This document provides information about glioblastoma multiforme (GBM), the most common and aggressive type of primary brain tumor. It discusses the causes, pathophysiology, clinical features, diagnosis, treatment, and prognosis of GBM. Key points include that the exact cause is unknown but genetic factors are involved; common symptoms depend on the tumor location in the brain; diagnosis involves biopsy and imaging; treatment involves surgery, radiation, chemotherapy and newer approaches; and prognosis is generally poor with median survival of 14 months despite treatment.

1. Institute of Basic Medical Sciences
IBMS
Glioblastoma Multiforme
Assignment submitted by:
Dr Mohammad Manzoor Mashwani,
M.Phil Scholar,
Subject: Histopathology
Assignment submitted to:
Dr Nuzhat Sultana Khattak,
Assistant Professor,
Histopathology,
IBMS, KMU
1

2. Table of Contents
Introduction 3
Causes 3
Pathophysiology Pathogenesis 4
Clinical features 6
Diagnosis 7
Histopathology 8
Treatment 9
Prognosis 10
References 12
2

3. Introduction
Gliomas:
1. Astrocytomas Infiltrating & Non-infiltrating
2. Oligodendrogliomas
3. Ependymomas
Diffuse astrocytoma (grade II/IV)
Anaplastic astrocytoma (grade III/IV)
Glioblastoma - GBM (grade IV/IV).
(The grade I/IV category is limited to pilocytic astrocytoma.)
Glioblastoma Multiforme. It is the most common malignant primary tumor of the brain. It is
very aggressive, involving glial cells. GBM is 20% of all intracranial tumors and 52% of all
tissue brain tumors. In North America and Europe incidence is two to three per hundred
thousand.GBM incidence is only 2–3 cases per 100,000 people in Europe and North America. Of
the 17,000 brain tumors in the USA per year, 60% are gliomas. GBM differ in location within
the CNS, in age and sex distribution, in growth, in invasiveness, in histological features, in
progression, & in response to therapy.
There are 2 variants of GBM:
1. Gliosarcoma
2. Giant Cell Glioblastoma.
GBM treatment can be Chemotherapy, radio surgery, radiation, corticosteroids, surgery,
antiangiogenic therapy and gene transfer.
Prognosis is worst. Median survival time despite of multimodality treatment is fourteen months.
Causes
The exact cause is unknown but changes or loss of chromosome 17 &
inactivation of p53 has a role.
Gender: Men are more affected than women.
Most cases are sporadic.
Viruses like CMV or SV40 may be the cause.
There is some association of GBM with polyvinyl chloride, radiation, malaria and lead exposure.
Age: above fifty years.
3

4. Ethnicity: Asians, Caucasians
Pathophysiology /Pathogenesis
GBM have necrotizing tissues which are surrounded by anaplastic cells. This along with
hyperplastic vessels distinguishes GBM from astrocytomas grade III.
Types of GBM:
1. Classical GBM:
This type has extra copies of the EGFR gene in 97% of cases. They have higher
expression of EGFR gene.
2. Proneural GBM:
This type shows greater alterations in IDHI, TP53, & in PDGFRA.
3. Mesenchymal GBM:
Alterations & mutations in Neurofibromatosis type 1(NF1).
4.
G BM can be primary or secondary.
Primary GBM is sixty percent. These manifest de novo .
Secondary GBM is 40% develop in younger patients less than forty five years of age. Malignant
transformation from a low to anaplastic astrocytoma requires one to ten years. There is
genuine evidence which indicates that primary & secondary GBMs are distinct entities.
Different genetic pathways involve in GBM.
Common genetic abnormalities are:
1. LOH: Loss of heterozygosity on arm 10q is the most common gene change for
glioblastomas.This occurs in sixty to ninety percent of cases. This alteration is specific
for GBM associated with poor survival.
2. p53:. The p53 gene deletes or alteres in 25-40% of GBM, more frequently in
secondaryGBM.[6]
3. Epidermal growth factor receptor gene: It is involved in the control of cell proliferation. There is
over expression as well as rearrangement of receptor. It is more common (40-50%) in primary
GBM. EGFRvIII is a target for kinase inhibitors & peptide vaccines.[11, 12, 13, 14, 15, 16, 17]
4. MDM2: Overexpression or amplification of MDM2 is an alternative mechanism to escape from
p53 -regulated control of cell growth. It binds to p53 and diminishing its activity.
4

