Glioblastoma

=**Introduction **=

Glioblastoma, also commonly known as glioblastoma multiforme or grade IV astrocytoma, is the most commonly diagnosed brain tumor among adults [1]. A glioblastoma falls under the broader category of astrocytoma, which begin development in astrocytes [2]. Astrocytes are specialized glial cells that are responsible for a variety of regulatory and neural functions, including assisting in synaptic transmission as well as processing, synaptic remodeling and pruning, and regulation of CNS blood flow and metabolism [3]

Glioblastoma is the most common grade IV brain cancer [1] and most commonly begins growth in the frontal and temporal lobes of the brain [4]. However, glioblastoma can develop in any part of the CNS including the spinal cord and brain stem [4]. Glioblastoma is not a metastatic cancer [5], meaning it does not spread to other areas of the body. There are two types of glioblastoma: primary and secondary [6]. The primary strain is significantly more common (90% of patients with glioblasto ma have the primary strain) and aggressive, while the secondary strain begins as a lower-grade astrocytoma and is almost always found in individuals age 45 or younger [2]. The cause of glioblastoma is not usually known, though specific genetic syndromes such as neurofibromatosis type 1, Turcot syndrome, and Li Fraumeni syndrome have been connected to the development of glioblastomas [7]. With that said, however, most glioblastomas occur erratically in individuals with no family history of brain cancers [7].

Symptoms of glioblastoma vary greatly depending on the location of development, as with all brain tumors. The most common symptoms include increasingly frequent headaches, nausea, seizures, changes in mood and speech as well as general reduction in focus [5]. The treatment of glioblastoma is multifaceted. In most cases treatment begins with surgical intervention, which attempts to remove as much of the tumor as possible without damaging the surrounding brain tissue [4]. Secondary treatments include radiation therapy and chemotherapy, often administered together, each of which have their benefits and drawbacks [4]. The particulars of each cancer treatment is highly specific and based upon the patient's medical history, age, cancer stage and location, as well as personal preference.

Brain cancer, particularly glioblastoma, is a terrible diagnosis that leaves little room for hope for the patient and their family. Glioblastoma can often steal away parts of a patient's personality and processing ability (a worry many people have of Senator John McCain's recent glioblastoma diagnosis), making the patient's loved ones feel as though the cancer has robbed them of their friend even before death finally comes. Additionally, the recurrence and mortality rate of glioblastoma is near 100%, with only a few reported cases of curative outcomes. Survival rates for glioblastoma are as follows [1]:
 * One year: 39.3%
 * Two years: 16.9%
 * Three years: 9.9%
 * Four years: 7.0%
 * Five years: 5.5%
 * Ten years: 2.9%

While there is no current cure for glioblastoma, there are hundreds of ongoing clinical trials (845 to be exact) [8] researching treatments that will hopefully improve the above survival rates dramatically.

=**Overview of Cancer **=

Cancer results from the abnormal, unregulated proliferation of cells throughout the body caused by genetic mutations [9]. Cancers are classified based on the type of cell that the cancer proliferates from. The most important topic in cancer pathology is the distinction between benign and malignant tumors. A benign tumor does not invade surrounding tissue, remains forever in its original location, and is not //technically// cancer. A malignant tumor, however, has the capacity to invade surrounding tissue and even spread throughout the body (metastasis) [9]. Additionally, malignant tumors are categorized by different grades (I-IV) based, essentially, on how deadly they are. See the below table for more detail.

There are a few major differences between cancer cells and normal, non-mutated cells. First, when normal cells reach a certain density they cease to proliferate, however, most cancer cells lack this inhibition which would normally cause cessation of growth [9]. This allows cancer cells to grow in an uncontrolled manner. Second, large tumors require blood supply in order to have enough oxygen and nutrients to sustain life. Because of this, many malignant tumors stimulate angiogenesis by secreting specific growth factors [9]. Additionally, this allows cancers to begin the metastatic process by infiltrating the circulatory system [9]. Lastly, cancer cells do not undergo apoptosis (programmed cell death) [9]. Normally, cells will undergo apoptosis when there is a significant homeostatic imbalance, an absence of growth factors, or DNA damage. However, cancer cells fail to respond to any of these signals [9]. This causes vastly increased cell life allowing the tumor to continue to develop for long periods of time.

