Glioblastoma Multiforme: The Terminator
Masih Tazhibi
December, 2020
Glioblastoma Multiforme (GBM) is by far the most aggressive form of brain tumor, developing from star-shaped glial cells or their progenitors. Devastating to their victims and widely feared amongst the neurosurgery community, GBMs comprise approximately 17% of all primary tumors of the brain, have a median survival rate of less than one year (2 months if untreated), and harbor a mortality rate of essentially 100%. While stark outcomes in these cases have drawn significant international attention to the etiology of GBM, especially following John McCain’s and Beau Biden’s recent deaths to the illness, this tumor has time and time again circumvented increasingly complex and innovative attempts at therapy over the last fifty years.
The current standard of care is to perform a craniotomy with three primary objectives: resect as much solid tumor tissue as possible, eliminate radiation and/or chemotherapy resistant cells in the tumor’s epicenter, and minimize intracranial pressure or swelling. Surgical intervention is then followed by postoperative treatments including co-administration of external beam radiotherapy and temozolomide chemotherapy, although these methods have only shown long term tumor control in 20% of cases and have rarely (if at all) led to remission. As such, GBM tumors to this day remain essentially incurable and indiscriminately fatal.
One of the primary reasons that gliomas are inoperable through conventional surgical resection techniques utilized for other types of tumors (i.e. meningiomas and acoustic neuromas) is the topographically dispersed nature of the tumor’s growth and proliferation. They begin as benign tumors that are shaped like a snowball, which continues to grow uniformly at a localized neural origin until some glioma cells diffuse away from the tumor epicenter by hijacking the brain’s natural transport machineries. This migration most readily targets pial margins, neurons and blood vessels, and especially the white matter tracts (i.e. intrafascicular spread); the characteristic pattern of GBM proliferation is collectively referred to as the secondary structures of Scherer. In exactly this way, GBMs spread over long neural distances and invade surrounding tissues, making total resection virtually impossible under current therapeutic interventions.
Figure 1(a-d): Bi-hemispheric invasion of the anterior corpus callosum by “Butterfly GBM.”
In Figure 1(a-d), you can appreciate an example of intrafascicular spread called a Butterfly Glioma. This is an especially rare type of GBM characterized by a distinct pattern on MRI studies due to the tumor’s bi-hemispheric invasion of the anterior corpus callosum (CC). Median overall survival in these cases from the time of diagnosis is 3.2 months, with an overall 6-month survival rate of 38.1%.
In Figure 2 below, we see neuroimaging evidence of GBM’s expedient mobilization and invasion into adjacent brain tissue. In 2a, fluid-attenuated inversion-recovery imaging is used, which is a tool for defining not only the main tumor body itself, but also its malignant boundaries. Of additional importance here is the exceedingly small distance between the tumor’s malignant boundary and the anterior CC situated at the midline, making bi-hemispheric invasion extremely likely as the tumor progresses. The scan therefore reveals that the entire quadrant of the brain that has been overtaken by cancerous cells.
Conventional MRI scans show a small Grade III astrocytoma (a type of GBM) localized to the right hemisphere of the brain (2b).
Masih Tazhibi
December, 2020
Glioblastoma Multiforme (GBM) is by far the most aggressive form of brain tumor, developing from star-shaped glial cells or their progenitors. Devastating to their victims and widely feared amongst the neurosurgery community, GBMs comprise approximately 17% of all primary tumors of the brain, have a median survival rate of less than one year (2 months if untreated), and harbor a mortality rate of essentially 100%. While stark outcomes in these cases have drawn significant international attention to the etiology of GBM, especially following John McCain’s and Beau Biden’s recent deaths to the illness, this tumor has time and time again circumvented increasingly complex and innovative attempts at therapy over the last fifty years.
The current standard of care is to perform a craniotomy with three primary objectives: resect as much solid tumor tissue as possible, eliminate radiation and/or chemotherapy resistant cells in the tumor’s epicenter, and minimize intracranial pressure or swelling. Surgical intervention is then followed by postoperative treatments including co-administration of external beam radiotherapy and temozolomide chemotherapy, although these methods have only shown long term tumor control in 20% of cases and have rarely (if at all) led to remission. As such, GBM tumors to this day remain essentially incurable and indiscriminately fatal.
One of the primary reasons that gliomas are inoperable through conventional surgical resection techniques utilized for other types of tumors (i.e. meningiomas and acoustic neuromas) is the topographically dispersed nature of the tumor’s growth and proliferation. They begin as benign tumors that are shaped like a snowball, which continues to grow uniformly at a localized neural origin until some glioma cells diffuse away from the tumor epicenter by hijacking the brain’s natural transport machineries. This migration most readily targets pial margins, neurons and blood vessels, and especially the white matter tracts (i.e. intrafascicular spread); the characteristic pattern of GBM proliferation is collectively referred to as the secondary structures of Scherer. In exactly this way, GBMs spread over long neural distances and invade surrounding tissues, making total resection virtually impossible under current therapeutic interventions.
Figure 1(a-d): Bi-hemispheric invasion of the anterior corpus callosum by “Butterfly GBM.”