5. MDM2 overexpression is the 2nd most frequent (10-15%) gene mutation in GBM. This mutation
is associated with a worse prognosis.[7]
5. Platelet-derived growth factor–alpha gene: This is a major mitogen for glial cells. It binds to
plate-derived growth factor receptor. In secondary GBM it is typically overexpressed.
6. PTEN: It is also called MMAC &TEP1 encodes a TP located at 10q23.3. It is more frequently found
in primary GBM.[14, 18, 19]
Rare mutations:
MAC1-E1 - A
MAGE-E1 - A
NRP/B – A
Additional alterations in primary GBM :
p16INK4A, p16 deletions (30-40%), & retinoblastoma (RB) gene.
Genetic alteration in 2ndary GBM:
LOH at chromosome arm 19q (50%),
RB protein alterations (25%),
PTEN mutations (5%).
GBM occur most frequently in the subcortical white matter (the cerebral hemispheres). The
commonly affected sites are the temporal (31%), parietal (24%), frontal (23%), and occipital
(16%) lobes.[20] The typical location is frontotemporal. Tumor infiltration commonly extends into
the adjacent cortex /the basal ganglia. Glioblastoma Multiforme grow quickly, producing
symptoms when become sufficiently large.
1. Some (< 10%) form slowly. These follow degeneration of low-grade
astrocytoma/ anaplastic astrocytoma. These are common in younger patients and
are called secondary Glioblastomas and are more common in younger. Mean age
forty five versus sixty years.
GBM may extend into the meninges or ventricular wall, leading to high protein content in
the CSF. Cancer cells carried in the CSF may spread (rarely) to the spinal cord or cause
meningeal gliomatosis. About half of GBMs are bilateral. GBM may take on a variety of
appearances, depending on the amount of hemorrhage, necrosis, or its age.
5

6. Clinical Features:
Clinical features largely depend on the location of the tumor than on its pathological
characteristics.
Following are signs and symptoms found in Glioblastoma multiforme:
Headache
Personality change
Visual loss
Paralysis or sensory loss
Increased pressure inside skull
Headache frontal lobe tumor
Vomiting frontal lobe tumor
Impaired memory frontal lobe tumor
Intellectual disability frontal lobe tumor
Convulsions frontal lobe tumor
Paralysis on one side of body
Seizures parietal and frontal lobe tumor
Poor coordination temporal lobe tumor
Impaired speech
Personality changes frontal lobe tumor
Lack of emotion frontal lobe tumor
Reduced ability to interpret language temporal lobe tumor
Motor disturbance temporal lobe tumor
6

7. Agraphia parietal lobe tumor
Paresthesia parietal lobe tumor
Loss of positional awareness of body parts parietal lobe tumor
Sensory changes parietal lobe tumor
Spatial disorientation parietal lobe tumor
Diagnosis
Biopsy is the gold standard.CT, MRI, stereotactic biopsy, craniotomy along with tumor resection
and microscopy are required to confirm the diagnosis.
A neurologic examination by the neurologist should be done if there signs and symptoms of
increased pressure inside the skull that is signs of mental dysfunction, seizures, persistent
headaches vomiting, and swelling of the eye.
To determine that whether the tumor is primary or secondary complete examination is necessary
that is MRI, CT scan, and a chest X-ray. Magnetic Resonance Imaging finds low-grade
astrocytomas earlier than computed tomography scan.
Following are some specialized tests which may be done depending on the clinical features:
Field of vision,
7