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Anatomical Presentation of Glioblastoma **=

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Glioblastoma can develop in any area of the CNS including the brain stem, cerebellum, and spinal cord; though over 80% of all primary gliomas develop in the four lobes of the brain [10]. It is commonly believed that glioblastoma is derived solely from glial cells, specifically astrocytes [7]. Astrocytes appear as many branchings of fine fiber-lik e<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;"> processes which allow them to synapse with other glial cells and neurons [3].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">There is recent research suggesting that glioblastoma may arise from other cells (not just astrocytes) with stem-cell like properties [11]. These cells may be at multiple stages of differentiation from stem cell to neuron to glia when the glioblastoma begins to grow [11].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">The anatomical presentation of glioblastoma varies widely. Glioblastoma tumors typically arise in the subcortical white matter and deep gray matter of the cerebral hemispheres in the temporal lobe [12]. They range from being a very firm to very gelatinous and, in color, fall somewhere between white and yellow [12]. One important anatomical characteristic of glioblastoma is that it is always infiltrating tissue beyond the visible boundaries of the tumor, which causes it to be particularly deadl y <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">[6].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Lastly, glioblastomas, as well as other high grade brain lesions, cause microvascular proliferation (angiogenesis) in the brain which causes the sprouting of capillaries from preexisting blood vessels throughout the brain [9]. This creates a vascular network that surrounds the glioblastoma.



//<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Pictured to the right are three MRIs of glioblastoma located in the brain //

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Diagnosis **=

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">There are three main ways to diagnose glioblastoma: radiologically, histologically, and clinically [13]. The initial diagnosis, or suspicion of diagnosis, is done clinically. When individuals present with a headache along with seizure, papilledema, or changes in consciousness, a physician would likely order radiological imaging. Additionally, a physician should look for progressive worsening of symptoms or the presence of severe neurological symptoms to begin a glioblastoma diagnosis.

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">The initial preferred radiological diagnosing tool is MRI, although CT scans are usually used as well to evaluate patients with suspected glioblastoma [13]. An MRI is the most sensitive imaging method for glioblastoma tumors. On an MRI scan the tumors appear as irregular lesions that are isointense or hypointense, which present as cysts with irregularly thick margins [13]. Unfortunately, it is often difficult to have full confidence in a glioblastoma diagnosis based solely on MRI or other current imaging mediums, and some differential diagnoses for glioblastoma include radiation-induced necrosis, metastasis, primary CNS lymphoma, and other high-grade gliomas [13]. With that said, new radiological technologies are being produced in order to make diagnosing glioblastoma easier and more accurate. One such technology is perfusion MRI. Perfusion MRI assesses blood flow around the tumor site [13]. Due to angiogenesis in high level brain tumors, the amount of blood perfusion detected around the tumor directly correlates with tumor grade [13]. Using specific parameters, perfusion MRI is able to observe this angiogenesis and provide important diagnostic information. It also improves the accuracy of biopsy, as it is able to locate the most malignant part of the tumor, and thus optimizing target selection during surgery [13]. Lastly, perfusion MRI is capable of differentiating between a tumor that has recurred and necrosis of brain tissue caused by radiation therapy [13]. This is because necrotic brain tissue leads to decreased blood flow contrasted with increased blood flow caused by the angiogenesis stimulated by glioblastoma [13].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;"> <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">The third, and most effective, diagnostic tool available is biopsy. The identification of glioblastoma is performed through recognition of tissue pattern, rather than discovery of certain cell types, as the cell morphology of glioblastoma is highly variable, leading to it being termed glioblastoma //multiforme// [13]. The histological characteristics of glioblastoma are four-fold and make up the acronym AMEN. They are: nuclear Atypia, Mitosis, Endothelial proliferation, and Necrosis (pseudopalisading pattern) [13]. Most cases of glioblastoma can be diagnosed through histology alone - though every once in a while atypical morphology may present itself [13]. This is where immunohistochemical stainings come into play. By staining the tissue for GFAP, S-100, CK, CD45, and synaptophysin, the pathologist is able to rule out certain diagnoses, while becoming more confident in others [13]. However, immunohistochemical stainings are not 100% accurate as, for example, some glioblastomas can have positive tests for GFAP and other negative, while S-100 can also be found in melanomas [13].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">It is clear that the diagnosis of glioblastoma is no simple process. Often a series of tests, in combination with a well trained physician, are necessary to diagnose glioblastoma, and even then, medical professionals are not always correct when dealing with complex tumors such as these.

