The Cancer:
The patient is a boy age 3, and has Acute Lymphoblastic Leukemia more commonly known as Childhood ALL. The age group that is most often affected by Childhood ALL is 2-4 years old, and Childhood ALL is the most common type of cancer in children, with about 3000 new cases found every year in the US.[1] Childhood ALL is a cancer of blood and bone marrow, in particular the creation of too many immature lymphocytes,[2] which is a type of white blood cell. In a healthy child, bone marrow makes blood stem cells that over time become mature blood cells, as seen in Figure 1. These stems cells then start to become more specialized by becoming either myeloid stem cells or lymphoid stem cells.[3] Myeloid stem cells then mature and further specialize to become red blood cells, platelets and certain types of white blood cells, while lymphoid stem cells mature into lymphocytes (B & T) and natural killer cells, as seen in Figure 1. In childhood ALL patients, a DNA error in the bone marrow develops causing continuous growth, creating abnormal blood cell production.[4] These cells are immature lymphocytes, that are unable to function properly. These immature lymphocytes crowd in the bone marrow causing difficulty in producing more healthy blood cells. A risk factor is something that increases ones chance of developing cancer.
The risk factors for childhood ALL include, being exposed to x-rays before birth, exposure to radiation, past chemotherapy treatment, having certain changes in the chromosomes or genes. Certain genetic conditions such as: Down Syndrome, Neurofibromatosis type 1 (NF1), Shwachman Syndrome, Bloom Syndrome and Ataxia-telangiectasia, are risk factors for childhood ALL because they have the DNA changes that are a cause of childhood ALL.[5] This could because these genetic conditions cause a mutation in DNA that causes the increase in immature lymphocytes creation. While there are some children with ALL that have one or more of these risk factors before diagnosis, for the most part, patients, including this 3 year old boy, do not have any risk factors.




CDR755927-750.jpg
Figure 1.


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Figure 2.


















The patient did have several symptoms that can be caused by childhood ALL. The patient came in with a fever, fatigue, easily and persistent bruising, petechiae, which are flat, pinpoint, dark-red spots under the skin[6] and bone pain located in several bones. The fatigue may have been caused by the creation of too many immature lymphocytes, making it harder for the bone marrow to create other blood cells such as red blood cells as well as crowding the red blood cells. The lack of red blood cells can create an environment in which oxygen has a difficult time reaching the muscle, causing them to be starved for oxygen and unable to perform for long periods of time. The bone pain could be a symptom because the blood cells are created in the bone marrow, located in the bones of the body, and when leukemia cells are present and growing they cause a build up and crowding around the bone marrow that creates the pain. The bruising easily and petechiae, could be due to the crowding out of other healthy blood cells by the cancerous cells platelets are not created as regularly. Plates are used to to help the blood clot, however since the patient did not have enough platelets the body may have been unable to seal off the broken blood vessels.
There are three different types of risk groups associated with childhood ALL, standard-risk, high-risk, and very high-risk. Determination of this risk is calculated through several different factors, the main ones including the subtype of ALL, age at diagnosis, white blood cell (WBC) count, and the spread to certain organs. There are two subtypes of childhood ALL, B-cell ALL and T-cell ALL. B-cell ALL is the most common type of ALL, and is when too many immature B-cell lymphoblasts are found in the bone marrow and blood. B-cells are the white blood cells that create the antibodies that are used to fight infection. The second type of childhood ALL is T-cell All. This subtype of ALL is when too many T-cell lymphoblasts are found in the bone marrow and blood.[7] T-cells while also used to fight infection they help the B-cells create the antibodies, T-cells do not create the antibodies on their own. Children diagnosed between the ages of one and nine with B-cell ALL, tend to be considered standard-risk patients, while those under the age of one and over the age of 10 are considered to be high risk patients.[8] Children with a high WBC count, which is anything above 50,000 cells per cubic millimeter are classified as high-risk and are in need or more intensive treatment.[9] The spread of ALL to the cerebrospinal fluid, of the testicles increases the chances of a poor outcome. While the patient is between the ages of one and nine, and his ALL has not spread to other organs, he has still been placed in the high-risk group because his white blood cell (WBC) count was high. While the patient is deemed to be a high-risk in his diagnosis this does not mean there is no hope in survival, the 5-year survival for children with ALL is 85% overall.[10]

The Treatment:
For many children, like the patient, ALL is curable with current therapies. There are several steps that must be taken in order for treatment to be successful. Sometimes when children first come in for treatment for ALL they are critically ill, and those illnesses need to be taken care of first. This could be for a couple different reasons, a shortage of normal white blood cells can lead to very serious infections, low levels of platelets and/or clotting factors can cause severe bleeding, and a lack of red blood cells can lower the amount of oxygen getting to body tissues which puts a tremendous strain on the heart. [11] If one of these problems is present, and before any treatment to fight ALL is started, it must be taken care of with the use of antibiotics, blood growth factors and/or transfusions of platelets and red blood cells. The patient did not show any signs of critical illness at the time of diagnosis or at the time he was admitted for the first step of treatment.

