Wei,+William

=Anaplastic Oligodendroglioma=




 * Profile**

Abra Lee Granger was a white, caucasian female of 24 years of age. She grew up in Ojai, CA and was a college graduate from UC Santa Cruz with honors with a bachelor’s degree in Psychology as well as a minor in Anthropology. She worked as a salesperson and regional manager at a holistic medical company in Cupertino, CA. She was a hard worker who was very generous with sharing tips on how to do a better job at her company.


 * Disease Onset **

One day, after a Christmas vacation, she began having headaches. She remembered she had dizziness in college, though it had not reappeared until that point. The headaches worsened and over the course of only two weeks she was exhibiting full blown migraines and dizziness accompanied by blurred vision. Since she was concerned about her symptoms, she turned to chiropractic medicine to see what could be the cause of her symptoms since the company she worked for had connections to alternative medical sources. She was told she had problems with her pituitary area. Since she did not have insurance, she enrolled in it but was forced to wait another ten days until she could rely on her insurance for healthcare. During these ten days, she took certain medicines and was able to cope with her headaches enough to sleep.

Once she was able to use her insurance, she went to the doctor and immediately underwent an MRI. A mass was found near her brain stem and she was advised to undergo surgery to remove the mass. Two days later, the mass was removed and no complications occurred, she seemed to be in good condition and was recovering. But, one week later, her recovery was slowing, her eyes would not open, and she could not see. To make matters worse, her doctors discovered that the mass was a cancerous mass. She was immediately placed on chemo with the hope that any residual cells would disappear. Six weeks later, her vision had not returned and she decided to return home. Two weeks later, she passed away due to a massive cerebral hemorrhage.


 * Form of Cancer **

It is unknown exactly what cancer she suffered from, but from the speed of the cancer, the statement that it was a rare form of cancer, and the speculation that she suffered strange headaches in college, she probably suffered from anaplastic oligodendrogliomas. Anaplastic Oligodendrogliomas are the aggressive form of Oligodendrogliomas, cancers of specific glial cells, cells that support the brain, called oligodendrocytes, cells that make myelin the fatty substance that surrounds and insulates the nerve cell axons of the brain and spinal cord. Oligodendrogliomas grow slowly but may evolve into more aggressive forms over time and account for only 2% of all brain tumors. Though the type of cancer is only a guess, the symptoms of such a cancer, based on location, are consistent.



** Symptoms **

The symptoms of brain cancer located at the back of Abra’s head, near her brain stem match Abra’s symptoms since the symptoms are specifically dizziness, headaches, and intense vision problems. The size of the cancer caused headaches because the tumor pressed her brain against her skull. Because the tumor was located near her brain stem, the vision problems would arise from pressure against the occipital lobe and optic nerve. Since dizziness is caused by a deficiency in one of the multiple parts of the body needed to maintain balance, it may have come about by the tumor pressing against one of the areas near the back of the head responsible for motor functions such as the cerebellum. The headaches, dizziness, and vision problems would probably have been linked. Vision problems include double vision which is known to cause disorientation and thus dizziness. Headaches and dizziness follow a positive feedback loop since headaches may be a sign of the brain demanding more blood from the extremities thus creating a shift in blood supply from important balance organs to the brain, thus making dizziness worse. As it is, the cancer may have also been pressing at the Abra’s cranial nerve which would cause the vision problems and from there, the other symptoms may have cascaded as well.

** Prognosis **

If Abra had anaplastic oligodendrogliomas, her prognosis would have been pretty grim though somewhat hopeful with evidence of a 5-year survival rate of 67% for patients aged 20-44 years. In other words, she should have had only a 67% chance of surviving the disease without remission and with treatment. It can be said that this prognosis took into account the sheer size and location of the tumor. It may have been a prediction predicated on such complications such as the tumor was pressing against the occipital lobe and the cranial nerve. A complication that would render surgery incomplete since incisions to remove the tumor occurred too close to those vital structures and thus incur the risk of causing permanent vision loss from damage to those structures. Even if the surgery was at a different location, oligodendrogliomas tend to infiltrate nearby brain tissue and thus would impossible to be completely removed by surgery. This would ensure that she would need chemotherapy of some kind in order to remove any residual cancer cells that could not extracted by the initial surgery. Unfortunately, because of the oligodendroglioma grew to such a size, it was also pressed against the valuable arteries or veins, and thus its removal caused dilation of those structures. This caused a weakening of the blood vessel walls and increased the risk of internal bleeding. This dilation, coupled with chemotherapy, weakened the blood vessel walls even further and thus made internal bleeding and death almost a certainty. Perhaps without chemotherapy, she would have lived longer since her occipital blood vessels would have been give time to heal. Then again, she would have died from a relapse if the chemotherapy did not occur.