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Signs and Symptoms **=

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Like most brain tumors, the most common initial symptom of glioblastoma is headache [14]. This is due to the increase in intracranial pressure that the tumor causes [14]. Many individuals will also complain of nausea or vomiting as well as seizures (50% of glioblastoma patients) [15]. For glioblastoma patients, headaches, nausea, and seizures can be particularly painful and intense when waking up in the morning. While headaches, seizures, and nausea are present in many individuals with glioblastoma, the symptoms that follow differ greatly with each individual case.

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Non-universal glioblastoma symptoms vary depending on the area of the brain or CNS structure that the tumor is present in, as well as the type of strain that they are putting on the structures around them. Glioblastoma not only invades and destroys brain and CNS tissue and increases intracranial pressure within the brain, it can also block the normal circulation of cerebrospinal fluid throughout the brain and CNS which causes an excess of fluids to accumulate in the brain and CNS [16]. Additionally, glioblastoma can cause hemorrhaging of cranial blood vessels. These cranial aberrations will alter normal functioning severely [16].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Incidence of the most common symptoms are as follows: memory loss (35%), cognitive changes (34%), motor deficits (33%), language deficits (32%), seizures (32%), personality changes (23%), visual problems (22%), changes in consciousness (16%), nausea or vomiting (13%), sensory deficits (13%), and papilledema (5%) [10].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Below are the most common locations, as well as their incidence rates [10], for glioblastoma and their associated symptoms:

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Frontal Lobe (40%) **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">If located in the frontal lobe, glioblastoma may cause behavioral and emotional changes, impaired judgement, impaired sense of smell if located near the olfactory bulb, memory loss, paralysis or loss of motor function if located near the motor cortex, reduced mental abilities, difficulty with word association and expressive difficulties if located near Broca's area, and vision loss if located near the cranial nerves [16,17 ].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Parietal Lobe (14%) **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">A parietal lobe glioblastoma can cause impaired speech, inability to write, numbness, and loss of ability to feel heat, cold, pressure or light touch if located near the somatosensory cortex [16,17].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Occipital Lobe (3%) **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">Occipital lobe glioblastoma can cause vision loss if located near the visual cortex [16,17].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Temporal Lobe (29%) **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">A temporal lobe glioblastoma may lead to memory difficulty or loss of ability to comprehend spoken words [16,17].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Pituitary Gland (6%) **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">If a glioblastoma puts significant pressure on the pituitary gland, a number of symptoms may occur. It may cause an increase in the secretion of pituitary gland hormones (ACH, LH, GH, Prolactin, TSH, anti-diuretic hormone, and oxytocin), causing a number of symptoms including a stop in menstruation, abnormal secretion of milk and decreased libido. Additionally, the 6% incidence rate relates to the rate that glioblastomas form near enough to the pituitary glad to have significant affects [16,17].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Brainstem (4%) **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">Brainstem glioblastoma may cause behavioral and emotional changes, difficulty speaking, uncoordinated gait, drooping eyelids, and double vision. These symptoms are due to pressure on cranial nerves in the brain stem as well as certain nuclei, like the vestibular nuclei, located in the brainstem [16,17].

**<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">Spinal Cord (2%) **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">All spinal cord glioblastomas are intramedullary tumors which can cause radiating back pain due to pressure placed on the spinal column, loss of sensation, loss of motor function, decreased sensitivity to pain, and muscle weakness. All of these symptoms are due to increased pressure within the spinal cord and the restriction of spinal pathways such as the DCML (loss of sensation), anterolateral spinothalamic tract (decreased sensitivity to pain), and descending pathways (medial and lateral pathways) responsible for motor functions [15,16,17].

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Usually, symptoms begin rapidly when a glioblastoma tumor begins to form, however, if it remains small in size for an extended period of time, symptoms may go unnoticed until it grows substantially [15].

