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About This Lesson Plan

SUBJECT
Human Body

GRADE
9-12

DURATION
1 Class Period

COLLECTION
About Blood: Lesson Plans & DVD

Lesson 8: Case Study

Through this lesson, students will learn about the symptoms, diagnosis, and treatment of one form of cancer, chronic myeloid leukemia (CML). This case study reinforces general concepts of the cell cycle and cancer, and gives students a deeper understanding of how molecular biology research directly impacts the diagnosis and treatment course for cancer.

OBJECTIVE
By the end of this lesson, students will be able to:

  • Conduct background research on CML
  • Become familiarized with how doctors conduct a history and a physical and the concept of a differential diagnosis
  • Describe the functions of the cellular components of the blood
  • Describe the chromosomal translocation that causes patients to develop CML
  • Describe the procedures used to diagnose, monitor, and treat CML patients
  • Examine a blood smear and karyotype in order to diagnose a patient with CML
  • Become familiarized with the role of tyrosine kinases in the cell cycle and how these enzymes are targeted by drug treatments, specifically how imatinib disrupts the formation of CML cells
  • Describe the connection between molecular biology research and clinical outcomes
  • Discuss the social and emotional impact of a cancer diagnosis

MATERIALS

DIRECTIONS

Instructions for Teachers
This case study is meant to familiarize students with the diagnosis and treatment of chronic myeloid leukemia (CML). It is geared toward students in a high school biology course, and it is recommended that students already have a general familiarity with the cell cycle and cancer. This case study reinforces general concepts of the cell cycle and cancer, and uses a case-based approach (mostly via dialogue) to give students a deeper understanding of how molecular biology research can be used to directly determine the treatment course for cancer, a molecular disease. Students will also become familiarized with how doctors collect information from patients in order to perform a differential diagnosis.

This case should take approximately one 50-minute class period for each part, though students may have to finish some questions for homework depending on what resources are available for use in the classroom. Part 2 in particular can lead to a long in-class discussion as students may have questions about why Dr. Owen asks Susan for certain information. The entire case study should take about one week (five class periods) to complete all parts and have a wrap-up at the end. The case study should be distributed to students one part at a time. It is recommended that students read each part of the case study (either at the start of each class period or for homework the day before) and then discuss the content of each part of the case as a small group and work together to answer questions. Access to the Internet and print resources during class is recommended. The questions for each part can be collected from each group at the end of each class period and/or discussed as a whole class. Answer keys for teachers are provided separately.

Extension activities may include having students examine RQ-PCR data or Western Blot data for the detection of the BCR-ABL protein. Gel electrophoresis with Kool-Aid dyes can be used to simulate Western Blotting. See
http://www.tccbiotech.org/files/documents/Flavored_Drink_and_Fabric_Dye_Electrophoresis.pdf for one example of this activity. Since the size of the abnormal protein is known, the students could perform gel electrophoresis on "patient samples" and "control samples" to determine whether that abnormal protein is present. Another possible extension activity is to have students perform PCR and gel electrophoresis, or a simulation of these techniques, in order to learn how these techniques work and what they are used for. Several scientific companies have kits available that are geared toward high school students. Some examples are Bio-Rad, Ward's Natural Science, and Carolina Biological Supply.



ANSWER KEYS

Part 1 Questions

1. Describe the main characters in this case study. What do you know about this family so far?
Susan Forest: 67-year-old grandmother of two
John Forest: Susan's son
John Jr.: John's son
Mary: John's daughter
John's wife passed away from breast cancer two years ago, and Susan helps him take care of the children. John works the night shift at the local airport and Susan works in an accountant's office.

2. Describe Susan's symptoms. Conduct background research and give some possible explanations (at least three) for what could be causing Susan's symptoms. Be sure to include a description of the ailments you think Susan may be suffering from, an explanation of your reason for choosing those particular ailments, and a list of sources you used.  
Susan's symptoms started out as a common cold, but the fatigue and fevers remained. She has felt generally run down for two to three months and wakes up at night due to general pain throughout her body. Answers will vary as students may suggest a wide variety of ailments, including leukemia (which Susan is actually suffering from) but also any type of infection, lupus, chronic fatigue syndrome, arthritis, etc. 

Part 2 Questions: 

1. Look back at your original list of possible causes of Susan's symptoms. Discuss with your group whether the ailments you originally thought Susan had were accurate or inaccurate, based on the information in the history and physical. This is what physicians refer to as a differential diagnosis. Discuss the possibilities with your group members, and narrow down the possible diagnoses based on the information you have. Has your opinion changed now that you have more information? Why or why not?
Answers will vary depending on students’ prior list of ailments.