** Risk Factors **

Such a situation may prompt speculation and questions such as why she caught such a disease. Perhaps, she had neurofibromatosis type 1, an inherited genetic disorder that would increase her risk of getting cancer, which would make her developed another kind of cancer later on because of the nature of the disease. Inherited risks are a likely source of risk factors that would increase one’s chance of getting brain cancer and thus be a possible explanation for why Abra developed brain cancer. The specific genetic disorder that may have increased the Abra’s risk of getting cancer is called neurofibromatosis, specifically neurofibromatosis type 1 (NF1). neurofibromatosis type 1 “also known as von Recklinghausen disease, is the most common syndrome linked to brain or spinal cord tumors. People with this condition have higher risks of schwannomas, meningiomas, and certain types of gliomas, as well as neurofibromas (benign tumors of peripheral nerves). Changes in the NF1 gene cause this disorder. These changes are inherited from a parent in about half of all cases. In the other half, the NF1 gene changes occur before birth in people whose parents did not have this condition.” NF-1 causes tumors, called Neurofibromas, along the nervous system and, as a result, spawns multiple chances of getting a cancerous tumor. As it is, with the available knowledge and without interrupting her family’s silent mourning, there can only be speculation on the true identity and cause of her cancer.

What follows is a simple simulation of her case if she has anaplastic oligodendroglioma.

**Treatment** AFTER DIAGNOSIS

Hello Ms. Granger. our team just got your lab results back for the unusual and large mass we found located in the back of your brain. We think it is an oligodendroglioma, and from your description of the symptoms and speed of the symptoms, we think it may be the most aggressive form called anaplastic oligodendroglioma. Nevertheless, to ensure we can get the right diagnosis as well as create the best prognosis possible for you, we will be performing the standard treatment for the disease. The standard treatment for this anaplastic oligodendrogliomas involves three steps: surgical removal, chemotherapy, and radiotherapy.

The surgical removal will accomplish three steps: it will allow us to perform a biopsy to determine the exact nature of the unusual mass, it will allow us to remove as much of the tumor as possible and thus alleviate your most pressing symptoms- migraines and dizziness, and by removing as much of the tumor as possible, we will be ensuring the best prognosis possible. You are somewhat fortunate since your tumor is located on the peripheral portions of your brain because this will allow us to perform what is called an “open biopsy.” An open biopsy involves opening your head by removing a piece of skull through a craniotomy and then cutting as much of the tumor out as possible while examining that tumor tissue to determine if the tumor is cancerous. Generally, as long as the entire tumor is removed, a person can expect a better survival rate than if only part of the tumor is removed.

AFTER SURGERY

Hello again Ms. Granger, the surgery was a success and we were able to remove all of the detectable tumor, but since your recovery has been a lot slower than expected, the tumor was confirmed categorically as an anaplastic oligodendroglioma, and your vision has not yet returned we suspect that there are residual cancer cells that need to be treated. Fortunately, we found that the tumor has the 1p/19q codeletion. This feature would allow the tumor to be more responsive to certain chemotherapy.

While the standard treatment for this disease involves the use of both chemotherapy and radiotherapy, we recommend deferring radiotherapy and first using chemotherapy for your treatment. While chemotherapy and radiotherapy both have their risks and benefits, in your case, the risks of using radiotherapy so soon after surgery outweigh the rewards.