In Figure 1(a-d), you can appreciate an example of intrafascicular spread called a Butterfly Glioma. This is an especially rare type of GBM characterized by a distinct pattern on MRI studies due to the tumor’s bi-hemispheric invasion of the anterior corpus callosum (CC). Median overall survival in these cases from the time of diagnosis is 3.2 months, with an overall 6-month survival rate of 38.1%.
In Figure 2 below, we see neuroimaging evidence of GBM’s expedient mobilization and invasion into adjacent brain tissue. In 2a, fluid-attenuated inversion-recovery imaging is used, which is a tool for defining not only the main tumor body itself, but also its malignant boundaries. Of additional importance here is the exceedingly small distance between the tumor’s malignant boundary and the anterior CC situated at the midline, making bi-hemispheric invasion extremely likely as the tumor progresses. The scan therefore reveals that the entire quadrant of the brain that has been overtaken by cancerous cells.
Conventional MRI scans show a small Grade III astrocytoma (a type of GBM) localized to the right hemisphere of the brain (2b).
Figure 2: (a) Fluid-attenuated inversion-recovery imaging in axial plain, indicating metastatic margins of GBM. (b) conventional MRI depicting apparent GBM localization to the right hemisphere.
As such, figure 2 provides some explanation for why epicenter-centric resection of GBMs in common surgical practice today cannot mitigate the tumor’s astronomically high rates of recurrence.
Figure 3: Coronal MRI of Right Anatomic Hemispherectomy at level of anterior frontal lobe.
Even the most drastic surgical interventions in glioma treatment have proven futile, leading to a general sense of nihilism in the neurosurgery community with respect to the ability to treat these tumors. Walter Dandy, one of the fathers of neurosurgery (along with Victor Horsley and Harvey Cushing), famously performed five complete hemispherectomy procedures for the treatment of glioma in already hemiplegic patients, removing the entire affected hemisphere of the brain in order to prevent the progression of GBM into the contralateral side. Given this procedure’s intensive resection of the affected tissue, the lack of any overt indication of contralateral invasion pre-operatively, and the removal of the bi-hemispheric neural link via the CC, Dandy expected that this procedure (while imperfect) would ultimately stop the progression of GBM. Dandy however, did not have access to the modern, sophisticated imaging techniques in use today, and as such, was unable to meaningfully track the tumor’s malignant margins (figure 2a). Thus, the glioma that seemed only present in the right side of the brain had already infiltrated the anterior CC and subdural space, causing tumor recurrence on the contralateral hemisphere within weeks following surgery. Three-and-a-half months later, Dandy’s patient was dead and GBM had claimed yet another victim.
Ultimately, this converging evidence indicates that even the most invasive interventions up to the present moment have only marginally prolonged GBM’s inevitable course of action. In this way, Glioblastoma Multiforme is not only intensely aggressive and fast moving; it is not only topographically diffuse and surgically irretractable; but it also represents a fundamentally unacceptable deficit in the therapy of malignant brain tumors today. GBM is a force to be reckoned with, a deadly and unsolved medical marvel whose termination will require the combined intellectual brainpower of an emerging body of neuroscientists and clinicians as we enter a new decade of medical innovation. Ultimately, it is critical that we continue to fund ongoing projects and develop innovative therapeutics to change the landscape of medical treatment within this domain. Perhaps one day, GBM – like polio and smallpox before it – will become a disease of the past.
You can learn more about Masih Tazhibi’s work by checking out: https://adeepthought.com/2019/11/17/glioblastoma-multiforme-the-terminator/
References
DANDY WE. REMOVAL OF RIGHT CEREBRAL HEMISPHERE FOR CERTAIN TUMORS WITH HEMIPLEGIA: PRELIMINARY REPORT. JAMA. 1928;90(11):823–825.
“Glioblastoma Multiforme.” AANS, http://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Glioblastoma-Multiforme.
“Hemispherectomy.” Cleveland Clinic, my.clevelandclinic.org/health/treatments/17092-hemispherectomy.
Upadhyay, N., & Waldman, A. (2011). Conventional MRI evaluation of gliomas. The British journal of radiology, 84(special_issue_2), S107-S111.
Wang, L., Liang, B., Li, Y. I., Liu, X., Huang, J., & Li, Y. M. (2019). What is the advance of extent of resection in glioblastoma surgical treatment—a systematic review. Chinese Neurosurgical Journal, 5(1), 2.
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An Insomniac’s Brain
Joanna Gao
November, 2019
The clock reads 3:13 AM. You have an unfinished sociology paper due the next day at midnight, a mechanical physics exam the day after, and a dreaded family gathering after the seemingly endless midterm season. Meanwhile, you are still laying awake, eyes wide open, pondering about how many hours you still have to get some sleep before you have to rush to an 8:40 AM lecture.