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Risk Factors and Causes **=

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Risk Factors **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">While the precise cause of glioblastoma is not known [18] there are certain risk factors and genetic predispositions that may lead to a greater susceptibility of glioblastoma. The epidemiology of glioblastoma shows that it is more likely for individuals to develop glioblastoma if they are between 50-70 years old, a male, and Caucasian [19].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Causes **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Many researchers posit that contact with certain chemicals and ultraviolet rays can significantly increase an individual's risk of developing glioblastoma [21]. Specifically, there is evidence that individuals who work in oil refining, rubber manufacturing, and drug manufacturing have a higher likelihood of developing glioblastoma [19]. Additionally, there are some studies which have related increased cell phone use (which release a small amount of non-ionizing electromagnetic radiation) and pesticide exposure to glioblastoma [20]. While seeming to be a stretch, there is even experimental data that shows that head trauma can lead to glioblastoma [20]. When glial cells experience a trauma they may undergo a process called gliosis, in which they hypertrophy and multiply. This is thought to result in changes in the blood-brain barrier which may cause the brain to become more susceptible to exposure to carcinogens and growth factors, leading to malignancy and therefore glioblastoma [20]. The only risk factor that is //proven// to increase the risk of developing glioblastoma is exposure to ionizing radiation. Ionizing radiation is powerful enough to damage DNA, which can lead to tissue necrosis and therefore tumor development [20]. The correlation between ionizing radiation and glioblastoma is strong, as 116 cases caused by ionizing radiation have been reported [20].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Genetic Diseases **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">There are certain genetic diseases which may lead to an increased risk of glioblastoma development. They include neurofibromatosis type 1 and 2, tuberous sclerossi, Li-Fraumeni syndrome, retinoblastoma, Von Hippel-Lindau disease and Turcot syndrome. However, less than 1% of individuals with glioblastoma have a known hereditary disease [15].

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Pathology **= <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">The pathology of glioblastoma, as is the case with all cancers, is complex as the combination of many oncogenomic factors contribute to the development of glioblastoma. Mutations of different molecular pathways, as well as the genetic diseases listed above, can lead to gliomagenesis, or the growth of a glioma. The most common cause of glioblastoma is the deletion of chromosome 10 [20]. This suggests the presence of a tumor suppressor gene on that specific chromosome. Another common gene mutation that causes glioblastoma is the amplification of epithelial growth factor receptor (EGFR) located on chromosome 7 [20]. EGFR amplification is present in 40-60% of all glioblastomas. An amplification in EGFR, which normally regulates cellular development, proliferation, and migration allows for growth factor ligands to bind to EGFRs which activate the RAS protein [20]. This RAS protein, then, alters transcription of cellular regulation genes within the nucleus, leading to potential for gliomagenesis. Additionally, Chromosome p53 mutation, RB1 and MGMT methylation, or the deletion of p14ARF, may lead to a mutator phenotype which causes mutations in DNA repair mechanisms, often leading to gliomagenesis [20].