Radiation therapy, radiotherapy for short, uses high energy radiation to shrink or kill tumor cells, in other words, we will be shooting beams of radioactive energy at your tumor to kill your tumor. While the advantages of using radiotherapy in your situation include shrinking tumors, safety for your through focusing only on the tumor, and the ability to kill a large number of cancer cells in your body, these advantages no longer apply since your tumor was mostly extracted. Since there is no more detectable tumors on the MRI, going through radiotherapy would be unable to target the tumor, complicate and thus slow down your recovery from surgery, and potentially damage the surrounding brain tissue- including the vision centers in your brain. This damage would manifest as a side effect of radiotherapy on brain cancers called brain necrosis, aka, a focused brain injury at the same location as the tumor. Since your eyesight has not returned, we think that there may have been some form of injury that occurred regarding the visual centers of your brain and that initiating radiotherapy at this point may serve to exacerbate or make permanent your vision loss. Nevertheless, since your recovery is slower than usual and the tumor cells we biopsied were cancerous, we suspect that there may be some cancer that was not surgically removed. As a result of this, we have decided that you should first undergo chemotherapy for the cancer since this may be gentle, yet effective enough to treat your cancer without provoking permanent vision loss. This will also give you time to recover your eyesight and perhaps become ready for radiotherapy.

Chemotherapy is the use of drugs to directly kill or slow the growth of cells. Since cancer cells are faster growing than normal cells it is expected that they will incur greater damage than normal cells. Since chemotherapy is diffuse throughout the body it is useful for killing any residual cancer cells that remain after surgery, including cells that may not be visible via MRI or CTscan. The common side effects of chemotherapy involve fatigue, pain, sores in the mouth and throat, diarrhea, nausea and vomiting, constipation, and blood disorders. While these side effects seem to be a burden, the rewards are great because anaplastic oligodendroglioma the tumor has the 1p/19q codeletion and so may respond better to the specific treatment called PCV for the three drugs: Procarbazine, Lomustine (also know as CCNU ®), and Vincristine. Procarbazine and Lomustine are both alkylating agents-drugs that inhibit transcription of DNA into RNA. While both are most active when the cell cycle is at rest and are non-cell cycle specific Procarbazine is a hydrazine-type alkylate that can inhibit transmethylation and general DNA synthesis, while Lomustine is a nitrosoureas-type alkylate that can cross the blood-brain barrier. Vincristine, in contrast, is a plant alkaloid that is cell-cycle specific and attacks cells during cell division. Vincristine, specifically is an antimicrotubule agent which inhibits microtubule activities, meaning it inhibits the structures needed for cell division and repair. Altogether, this regime works best by penetrating the blood brain barrier, inhibiting transcription of DNA, and destroying the ability of the tumor cells to self-repair and replicate. The therapy and regimen has had a profound effect on patients when in combination with radiotherapy, though when the optimal timing for taking chemotherapy and radiotherapy has not yet been established. However, there has been evidence that suggested that the radiotherapy and chemotherapy do not have to be taken concurrently which may give you time to recover and get your eyesight back.

**Molecular Basis**

Hi Abra, I received your request for information regarding your disease and have come here to explain it to you. Perhaps with this review we can help you decide what to do next regarding your treatment.

Anaplastic Oligodendroglioma, or AO, is a brain tumor, specifically a glioma, a cancer that arises from glial cells or central nervous system cells. Your tumor is specifically comes from oligodendrocytes, or cells that provide insulation and protection to your nervous system, mainly in the myelin sheath of your spinal cord but also in parts of your brain. The unique feature of AO is the presence of 1p19q codeletion. While the explicit effects of the genetic deletions are not understood, what is known is that this mutation is mutually exclusive with both TP53 mutation and EGFR amplification. This means that the TP53 gene and EGFR gene are both normal and thus AO may still be subject to some of the effects of TP53 induced apoptosis, while being slow growing because EGFR is needed to produce cell growth.

More important, though, is that

MGMT promoter hypermethylation is significantly more frequent and the percentage of methylated CpG sites was significantly higher in 1p/19q codeletion tumors compared with 1p and/or 19q intact tumors. __[24,25]__ The high frequency of MGMT promoter methylation in 1p/19q codeletion gliomas might partly explain their chemosensitivity.

In other words, the codeletion is linked with MGMT hypermethylation. Normally DNA incurs damage from a vast variety of sources. The MGMT promoter is responsible for repairing DNA damage. Thus, when MGMT is hypermethylated, DNA damage is not repaired. When a cancer has MGMT hypermehtylation, it cannot repair its DNA, therefore both TMZ and PCV would do well in treating cancer by destroying cancerous DNA since both PCV and TMZ work by causing DNA damage.