8. The sharpness of vision &
Hearing.
Fluid examination may be done in case the above mentioned tests are not conclusive. Fluid that
surrounds the brain and spinal cord is done.
Histopathology:
Macroscopy or Gross: Lesions are poorly delineated. The tumor mass consists of necrotic
tissues. Necrotic tissue is surrounded by hypercellular tissue. Macroscopic appearance of the
GBM from region to region is different. Some areas are yellow & soft, some areas are firm and
white others show areas of cystic degeneration, hemorrhage and necrosis.
Microscopy: It is characterized by poorly differentiated, pleomorphic, neoplastic
astrocytes. There is marked nuclear atypia & high mitotic activity. Necrosis & vascular
or endothelial cell proliferation are important for diagnosis. Necrosis in GBM commonly
occurs in a serpentine pattern in regions of hypercellularity. Cancer cells gather along the edges
of the necrotic areas, producing a specific pattern known as pseudo-palisading. Vascular cell
proliferation is has tufts of piled-up cells. These bulge into the lumen. Double layer is the
minimal criterion for this feature. The glomeruloid body can be seen, which is a rounded
structure formed by the tuft due to increased vascular cell proliferation. Vascular endothelial
growth factor causes this vascular change. Hypoxia makes malignant astrocytes to produce
VEGF.A small single biopsy may be deceivable because of different histological features in
different areas.
8

9. Treatment
Treatment of GBM is difficult due to the following factors:
The cancer cells are resistant to conventional therapies
The brain is vulnerable to damage due to conventional therapy
The brain has a limited capacity to repair itself
Many drugs cannot cross the BBB to act on the tumor
Symptomatic therapy
Anticonvulsants & corticosteroids are used to relieve symptoms and improve neurological
functions of the patient.
Palliative therapy
It improves quality of life and achieves a longer survival time. It includes
chemotherapy, surgery and radiation therapy. Prognosis is strongly associated
with gross total resection of tumor.
Surgery
It is the 1st stage of treatment of GBM. After surgery a reduction of 99% occurs in tumor
cells. It is better to remove more than 98% of tumors which has better survival rate.
9

10. Surgery is used for the purpose of biopsy, to remove a large mass pressing against the
brain, to remove disease before secondary resistance to radiotherapy and chemotherapy,
and to prolong survival. Recurrence is common despite total resection.
Radiotherapy
It is the main treatment after surgery. It increases the median survival time more than
double. It can reduce the tumor size to 107 cells. The more precise and targeted three-
dimensional conformal radiotherapy is sufficient. Radiation dose of 60–65 Gy is optimal
for treatment.
Chemotherapy
Temozolomide sensitize tumor cells to radiation and improves median survival.
Avastin (bevacizumab) reduced tumor size in some GBM patients. Bevacizumab reduces
brain edema and consequent symptoms.
Gene transfer
It is a promising approach for fighting GBM. Trial for the potential treatment of GBM is
continued.
Protein therapeutics
APG101 inhibits the invasive growth of GBM cells. It inhibits the binding of the CD95-
Ligand to its cognate receptor which stimulates the invasive growth of the tumor cells.
Thus, the inhibition of this interaction by APG101 reduces tumor cell migration.
Immunotherapy
Relapse of GBM is due to the recurrence and persistence of tumor stem cells. A tumor
B-cell hybridoma vaccine against tumor stem cells elicited a specific tumor immune
reaction thus enhancing immune response to the GBM. Tests of different EGFR
signaling patterns and their relationship to tumor stem cells are in progress to further
assess this approach to treating GBM.
Alternating electrical fields
These interfere with the division of cancer cells. It is a new approach to GBM treatment.
AEF is being explored for the 1st time in the treatment of GBM. In an EFof given
wavelength, cells attempting to divide will be destroyed. This treatment is optimal for
brain tumors in that normal brain cells do not divide, but malignant cells within the brain
divide. GBM patients treated with AEF wear electrodes attached to the device.
Metabolic therapy
Malignant cells are unable to use fats as an energy source. They are completely reliant
on glucose, and glutamine for their energy. Healthy neurons use ketones as efficient
energy sources. Removing carbohydrates from the diet starves the malignant cells
without damaging the healthy neurons
Recurrences
GBM usually reappears although disease free condition is achievable. Mostly it occurs
within 3 cm of the original site but may occur in 10–20% cases at distant sites.
Prognosis
10