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Treatment **=

**<span style="font-family: Times New Roman,Times,serif; font-size: 14pt;">Current Treatment **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Glioblastoma multiforme is very complicated to treat as the tumor may be made up of a variety of different cells (making radiation and chemotherapy difficult), and there are portions of the tumor that spread, almost invisibly, throughout the brain making safe surgical intervention challenging [18]. Once diagnosed with glioblastoma, treatment begins in most cases with surgical intervention which attempts to relieve pressure on the brain and safely remove as much of the tumor as possible, followed by radiation and chemotherapy [22]. Surgery also provides an opportunity to biopsy the tumor and determine the most effective course of radiation and chemotherapy. Surgical intervention alone results in survival of about 6 months. When treated additionally with radiation therapy, median survival length increases to 12.1 months and addition of chemotherapy increases the median survival length to 14.6 months [22].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Surgery **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">As mentioned above, surgical removal of a glioblastoma tumor is extremely difficult as the tumor often has tentacle-like projections that run throughout the brain. However, there have been advances in surgical techniques, specifically for difficult-to-remove brain tumors, like glioblastoma. One approach, known as the //Six Pillar Approach//, combines the use of 6 tools or principles to provide the least invasive, most effective surgery [23]. They include brain mapping, GPS brain navigation technology, sophisticated optics, resection, a targeted approach, and the BrainPath, which allows the surgeon to move safely through the brain to reach the tumor by displacing healthy brain tissue without damaging it [23]. The //Six Pillar Approach// is currently being used to treat patients suffering from glioblastoma and metastatic cancers [23]. Another new surgery technique involves the utilization of oral aminolevulinic acid which helps the surgeon see the tumor during surgery [24]. The patient will take the oral medication 2-4 hours before anesthesia induction, then during surgery the surgeon will use an operating microscope adapted with a blue-emitting light source and filters for excitation light of wavelengths 375-440 nm, and observation at wavelengths of 620-710 nm, allowing him to see the tumor as red fluorescence [24]. Additionally, during surgery carmustine wafers may be introduced into the area of the brain where the tumor was [4]. These wafers will dissolve, treating the surrounding tissues with the medication. This medication works to kill remnants of the tumor cells after surgery [4]. While maximal surgery resection remains critical to glioblastoma treatment, glioblastoma ultimately does not have a surgical solution [22].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Radiation Therapy **
<span style="font-family: Times New Roman,Times,serif;"> Radiation therapy is sometimes used as the sole therapy for the treatment of glioblastoma (when surgery is deemed unsafe), but it is most commonly used in combination with other therapies [4]. A variety of methods of radiation therapy are currently available to treat glioblastoma. Intensity modulated radiation therapy (IMRT) is a recently developed radiation delivery system [4]. It uses very small beams of radiation, all of which can have their intensity changed, that are focused on the tumor [4]. By using small beams of radiation, this therapy prevents the surrounding healthy tissue from being damaged and allows treatment of tumors near critical parts of the brain [4]. Another common radiation therapy technique is stereotactic radiation therapy. This treatment focuses beams of radiation on the outline of the tumor in an effort to destroy it [4]. This therapy is often used instead of surgery. The current standard of radiation therapy care, however, is external beam radiation therapy (EBRT) focused on the surgical resection cavity [22]. 60 gray (a unit of ionizing radiation) is delivered in fractions of 2 gray over a six week period of time [22]. This radiation causes single and double strand breaks in the DNA of the proliferating cells [22].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Chemotherapy[[image:Chemotherapy.png width="256" height="258" align="right" caption="[16] - Chemotherapy of brain tumor"]] **
<span style="font-family: Times New Roman,Times,serif;"> Up until 2005, surgical intervention and radiation therapy alone were considered the //standard// treatments used to treat glioblastoma [15]. However, after an important phase III trial confirmed that radiation therapy in addition to Temozolomide (TMZ) chemotherapy was more effective than radiation therapy alone, it became the standard treatment [15]. TMZ is an oral alkylating chemotherapeutic agent, which causes DNA damage in the tumor leading to apoptosis [22]. Specifically, TMZ adds a methyl group to O6-methylguanine in the DNA of the tumor [22]. This methyl, however, can be removed by O6-methylguanine methyltransferase (MGMT), which is a DNA repair protein [22]. High levels of methylation of MGMT in patients can lead to resistance of TMZ. When TMZ is given alongside radiation therapy it is typically administered at a dose of 75mg/m2 daily for 6 weeks [22]. This is followed by radiation therapy, and then a month of rest. When chemotherapy is started again, the dose is doubled for the first five days of the first month [22]. If this is relatively tolerated by the patient, the dose increases by 25% for five consecutive days per month for the rest of the therapy [22]. The therapy usually lasts for 12-18 months, though there is no conclusive data that extending chemotherapy treatment for longer than 6 months has any additional positive effect. TMZ can cause side effects such as nausea and vomiting. However, side effects are only seen in 4% of patients [20]. TMZ is currently considered the most effective chemotherapeutic treatment as it is associated with the lowest incidence of recurrent glioblastoma and longer patient survival rates [22].

<span style="font-family: Times New Roman,Times,serif;"> As mentioned in the 'surgery' section, carmustine wafers can be implanted into the previous location of the recently removed tumor. These carmustine wafers are a type of chemotherapeutic agent which, similar to TMZ, are DNA alkylating agents [22]. In combination with radiation and TMZ, carmustine wafers are shown to modestly prolong survival in some patients [22]. However, there are complications such as infection, swelling, and impairment of wound healing, which causes some cancer centers to shy away from using them [22].

**<span style="font-family: Times New Roman,Times,serif; font-size: 14pt;">Ongoing Research **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">As mentioned earlier, there are currently 845 different ongoing clinical trials working to discover better treatments for glioblastoma. Primarily under investigation are molecularly targeted therapies, immunotherapies, and gene therapies. Many of these therapies are extremely complex and boarder on being beyond the scope of this work. However, a basic overview of the direction in which glioblastoma therapies and treatments are heading is important to note.