2. What are the functions of each type of blood cell? Why do you think Dr. Owen requested a CBC? 
Red blood cells carry oxygen to the cells of the body. White blood cells fight infection. Platelets are responsible for blood clotting. All of these cells may be present at abnormal levels (either increased or decreased) when a person is sick, which is why Dr. Owen ordered the CBC. In particular, Susan describes being out of breath with activity, which could be due to anemia (reduced numbers or function of red blood cells). Also, Susan may have an infection, which would cause increased numbers of white blood cells. The CBC is a useful diagnostic tool for this reason. He ordered the test "with differential," meaning that he wants a breakdown of the numbers of each specific type of white blood cell, probably in order to rule out various types of leukemia.

3. What results to you expect to see in the CBC if Susan has an infection?
If Susan has an infection, the CBC should show elevated numbers of white blood cells.

4. Why do you think Dr. Owen requested a blood smear? A chest X-ray?
The blood smear is used in order to detect various types of leukemia. The chest X-ray can be used to rule out pneumonia, since Susan did have cold/flu symptoms when she first started feeling ill, and continued to have fevers for some time.

*Students may have questions regarding other information that Dr. Owen asks for. This is an excellent opportunity for discussion of how physicians take a history and physical, and what types of information they need in order to make a diagnosis. Below is an annotated version of Susan and Dr. Owen's conversation, with explanations (in italics) for why he was asking for each piece of information:  

"OK, Mrs. Forest. I'm going to do a history and physical right now. I'll ask you some questions about your symptoms, your general medical history, and your lifestyle, and then I'll perform a physical exam to try to determine what is causing your symptoms. How old are you, Mrs. Forest?"
"Sixty-seven," she replied.
Age is a risk factor for many diseases. CML is much more common in adults over the age of 60.
"And how long ago did you begin having symptoms?"
"About three months ago, in February, I caught a cold that I couldn't seem to get rid of."
"Are you still producing mucus when you cough or sneeze? Are you blowing your nose a lot?"
"Not anymore."
"Did you take any over-the-counter medications?"
"Yes, for about two weeks I took an over-the-counter decongestant and pain reliever."
Dr. Owen is trying to get an idea of when Susan started feeling better after her initial cold symptoms. If she stopped taking the medicine, that means her symptoms had probably subsided at that point.
"So at that point you weren't really having the cold symptoms anymore?"
"Right."
"What about fevers? Did you take your temperature?"
"No, but I felt feverish once in a while even after the cold symptoms stopped. I don't think it was a very high fever, though."
A low grade fever is a common sign of infection (among other things) but it is important to note whether the patient took an accurate temperature.
"And you said you are feeling tired a lot. How much sleep do you usually get each night?"
"About five or six hours per night, which I don't feel is enough."
Obviously lack of sleep can lead to fatigue.
"Why do you think you aren’t getting enough sleep?"
"Well, I work in an accountant's office, so tax season is our busiest time. In early March I started working about 60 hours per week. Also, my son started working the night shift a little after that, and that's when I began picking up my grandchildren after their sports practices and watching them until their father gets home."
Note that this is AFTER Susan's initial symptoms began, so Susan's schedule is probably not the only explanation for her fatigue.
"Any shortness of breath after activities?"
"As a matter of fact, yes. I've been exercising a lot less than usual because I become out of breath. Even after just cleaning..."
In many types of leukemia, the increased number of white blood cells results in a decrease in red blood cells, as more of the precursor cells in the bone marrow differentiate into white blood cells. A reduction in red blood cells means less oxygen is being carried to the tissues, which may result in shortness of breath even with mild activity because the tissues need more oxygen.
"Have you been around anyone who was sick with the flu or any other contagious illness?"
This is important in determining whether Susan was exposed to any infectious agents.
"I don't think so. No one at work or in my family has been sick."
"Have you had any nausea or diarrhea or stomach upset in general?"
"No."
This is also a sign of infection.

"Have you been urinating more frequently or had blood or pain with urination?"
"No."
These are signs of a urinary tract infection.
"You said you've been having pain at night? Is this only at night, or do you feel pain upon waking up in the morning?"
Pain upon waking up is usually caused by inflammation in the joints due to injury or arthritis.
"Only during the night."
"Does the pain wake you from sleep?"
"Yes, sometimes."
Awakening pain is associated with cancer.
"Is the pain localized in one specific place?"
"No, it's just general achiness, almost like my bones hurt. Sometimes it's in my upper legs, sometimes my back hurts. But I can't pinpoint it to one location."
This is often associated with bone or blood cancers (leukemias, lymphomas, and myeloma).
"Do you find that the pain increases with more activity?"
"No, not really."
Pain during activity is often associated with tendinitis or osteoarthritis.
"Have you lost any weight?"
"No."
Weight loss is also associated with cancer.
"Do you or any close family members have high blood pressure, diabetes, cancer, or heart disease?"
All of these diseases tend to run in families, though not all forms of cancer run in families. Breast cancer does run in families (although Susan and her daughter-in-law are not blood relatives), but other forms of cancer, such as CML, are sporadic, meaning they occur due to spontaneous mutations later in life. People are not born with the mutation for CML.
Susan shook her head. "No. My daughter-in-law died of breast cancer, but none of my blood relatives have had it. My grandmother had diabetes, but no one else that I know of has had anything else you mentioned."
"Do you smoke or drink alcohol? Are you taking any drugs or prescription medications?"
Lifestyle questions are also important since abuse of alcohol, drugs, or prescription medications can obviously cause a person to become ill.
"No, I don't smoke or drink. I have a prescription medication for migraine headaches, but only take it when I get a migraine, which is usually about once a month or so. I don't take any other medicines, and I don't use any illegal drugs for heaven's sake."
"OK. I have to ask these questions just so I can get a clear picture of your overall health."