11. Prognosis without treatment is three months survival and with treatment it is upto two
years. Older patients have worse prognosis. Cerebral edema is the common cause of
death.
Karnofsky Performance Score and MGMT methylation are associated with longer
survival. Patients with a methylated MGMT promoter have been associated with greater
long-term benefit than patients with an unmethylated MGMT promoter..
Patients who receive surgery, radiotherapy, and Temozolomide chemotherapy have long
–term benefit.
11

12. References:
1. ^ Lipsitz, D.; Higgins, R. J.; Kortz, G. D.; Dickinson, P. J.; Bollen, A. W.; Naydan, D. K.;
Lecouteur, R. A. (2003). "Glioblastoma Multiforme: Clinical Findings, Magnetic Resonance
Imaging, and Pathology in Five Dogs". Veterinary Pathology 40 (6): 659–69. doi:10.1354/vp.40-
6-659. PMID 14608019.
2. ^ Gina Kolata and Lawrence K. Altman, M.D. (August 27, 2009). "Kennedy Case Shows
Progress and Obstacles in Cancer Fight". New York Times.
http://www.nytimes.com/2009/08/28/health/28brain.html.
3. ^ Tai, Chien-Kuo; Kasahara, Noriyuki (2008). "Replication-competent retrovirus vectors for
cancer gene therapy". Frontiers in Bioscience 13 (13): 3083–3095. doi:10.2741/2910.
http://www.nhhs.net/ourpages/auto/2009/3/25/49144229/Ram_s%20second%20paper.pdf.
4. 4.^ Van Meir, E. G.; Hadjipanayis, C. G.; Norden, A. D.; Shu, H. K.; Wen, P. Y.; Olson, J. J.
(2010). "Exciting New Advances in Neuro-Oncology: The Avenue to a Cure for Malignant
Glioma". CA: A Cancer Journal for Clinicians 60 (3): 166–93. doi:10.3322/caac.20069. PMC
2888474. PMID 20445000.
//www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2888474. ^ Ohgaki, H;
Kleihues, P (2005). "Population-based studies on incidence, survival rates, and genetic
alterations in astrocytic and oligodendroglial gliomas". Journal of neuropathology and
experimental neurology 64 (6): 479–89. PMID 15977639.
5. ^ Zheng, T; Cantor, KP; Zhang, Y; Chiu, BC; Lynch, CF (2001). "Risk of brain glioma not associated
with cigarette smoking or use of other tobacco products in Iowa". Cancer epidemiology,
biomarkers & prevention 10 (4): 413–4. PMID 11319186.
6. ^ Huncharek, Michael; Kupelnick, Bruce; Wheeler, Lamar (2003). "Dietary Cured Meat and the
Risk of Adult Glioma: A Meta-Analysis of Nine Observational Studies". Journal of Environmental
Pathology, Toxicology and Oncology 22 (2): 129–37. DOI:10.1615/JEnvPathToxOncol.v22.i2.60.
7. ^ Savitz, David A.; Checkoway, Harvey; Loomis, Dana P. (1998). "Magnetic Field Exposure and
Neurodegenerative Disease Mortality among Electric Utility Workers". Epidemiology 9 (4): 398–
404. DOI:10.1097/00001648-199807000-00009. PMID 9647903.
8. ^ Inskip, Peter D.; Tarone, Robert E.; Hatch, Elizabeth E.; Wilcosky, Timothy C.; Shapiro, William
R.; Selker, Robert G.; Fine, Howard A.; Black, Peter M. et al. (2001). "Cellular-Telephone Use and
Brain Tumors". New England Journal of Medicine 344 (2): 79–86.
DOI:10.1056/NEJM200101113440201. PMID 11150357.
9. ^ Kan P, Simonsen SE, Lyon JL, Kestle JR. (2008). "Cellular phone use and brain tumor: a meta-
analysis". Journal of Neurooncology 86 (1): 71–78. DOI:10.1007/s11060-007-9432-1. PMID
17619826. http://www.springerlink.com/content/l0kr246374422341/.
10. ^ Hardell L, Carlberg M, Hansson Mild K. (2009). "Epidemiological evidence for an association
between use of wireless phones and tumor diseases". Pathophysiology 16 (2–3): 113–22.
DOI:10.1016/j.pathophys.2009.01.003. PMID 19268551.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBB-4VS3NYH-
2&_user=10&_coverDate=08%2F31%2F2009&_rdoc=1&_fmt=high&_orig=gateway&_origin=gat
eway&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid
=10&md5=d2b9014b8500f134ff1e7b60c33a9815&searchtype=a.
11. ^ Baglietto, L; Giles, GG; English, DR; Karahalios, A; Hopper, JL; Severi, G (2011). "Alcohol
consumption and risk of glioblastoma; evidence from the Melbourne Collaborative Cohort
Study.". International Journal of Cancer 128 (8): 1929–1934. PMID 21344375.
12. ^ Vilchez, R; Kozinetz, CA; Arrington, AS; Madden, CR; Butel, JS (2003). "Simian virus 40 in human
cancers". The American Journal of Medicine 114 (8): 675–84. DOI:10.1016/S0002-
9343(03)00087-1. PMID 12798456.
13. ^ "Target acquired", The Economist, May 29th, 2008
14. ^ Cavenee, WK (2000). "High-grade gliomas with chromosome 1p loss". Journal of neurosurgery
92 (6): 1080–1. PMID 10839286.
12