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Molecularly Targeted Therapies **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Most new molecularly targeted therapies attempt to inhibit the pathways that glioblastoma tumors use to grow and infiltrate surrounding brain tissue. These pathways include growth factor pathways, angiogenic pathways, and intracellular signaling pathways [22]. The growth factor pathways are inhibited by taking the oral tyrosine kinase inhibitors (TKI) Gefitinib and Erlotinib which inhibit the downstream signaling of EGFRs [22]. The angiogenic pathways are inhibited through a humanized monoclonal antibody called Bevacizumab, which is currently undergoing clinical trials for use in combination with radiation therapy and TMZ [22]. Bevacizumab binds to and neutralizes a ligand known as vascular epithelial growth factor (VEGF), reducing angiogenesis around the glioblastoma [22]. Lastly, intracellular signaling pathways may be blocked through the administration of Perifosine, which is an AKT (signaling pathway) inhibitor [22].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Immunotherapies **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">There are two types of immunotherapies that are currently under investigation for glioblastoma treatment: active and passive. Active immunotherapy is essentially performed through the use of a cancer vaccine. It works to boost a patient's immune system by exposing it to an antigen [22]. These antigens include intact tumor cells, tumor cell lysate, tumor‑derived peptides and mRNA, and synthetic peptides [22]. These antigens are administered to the patient in order to stimulate an immune response. Passive immunotherapy involves using stimulated immune effector cells to generate cell-based cytotoxic responses to attack glioblastoma cells [22].

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Gene Therapies **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Gene therapy involves administering genetic material into the glioblastoma tumor. This includes transgenes, toxins, and viruses. The most notable of the current gene therapies that are being studied are retroviruses. These retroviruses are delivered to the tumor itself in which it will integrate its genetic material [22]. Once they have integrated themselves, the retroviruses infect the dividing cells, allowing them to target the dividing glioblastoma cells while leaving the normal brain cells unharmed [22]. Unfortunately, there is currently little evidence that shows the effectiveness of these therapies, though that may be due to the difficulty in administering the genes into the tumor cleanly and correctly [22].

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Conclusion **=

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Glioblastoma, or glioblastoma multiforme, is a cancer of the CNS - most commonly the cerebral cortex of the brain. It is characterized by headaches, nausea, and seizures, followed by various deficiencies dependent upon the location of the CNS in which the tumor forms. Common deficiencies include memory loss, motor and language deficits, personality changes, visual problems, changes in consciousness, sensory deficits, and papilledema. Glioblastoma is commonly treated with surgery, followed by simultaneous courses of radiation and chemotherapy. Unfortunately, glioblastoma is a terminal disease with only 2.9% of patients living beyond 10 years following the diagnosis. While the major cause of glioblastoma is unknown, some hypothesize that increased cell phone use, exposure to pesticides, and head trauma, as well as genetic predisposition, may all play a role. The most recent research indicates that through the use of molecularly targeted, immuno-, and gene therapies, the outlook for glioblastoma patients may improve.

=**<span style="font-family: Times New Roman,Times,serif; font-size: 14pt;">Glossary of Terms **=

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Astrocytoma:** A brain cancer that begins its development in astrocytes. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Astrocyte:** S <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">pecialized glial cells that are responsible for a variety of regulatory and neural functions, including assisting in synaptic transmission and processing, synaptic remodeling and pruning, and regulation of CNS blood flow and metabolism. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Metastatic cancer:** A form of cancer that spreads to other parts of the body. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Proliferate:** To reproduce rapidly - specifically in relation to cells. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Malignant:** A cancer capable of both invading surrounding normal tissue and spreading throughout the body via the circulatory or lymphatic systems. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Angiogenesis:** Blood vessel formation - specifically around a growing tumor. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Apoptosis:** Programmed cell death. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Papilledema:** <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Swelling of the optic disk which can lead to a blind spot, blurring of vision, and visual obscurations. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Necrosis:** Cell death due to disease, injury, or lack of adequate blood supply. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Biopsy:** An examination of tissue removed from the body in order to discover a diagnosis or to determine the extent of a disease. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Hemorrhage:** The escape of blood from a ruptured blood vessel. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Six Pillar Approach:** A surgical technique used to treat patients with malignant brain tumors that specializes in displacing brain tissue without damaging it so that the surgeon can have clear access to the tumor. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Oral Aminolevulinic Acid:** An acid which marks tumor tissue in order to allow the surgeon to better visualize it. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Temozolomide:** A <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">n oral alkylating chemotherapeutic agent currently considered to be the most effective chemotherapeutic treatment. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Carmustine wafers:** A chemotherapeutic <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;"> DNA alkylating agent which works to destroy any leftover cancerous tissue post-surgery. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">**Immunotherapy:** Newly researched therapy that utilizes cancer vaccines to boost a patient's immune system.