Insomnia, the inability to sleep, is caused by a variety of reasons — from emotional distress to physical pain. As sleepless nights accumulate, the bedroom itself can become associated with the anxiety of restless nights. Insomniacs experience such high levels of stress at night that their brains hijack the stress response system, flooding the body with fight-or-flight chemicals. Cortisol and adrenocorticotropic hormones are pumped through the bloodstream, increasing blood pressure and and heart rate, which propels the body into a state of hyperarousal. This conscious state renders it impossible to ignore any slight discomfort or noise in the immediate surrounding. This sontant state of stress is significantly associated with high allostatic load — a measure of cumulative exposure to elevated neural and endocrine responses resulting from repeated stressful events — which can take a toll on the biological system.
When insomniacs finally fall asleep, their quality of rest is severely compromised. PET scans (Positron Emission Topography) demonstrate that the brain’s supply of cerebral glucose — primary source of brain’s energy — gets used up due to the adrenaline that prevents the insomniacs from sleeping. The adrenaline essentially speeds up their metabolism, causing the brain to work overtime while it should be conserving the glucose for waking hours. The symptom of poor sleep leaves insomniacs waking up in a state of confusion, fatigue and stress. This seemingly unsolvable loop is at the heart of insomnia.
Some elementary approaches to manage the stress associated with insomnia include ensuring the bedroom is dark and comfortably cool to minimize “threats” during states of hyperarousal, meditation, reading, or journaling before sleep, and setting consistent sleep-wake hours to help orient the body’s circadian rhythm. Positive sleep practices can help rebuild your relationship with bedtime.
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Alzheimer's May be Caused by the Bacteria found in Gum Disease
Nick Vaughan
February, 2019
Alzheimer's often involves the accumulation of two types of proteins, amyloid and tau, in the brain. For many decades the leading hypothesis has been that Alzheimer's is caused by defective control of these proteins, specifically the accumulation of amyloid in the brain, and the majority of research in Alzheimer's treatment has centered around this “amyloid hypothesis”. Unfortunately, despite billions of dollars in research, 99 percent of drugs that have been developed fail.
However, in the last several years scientists in independent laboratories have discovered P. gingivalis, the main bacteria found in gum disease, which is also a known risk factor for Alzheimer’s, in brain regions affected by Alzheimer's. Researchers have found two toxic enzymes that P. gingivalis uses to feed on human tissue in 99 and 96 per cent of 54 human Alzheimer’s brain samples taken from the hippocampus. Upon giving P. gingivalis to mice, they developed accumulations of amyloid, tangles of tau, and neural damage in areas linked with Alzheimer's, indicating that P. gingivalis in the brain may be the cause of Alzheimer's and not merely an effect.
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Diffuse Intrinsic Pontine Glioma
Charli Ann Hertz
November, 2018
Today I would like to discuss a really important neuroscience related illness, brain cancer. More specifically, Diffuse Intrinsic Pontine Glioma (DIPG). DIPG is a cancer of the brainstem and pontine region. DIPG is a highly aggressive form of brain cancer that appears most frequently in pediatric cases.They are most often classified in stage III and IV of glioma tumor grading, which lends to their aggressive nature and tendency to metastasize and spread to other areas of the body. The average prognosis is 9 months, even with the most intensive forms of radiation, small molecule therapy, and chemotherapy. Unfortunately, modern medicine has not been able to produce any forms of treatment that provide remission or reduction of symptoms. Often the best option for many families are experimental clinical trials that are run from hospitals throughout the country. Because DIPG affects the brainstem region, it is inoperable and usually only detected once the cancer has progressed to a high degree of malignancy. This also means that individuals suffering with DIPG experience difficulty with the most basic of human functions; like breathing, swallowing, and motor movement.
While this cancer is extremely rare, it is unacceptable that modern medicine has yet to provide any potential therapies. This may be attributed to the relatively small amount of funding pediatric cancer research receives, which is then further diluted by the relative occurrence of DIPG. In 2016, $198 billion dollars was allocated towards cancer research in the United States, 4% of this, $4.93 billion dollars was given to labs investigating pediatric cancers, and even a smaller amount was given to labs investigating pediatric brain cancers. DIPG may provide an interesting window of opportunity to evaluate the mechanism of cancer development as it is a cancer of the most highly conserved region of the brain. This summer I worked at the Breunig Lab at Cedars Sinai Medical Center which investigates the cellular mechanisms of early neuronal stem cell differentiation and the potential overlap in the development of pediatric brain cancer. Working in this lab, even though it was largely insignificant in the grand scheme of pediatric oncology research, was a very rewarding experience. This field is largely underdeveloped, which creates many opportunities for the amazing scientists that have dedicated their lives to this cause. As we have seen with other types of cancer, like breast and lung cancer, investing time and money into research produces tangible effects. If anything, I hope that this submission serves as inspiration to support scientific research in anyway you can!
Learn more about DIPG:
https://www.defeatdipg.org/dipg-facts/overview/what-is-the-prognosis-for-a-child-diagnosed-with-dipg/
Write a letter to your governmental representative urging them to push for better funding for pediatric cancer research:
http://www.neuroblastomacancer.org/write-your-representatives.php
Check out this amazing campaign, created for a college freshman battling DIPG:
https://www.cannonballsforkayne.org/