There may be confusion as to why deal DNA damage would be effective in killing cancer. That is understandable since tumorigenesis (genomic instability resulting from the oxidative environment) is a crucial factor in causing cancer. However it should be noted that too much DNA damage can kill AO cancer cells since the TP53 gene in AO is still normal and thus AO may still be subject to some of the effects of TP53 induced apoptosis. In other words, if too much DNA damage is done to AO cells, then the cells will self-destruct.

It should be kept in mind that DNA damage is what causes cancer in the first place. While it is assumed that healthy cells would have their MGMT promoter intact to mitigate the carcinogenic effects of a DNA damaging agent, it still should be noted that both PCV and TMZ are potent carcinogens since they damage DNA indiscriminately, thus it is preferable to seek alternative treatments for AO to eliminate the risk of secondary cancer. A promising avenue for new, less damaging drugs may be IDH1 and IDH2 mutation.

There are some experimental options available that focus on IDH1 and IDH2 gene mutation but they are not tested as of yet. The mutations of the IDH1 and IDH2 are a constant feature in 1p/19q codeletion gliomas and so are present in most all AO. Not only is IDH1 and IDH2 mutation commonly associated with 1p19q codeletion, it is also associated with MGMT hypermethylation and may have a causal relationship with MGMT hypermethylation by causing methylation. Therefore, if there are drugs that target this gene, then it can target and destroy AO as well as some other cancers.

The IDH1 and IDH2 gene normally plays an antioxidant role during oxidative stress. Therefore, when these genes are mutated, they contribute to “both tumorigenesis (genomic instability resulting from the oxidative environment) and response to treatment (reduced resistance to agents producing oxidative damages).” In other words, the IDH1 and IDH2 gene mutation may be a primary cause of this cancer since it consequently causes DNA damage and thus mutation of the cancer’s genomic structure but also the cause of its current weakness to alkylating agents. What is a more important factor is that IDH mutations also seem to generate an oncometabolite, i.e., a nutrient that facilitates tumor growth. Recently there are drugs that have been released that target IDH1, IDH2 or both IDH1 and IDH2 mutations which would eliminate a crucial factor of AO.

The relevant drug, AG-881, a Brain-penetrant, pan IDH mutant inhibitor, i.e., a drug that targets both IDH mutations that is able to treat brain tumors, will soon be put into Phase 1 testing. It would work by inhibiting the IDH mutations. This would inhibit any more mutations in the cancer as well as starve the cancer of a crucial nutrient. The best trait of this drug is that it is not an alkylating agent so it does not carry the risk of causing secondary cancer. That drug will soon undergo clinical testing and thus may provide a viable treatment for AO.

Conclusion

In the end, Abra Granger died. The adjuvant six week round of chemotherapy did not resolve her condition and she did not get the chance to try any clinical trials. What happened? Why did the treatments fail? The best explanation is that her cancer was not actually anaplastic oligodendroglioma or at least the type that treatment would help with. A lot of the explanations displayed in this article are speculations on the best case scenario. In truth, the odds were not in her favor. The prognostic factors that would allow a positive outlook, meaning an scenario in which she would respond well to chemotherapy, are that she has codeletion of 1p19q, IDH deletion, and MGMT hypermethylation. A 1p19q codeletion is present in 69% of cases of oligodendroglioma, whatever the type, which is 2% of all brain tumors, though if there is incomplete deletion, then her outlook decreases. The odds of her having any IDH mutation is 40% for all types of gliomas, brain cancers but 100% if she has 1p19q codeletion. MGMT hypermethylation is an independent factor that would also allow for better outlook but the chances of her brain tumor displaying this mutation are 45% in glioblastoma brain tumors and 88%  in oligodendroglial tumors. In this sense, if she actually had anaplastic oligodendroglioma, she would have had a better chance of surviving. As it is, she may have had the bad luck of having a brain cancer that was not responsive enough to chemotherapy.

 Apercu:  Cancer is a scary disease. People before saw it as a death sentence. Now, though, with modern advances in medical technology and research, we have effectively cured some cancers and have at least given people a fighting chance against others.