=**<span style="font-family: Times New Roman,Times,serif; font-size: 14pt;">List of Relevant Links/Suggested Readings **=

This provides a full discussion of the methods through which medical professionals diagnose glioblastoma multiforme. It informs about the present ways of diagnosis as well as areas in which improvements need to be made to more accurately diagnose glioblastoma multiforme. Additionally, it elaborates on potential differential diagnoses of glioblastoma multiforme.
 * Novel Strategies for Diagnosis of Glioblastoma Multiforme** in the //European Journal Of Clinical & Medical Oncology,// pp.125-133. By Adam N. Sonabend

This gives a comprehensive overview of the current standards of treatment for glioblastoma multiforme as well as the most recently discovered successfully researched treatments.
 * Glioblastoma Multiforme: State of the Art and Future Therapeutics** in the //Surgical Neurology International// pp. 298-315. By Taylor A. Wilson

This essay provides a thorough overview of all aspects of glioblastoma. It discusses risk factors, symptoms, diagnoses, pathology, and current treatment of glioblastoma.
 * A Dead End Review of Glioblastoma Multiforme** - [] by Ashleigh Porter

As the title suggests, this paper discusses glioblastoma as a whole as well as specific treatments that are currently used and researched.
 * Glioblastoma: Overview of Disease and Treatment** - [] by Mary Elizabeth Davis

This book provides an extensive overview of cancer.
 * The Development and Causes of Cancer** - [] by Geoffrey M Cooper

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Quiz Questions **=

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Multiple Guess **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">1. What lobe of the brain is glioblastoma most likely to form? <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">A. Frontal <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">B. Occipital <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">C. Parietal <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">D. Temporal

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">2. What is the primary initial symptom of glioblastoma? <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">A. Headache <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">B. Nausea <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">C. Papilledema <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">D. Seizures

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">3. What is the most effective way to diagnose glioblastoma? <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">A. Clinically <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">B. Histologically <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">C. Radiologically <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">D. Experimentally

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">4. What is the only proven cause of glioblastoma? <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">A. Head trauma <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">B. Increased cell phone use <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">C. Pesticide exposure <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">D. Exposure to ionizing radiation

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">5. Of the following, who is most likely to get glioblastoma? <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">A. 35 year old, female, waitress <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">B. 62 year old, male, baseball reporter <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">C. 22 year old, female, drug manufacturer <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">D. 55 year old, male, oil refiner

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">6. What sort of glial cell does glioblastoma invade? <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">A. Astrocyte <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">B. Schwann Cell <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">C. Oligodendrocyte <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">D. Microglia

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">True/False **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">7. (T / F) The most common strain of glioblastoma is primary strain. <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">8. (T / F) TMZ is a form of radiation therapy. <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">9. (T / F) Symptoms of a glioblastoma in the occipital lobe can cause vision loss. <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">10. (T / F) Oral aminolevulinic acid is used to help the surgeon navigate through healthy brain tissue during surgery.

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Short Answer **
<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">11. What is the incidence of EGFR amplification in glioblastoma and what is its role in increasing the risk of glioblastoma formation?

<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">12. What are the genetic diseases which may lead to an increased risk of glioblastoma development?

<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">13. How do most new molecularly targeted therapies attempt to treat glioblastoma?

**<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">Essay **
<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">14. Thoroughly explain and discuss what the three primary diagnosing techniques for glioblastoma are.

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;">Quiz Answers **=

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">1. A <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">2. A <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">3. B <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">4. D <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">5. D <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">6. A

<span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">7. T <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">8. F <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">9. T <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">10. F

<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">11. EGFR amplification is present in 40-60% of all glioblastomas. EGFR regulates cellular development, proliferation, and migration. This allows for growth factor ligands to bind to EGFR, activating the RAS protein which has the capacity to alter transcription of cellular regulation genes in the nucleus, leading to potential for gliomagenesis. <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">12. Eurofibromatosis 1 and 2, tuberous sclerossi, Li-Fraumeni syndrome, retinoblastoma, Von Hippel-Lindau disease and Turcot syndrome. <span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">13. They attempt to treat glioblastoma by inhibiting the pathways that glioblastoma uses to grow and infiltrate surrounding brain tissue

<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">14. The three primary diagnosing techniques for glioblastoma are clinical diagnosis, radiological diagnosis (CT/MRI), and histological diagnosis (biopsy). Clinically, a physician will look for worsening symptoms of glioblastoma to begin forming a suspicion of glioblastoma. Following a careful tracking of these symptoms, the physician will order radiological imaging including MRI and potentially CT scans. If there appears to be tumor formation within the brain or CNS, surgery may be performed in order to biopsy tumor tissue. Once the tumor tissue has been removed, the physician will look for nuclear atypia, mitosis, endothelial proliferation, and necrosis with a pseudopalisading pattern within the tissue to confirm a diagnosis of glioblastoma.