There are three steps to treating ALL. The first is induction therapy, which is the initial use of chemotherapy. To start a central line is placed surgically in an upper chest vein or in the arm.[12] The line is used as a means to administer medications, fluids, blood products as well as have the ability to withdraw blood samples for testing. Through the line that is set up a combination of drugs is delivered into the blood system. Children who are at standard-risk often receive 3 drugs, L-asparaginase,vincristine, and a steroid drug, usually dexamethasone which is primarily used to reduce inflammation and as an nausea reducer.[13] L‐asparaginase is an enzyme that catalyzes the degradation of L‐asparagine, an amino acid to aspartic acid and ammonia.[14] L-asparagine is necessary for the leukemic cell cycle to follow its growth course, with too much found in In the absents of L-asparagine in the plasma of a cell leads to the inhibition of DNA, RNA and protein synthesis and arrest in the G1 phase, which then leads to cell apoptosis.[15] By using the drug L-asparaginase during induction allows for the apoptosis of leukemic cells to take place. Vincristine is a sulfate salt of a natural alkaloid, which when used to stop cell division. The vincristine binds irreversibly to the spindle proteins and microtubules during S phase and interferes with formation of mitotic spindle, thus causing arrest of the cell cycle in metaphase.[16] However since the patient was deemed high risk a fourth drug, daunorubicin, which places itself in the DNA helix thus preventing replication to take place, ultimately stoping protein synthesis to form, will be added.[17] These drugs were chosen for the patient because the combination of the three drugs, L‐asparaginase, vincristine, and daunorubicin, attack the leukemic have a high success for stoping cell growth with “more than 95% of children entering remission after 1 month of induction treatment.”[18] If however remission is not seen after about a month of chemotherapy a new drug cocktail will be administered or more drugs will be added. There are some side effects to using chemotherapy, they include increase chance of infection, fatigue, loss of hair, nausea and vomiting.[19] The severity of the side effects depend on the child and not all are seen during chemotherapy. The goal of this therapy is to achieve remission, meaning to rid the bone marrow and blood of any visible leukemic cells.

After the initial step is completed and the patient is in remission, the second step, known as post-remission therapy is needed. The parents wanted to know why this necessary if their child is what they believed be is cured. Remission is not the cure but the first step towards being fully cured. This step is needed because while an examination of the blood and marrow may come back as being clean, residual leukemia cells are undetectable and need to be eradicated if the patient is going to stay ALL free. One of the first parts to this step is intrathecal chemotherapy. This type of chemotherapy is directed at the cerebrospinal fluid. This is because ALL cells often collect in the lining of the spinal cord and brain and these cells can be harbored there for some time and then cause relapse directly in these sites.[20] The chemotherapy is directly injected into the spinal chord and should administered at least twice during the first month and 4 to 6 times during the next couple of months.[21] To go along with intrathecal therapy, the patient’s parents asked if radiation would be necessary as they had read that in high risk patients, like their son, it was recommended. They were advised against it because recent studies have shown that children could be given a more intensive chemotherapy and receive the same results.[22] Radiation in the smallest of doses can cause problems in thinking, growth and development. This step, which typically lasts about 2 months, is given in cycles and several chemotherapy drugs are combined to help prevent the remaining leukemia cells from developing resistance.[23]

If ALL remains in remission after the first two steps; then the third step, maintenance therapy, can begin. Maintenance therapy last about 2 to 3 years in children and in the first months treatment procedures may include one or two intense treatment similar to the ones used during induction.[24] Afterwards the treatments will be given at lower doses over a long course of time.[25] These intensified treatments and the low dose treatments, in most cases, use drugs that were not used during induction, as the leukemia cells can start to form resistance against the drugs. Depending on how the first steps go for the patient, he may need more intense maintenance therapy.

The patient’s parents had heard that surgery is often needed as a treatment for cancer and were afraid that their child would need surgery on top of the chemotherapy. They were told that “surgery has a very limited role in treating” ALL because leukemia cells spread throughout the bone marrow, and to many organs though the blood that “it is not possible to cure [ALL] by surgery.”[26] The only thing that is deemed surgery their child will need is the insertion of the central line into their chest or arm that is used for treatment. The parents had also heard in a cancer support group that there are new therapies that target cancer cells, and were hoping that their child’s treatment could involve these instead of chemotherapy. There have been therapies created, known as target therapies, that target specific or unique features of cancer cells and are less likely to attack normal cells as well.These include tyrosine kinase inhibitor target therapy.[27] However this was not the best treatment for the patient for several reasons. The tyrosine kinase inhibitor therapy is used for ALL patients who also have the Philadelphia chromosome, which is an abnormality in chromosome 22 which creates a protein that helps leukemia cells grow.[28] The patient is known to not have the Philadelphia chromosome.