Upon physical examination, Dr. Owen noticed that Susan's spleen, located under the ribs on the left side of the abdomen, was swollen.
This finding upon physical exam is associated with leukemias and specifically is common in CML.  

Part 3 Questions: 

1. Conduct background research on multiple myeloma and chronic myeloid leukemia. What are the signs and symptoms of each? What changes occur in the blood composition of individuals with these diseases?
Multiple myeloma: Symptoms are similar to CML, and include unexplained fevers, pain, fatigue, and shortness of breath due to anemia. Plasma cells grow uncontrollably, causing the formation of tumors within the bone marrow. CML: Symptoms include fatigue, bone pain, and shortness of breath due to anemia. The myeloid precursor cells grow uncontrollably, resulting in a higher portion of immature blood cells in the blood and bone marrow.

2. Examine the blood smears or photographs from the normal individual, the individual with CML, and the individual with multiple myeloma. Then examine Susan's blood smear. What conclusions can you draw about Susan's diagnosis? 
Susan's blood smear confirms that she does in fact have chronic myeloid leukemia.

3. Describe the Philadelphia chromosome. How does this mutation come about? Does CML run in families?
The Philadelphia chromosome is present in individuals with CML. It is an abnormal chromosome that forms via a translocation between chromosome 9 and chromosome 22. In other words, chromosomes 9 and 22 exchange pieces, forming the Philadelphia chromosome. The Philadelphia chromosome contains the BCR-ABL gene, an oncogene that is a combination of two genes—one from chromosome 9 and the other from chromosome 22. This abnormal gene produces the BCR-ABL fusion protein, which is in the family of proteins called tyrosine kinases. Tyrosine kinases are involved in regulating the cell cycle. The BCR-ABL protein is always in its activated form, constantly stimulating cell growth. This is a sporadic mutation that occurs later in life. Therefore, CML does not run in families.

4. Describe PCR. What is this procedure used for? How is RQ-PCR used in the diagnosis of CML?
Polymerase chain reaction (PCR) is used to amplify (or make additional copies of) specific regions of a person's DNA. It can be used to detect the presence of a particular DNA sequence to determine, for example, whether someone has a disease-causing gene. It can also be used to compare DNA from different individuals, for example in order to perform paternity tests or forensic testing. Real-time Quantitative PCR not only amplifies specific regions of the DNA, it measures the quantity of that particular portion of the DNA present in a sample. This is especially useful in diagnosing CML and monitoring CML treatment since higher levels of the BCR-ABL gene transcript indicate that the person is coming out of remission and the cancer cells are proliferating.

5. What do you think is the emotional impact of this news for Susan? What adjustments will Susan have to make to her lifestyle if she is diagnosed with cancer?
Answers will vary but Susan will likely have to reduce her activity level, particularly while she is undergoing treatment. 

Part 4 Questions:
1. How do you think Susan's diagnosis will affect her lifestyle? What changes will she have to make?
Susan will have to reduce her activity level, particularly while she is undergoing treatment.

2. Conduct some research on other tyrosine kinase inhibitors used to treat CML. How effective are these treatments compared to imatinib?
Secondary tyrosine kinase inhibitors such as dasatinib are generally used as a second line of defense after use of  imatinib. Imatinib has been in use longer, though both of these drugs are effective in treating CML and are FDA approved.

3. What are the advantages and disadvantages of having a bone marrow transplant to treat CML?
A bone marrow transplant is the only cure for CML, since this completely eliminates all cells with the abnormal Philadelphia chromosome and replaces them with the donor cells. However, this is an invasive procedure and it is difficult to find a matching donor. Even with a matching donor there is always the possibility that the patient will reject (or mount an immune response against) the donor's cells.

4. What type of testing will Susan have to undergo in order to monitor her treatment? Conduct additional background research if necessary.
Susan will have to get regular blood tests, including CBCs, blood smears, and RQ-PCR to detect the BCR-ABL gene transcript. 

5. If you were Susan, what concerns and questions would you have at this point?
Answers will vary.

6. CML has been referred to as the "poster child" for translational medicine, i.e., the use of molecular biology research results to determine treatment for a disease. Do you agree with this statement? Explain why or why not. CML is caused by a very specific mutation (or change) in the DNA. Since the function of the resulting protein (BCR-ABL) is known, a drug (imatinib) was specifically developed to target and disable this protein. In this particular case, the knowledge gained through many years of molecular biology research was applied to solve a specific health problem, CML.

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