=**<span style="font-family: Times New Roman,Times,serif; font-size: 16pt;"> References **= <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[1] What Is Glioblastoma? (n.d.). Retrieved December 05, 2017, from https://www.webmd.com/cancer/brain-cancer/what-is-glioblastoma#1 <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[2] Glioblastoma: Survival Rates, Treatments, and Causes. (n.d.). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[3] Sofroniew, M. V., & Vinters, H. V. (2010). Astrocytes: biology and pathology. Acta Neuropathologica, 119(1), 7–35. http://doi.org/10.1007/s00401-009-0619-8 <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[4] Glioblastoma Multiforme. (n.d). Retrieved December 5, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[5] De Groot, J., M.D. (n.d.). Q&A: Understanding glioblastoma (GBM). Retrieved December 05, 2017, from https://www.mdanderson.org/publications/cancerwise/2013/04/understanding-glioblastoma.html <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[6] Gliomas - Neurologic Disorders. (n.d.). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[7] Glioblastoma. (n.d.). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[8] Search of: "Glioblastoma" | United States - List Results. (n.d.). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[9] Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. The Development and Causes of Cancer.Available from: [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[10] Larjavaara, S., Mäntylä, R., Salminen, T., Haapasalo, H., Raitanen, J., Jääskeläinen, J., & Auvinen, A. (2007). Incidence of gliomas by anatomic location. Neuro-Oncology, 9(3), 319–325. [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[11] Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. L., & Rich, J. N. (2015). Cancer stem cells in glioblastoma. Genes & Development, 29(12), 1203–1217. [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[12] Gaillard, F. (n.d.). Glioblastoma | Radiology Reference Article. Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[13] Sonabend, A. M., Yun, J., Canoll, P., & Bruce, J. N. (2010). Novel Strategies for Diagnosis of Glioblastoma Multiforme. European Journal Of Clinical & Medical Oncology, 2(2), 125-133. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[14] Symptoms of Glioblastoma Multiforme. (2015, January 07). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[15] Davis, M. E. (2016). Glioblastoma: Overview of Disease and Treatment. Clinical Journal of Oncology Nursing, 20(5), S2-S8. [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[16] Brain tumors. (n.d.). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[17] Brain Map. (n.d.). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[18] Glioblastoma (GBM). (n.d.). Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[19] Risk Factors. (n.d.). Retrieved December 5, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[20] Porter, A. (n.d.). A Dead End: A Review of Glioblastoma Multiforme. Retrieved December 05, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[21] Glioblastoma Multiforme. (n.d.). Retrieved December 05, 2017, from https://rarediseases.org/rare-diseases/glioblastoma-multiforme/ <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[22] Wilson, T. A., Karajannis, M. A., & Harter, D. H. (2014). Glioblastoma multiforme: State of the art and future therapeutics. Surgical Neurology International, 5(1), 298-315. doi:10.4103/2152-7806.132138 <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[23] Six Pillar Approach. (n.d.). Retrieved December 5, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[24] Glioblastoma Multiforme Treatment & Management. (2017, October 31). Retrieved December 05, 2017, from [|https://emedicine.medscape.com/article/283252-treatment#d6] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[25] Symptoms. (n.d.). Retrieved December 5, 2017, from [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[26] Das, S., & Marsden, P. A. (2013). Angiogenesis in Glioblastoma. The New England Journal of Medicine, 369(16), 1561–1563. [] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">[27] Moore K., Kim L. (2010) Primary Brain Tumors: Characteristics, Practical Diagnostic and Treatment Approaches. In: Ray S. (eds) Glioblastoma. Springer, New York, NY <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">[28]Case courtesy of Dr Ahmed Abd Rabou, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/22779">rID: 22779</a> <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">[29] Case courtesy of A.Prof Frank Gaillard, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/8939">rID: 8939</a> <span style="font-family: Times New Roman,Times,serif; font-size: 12pt;">[30] Case courtesy of Dr Sandeep Bhuta, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/15972">rID: 15972</a