13. 15. ^ http://www.brain-cancer-net.org/pvc-poly-vinyl-chloride.htm
16. ^ Van Wijngaarden, Edwin; Dosemeci, Mustafa (2006). "Brain cancer mortality and potential
occupational exposure to lead: Findings from the National Longitudinal Mortality Study, 1979–
1989". International Journal of Cancer 119 (5): 1136–44. DOI:10.1002/ijc.21947. PMID
16570286.
17. ^ Lehrer, Steven (2010). "Anopheles mosquito transmission of brain tumor". Medical Hypotheses
74 (1): 167–8. DOI:10.1016/j.mehy.2009.07.005. PMID 19656635.
18. ^ Glioblastoma multiforme at Mount Sinai
19. ^ Verhaak, R. G. W.; Hoadley, K. A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M. D.; Miller, C. R.;
Ding, L et al. (200). "The use of nuclease P1 in sequence analysis of end group labeled RNA".
Cancer Cell 7 (12): 98–0. DOI:10.06/j.ccr.2009.2.020. PMC 343228. PMID 202925.
//www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=343228.
20. ^ Hayden, Erika Check (2010). "Genomics boosts brain-cancer work". Nature 463 (7279): 278.
DOI:10.1038/463278a. PMID 20090720.
21. ^ Kuehn, B. M. (2010). "Genomics Illuminates a Deadly Brain Cancer". JAMA: the Journal of the
American Medical Association 303 (10): 925–7. DOI:10.1001/jama.2010.236. PMID 20215599.
22. ^ Ohgaki, Hiroko; Kleihues, Paul (2009). "Genetic alterations and signaling pathways in the
evolution of gliomas". Cancer Science 100 (12): 2235–41. DOI:10.1111/j.1349-
7006.2009.01308.x. PMID 19737147.
23. ^ Murat, A.; Migliavacca, E.; Gorlia, T.; Lambiv, W. L.; Shay, T.; Hamou, M.-F.; De Tribolet, N.;
Regli, L. et al. (2008). "Stem Cell-Related 'Self-Renewal' Signature and High Epidermal Growth
Factor Receptor Expression Associated with Resistance to Concomitant Chemoradiotherapy in
Glioblastoma". Journal of Clinical Oncology 26 (18): 3015–24. DOI:10.1200/JCO.2007.15.7164.
PMID 18565887.
24. ^ Smirniotopoulos, J. G.; Murphy, F. M.; Rushing, E. J.; Rees, J. H.; Schroeder, J. W. (2007). "From
the Archives of the AFIP: Patterns of Contrast Enhancement in the Brain and Meninges".
Radiographics 27 (2): 525–51. DOI:10.1148/rg.272065155. PMID 17374867.
25. ^ Lawson, H. Christopher; Sampath, Prakash; Bohan, Eileen; Park, Michael C.; Hussain, Namath;
Olivi, Alessandro; Weingart, Jon; Kleinberg, Lawrence et al. (2006). "Interstitial chemotherapy
for malignant gliomas: the Johns Hopkins experience". Journal of Neuro-Oncology 83 (1): 61–70.
DOI:10.1007/s11060-006-9303-1. PMID 17171441.
26. ^ Stevens, Glen H. J. (2006). "Antiepileptic therapy in patients with central nervous system
malignancies". Current Neurology and Neuroscience Reports 6 (4): 311–318.