The Molecular Basis of Treatment:

After talking with the patients parents about their child’s cancer, ALL and discussing/deciding the treatment options for their son; they wanted to better understand why the drugs chosen work to attack and destroy the cancer. That way they could help explain it to their child in terms that he would understand.The drugs that were used to treat their son were L-asparaginase,vincristine, dexamethasone, and daunorubicin.

The first drug, L-asparaginase is used to cause cell apoptosis through the degradation of an amino acid, asparagine. For the parents to understand why this drug is useful they first had to understand what the amino acid was used for. L-asparagine is involved in the control of cell function through the creation of a portion used in growth regulation, in normal cells.[29] For , asparagine to be used in the cell it must first be brought been (as seen in figure 1) by chemically converting it to aspartate so it can enter the through the cell membrane and then be synthesized in the cell to create protein synthesis.[30] However in patients with ALL asparagine synthase does not take place in the cell but must be brought in from an outside source.[31] because if this as the cell ages instead of the cell regulating itself by “realizing” that is it running out of synthase materials in the cell thus leading towards apoptosis; the cell continues to grow and divide creation tumors or leukemic cells. The use of the drug L-asparaginase creates an environment that causes the decrease in asparagine to be present in the plasma. The L-asparaginase is used to deplete the amount of asparagine found in the plasma creating an environment that allows for cell apoptosis because there is not asparagine for the cancer cells to take in to sustain cell growth regulation.[32]

The second drug is Vincristine, which is a sulfate salt of a natural alkaloid, and when used it stops cell division.[33] The drug does not alter DNA structure or function but interferes with mitosis. Seen in figure 2, in a normal cell mitosis microtubules are used to formed various sizes of tubulins, a protein used to create spindles. These spindles are used to pull the DNA apart during cell division. By injecting vincristine into the patient the drug binds irreversibly to the tubulins and microtubules during S phase creating a unstable environment for spindle formation. This then results in the induction of tumor protein p53 and in rapid alterations of protein kinase activities. “These protein kinases are directly or indirectly responsible for BCL-2 phosphorylation, which results in the inactivation of BCL-2 function.”[34] With the induction of BCL-2 phosphorylation the loss of the cells ability to form heterodimers follows suit. This coupled with the elevation of p53 leads to apoptosis.[35]

Daunorubicin, unlike the other two drugs given to the patient this one interacts directly with the DNA. It does so by inserting itself into the DNA between base pairs, with preference to adjacent G/C base pairs (Seen in figure 3.).[36] Thus inhibiting the progression of topoisomerase 11 complex activity, “by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.[37] This activity is needed to relax the supercoils of the DNA for transcription to occur. Because there is not relaxation before transcription single strand and double strand DNA breaks happen and are unable to repair themselves resulting in cell death.

The last drug administered to the patient was dexamethasone, a corticosteroid. The steroid enters the cells through “passive diffusion and forms a complex with the receptor protein.”[38] Dexamethasone is primarily used to reduce inflammation and as an nausea reducer and used mainly to combat the side effects of the three drugs explained above not to fight the cancer directly.[39]
With a better understanding of why the drugs being used to fight their son's cancer the parents were better equipped to handle the questions their child might ask about the drugs be used and why they had to be used.


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Figure 1.

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Figure 2.


Doxorubicin–DNA_complex_1D12.png
Figure 3.

While finding out that your child has cancer is a terrifying moment for parents, and fighting cancer is still a battle it is not always a battle that will be “lost.” Cancer can be overcome, Acute Lymphoblastic Leukemia (ALL) in particular can be overcome. For the patient in this paper he has a high survival rate, with the 5 year survival rate at 85%,[40] for beating his stage of cancer if treated quickly and with the right drugs. Through the use of the three different stages of chemotherapy: induction, consolidation and maintenance, he was declared “cancer free” after 2.5 years of maintenance therapy. He will continue to be monitored by his doctor as well as periodic assessments of the his blood to make sure the cancer stays in remission. As he gets older the likelihood that his ALL returns diminishes and he can go on to lead a normal life.


Aperçu: Finding out that you or a loved one has cancer can be scary and depressing. However, it doesn’t mean it is the end of the world. ALL is treatable and curable if caught quickly and treated.
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