different from other cells found in the marrow or blood. These special cells have the ability to reproduce identical copies of itself. As a pluripotent stem cell matures, it differentiates (changes) into committed progenitor stem cells, which then differentiate into a red cell, a white cell, or a platelet. All blood cells originate from this "mother cell". They are found in the marrow cavity as well as the circulating, peripheral blood. In the marrow, less than 1 in every 100,000 cells are pluripotent stem cells. That number is even smaller in the peripheral blood (about 1/100th of that in the marrow). Your child's doctor may choose to harvest stem cells from either route for several reasons. If your child has had cancerous cells in the bone marrow, the doctor may decide that the best method of collection is from the peripheral blood because there is less chance that diseased cells will contaminate the harvest. Your child may have had radiation to the pelvic area, which could limit the amount of stem cells available for collection through bone marrow harvesting. However, if these factors are not an issue, the cells are collected from the bone marrow because the supply is greater.
Transplantation using cells collected from the bone marrow of the child is called an autologous bone marrow transplant (ABMT). Transplantation using cells collected from the peripheral blood is called a peripheral blood stem cell transplant (PBSCT).
Accutane is also known as isotretinoin, 13-cis-retinoic acid, and 13-cis-RA. It is related to vitamin A and is given by mouth. Accutane has minimal toxicities when used as a therapy for children with neuroblastoma. The most commonly described side effects include dry skin and mucous membranes. Some children experience peeling of their palms and soles.
Accutane stops the growth of neuroblastoma and can induce differentiation in vitro (in a test tube). A 5 year, randomized CCG study (CCG-3891) included 539 children with high-risk neuroblastoma. The study concluded that accutane improved the event-free survival for children with the disease and recommended that it should be used for treating all neuroblastomas in the future.
These pages are intended for informational purposes only and are not intended to render medical advice. The information provided on Ped Onc Resource Center should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you suspect your child has a health problem, you should consult your health care provider.