DOI:10.1007/s11910-006-0024-9. PMID 16822352.
27. ^ Lacroix, Michel; Abi-Said, Dima; Fourney, Daryl R.; Gokaslan, Ziya L.; Shi, Weiming; Demonte,
Franco; Lang, Frederick F.; McCutcheon, Ian E. et al. (2001). "A multivariate analysis of 416
patients with glioblastoma multiforme: prognosis, extent of resection, and survival". Journal of
Neurosurgery 95 (2): 190–8. DOI:10.3171/jns.2001.95.2.0190. PMID 11780887.
28. ^ Stummer, W; Pichlmeier, U; Meinel, T; Wiestler, O; Zanella, F; Reulen, H; Ala-Glioma Study,
Group (2006). "Fluorescence-guided surgery with 5-aminolevulinic acid for resection of
malignant glioma: a randomised controlled multicentre phase III trial". The Lancet Oncology 7
(5): 392–401. DOI:10.1016/S1470-2045(06)70665-9. PMID 16648043.
29. ^ Walker, Michael D.; Alexander, Eben; Hunt, William E.; MacCarty, Collin S.; Mahaley, M.
Stephen; Mealey, John; Norrell, Horace A.; Owens, Guy et al. (1978). "Evaluation of BCNU and/or
radiotherapy in the treatment of anaplastic gliomas". Journal of Neurosurgery 49 (3): 333–43.
DOI:10.3171/jns.1978.49.3.0333. PMID 355604.
30. ^ Showalter, Timothy N.; Andrel, Jocelyn; Andrews, David W.; Curran Jr., Walter J.; Daskalakis,
Constantine; Werner-Wasik, Maria (2007). "Multifocal Glioblastoma Multiforme: Prognostic
Factors and Patterns of Progression". International Journal of Radiation OncologyBiologyPhysics
69 (3): 820–824. DOI:10.1016/j.ijrobp.2007.03.045. PMID 17499453.
31. ^ Fulton, DS; Urtasun, RC; Scott-Brown, I; Johnson, ES; Mielke, B; Curry, B; Huyser-Wierenga, D;
Hanson, J et al. (1992). "Increasing radiation dose intensity using hyperfractionation in patients
13

14. with malignant glioma. Final report of a prospective phase I-II dose response study". Journal of
neuro-oncology 14 (1): 63–72. PMID 1335044.
32. ^ Stupp, Roger; Mason, Warren P.; Van Den Bent, Martin J.; Weller, Michael; Fisher, Barbara;
Taphoorn, Martin J.B.; Belanger, Karl; Brandes, Alba A. et al. (2005). "Radiotherapy plus
Concomitant and Adjuvant Temozolomide for Glioblastoma". New England Journal of Medicine
352 (10): 987–996. DOI:10.1056/NEJMoa043330. PMID 15758009.
33. ^ Mason, Warren P.; Mirimanoff, René O.; Stupp, Roger (2006). "Radiotherapy with Concurrent
and Adjuvant Temozolomide: A New Standard of Care for Glioblastoma Multiforme". Progress in
Neurotherapeutics and Neuropsychopharmacology 1: 37–52. DOI:10.1017/S1748232105000054.
34. ^ "Temozolomide Plus Radiation Helps Brain Cancer – National Cancer Institute".
http://www.cancer.gov/clinicaltrials/results/glioblastoma0604. Retrieved 2007-09-15.
35. ^ Chamberlain, Marc C.; Glantz, Michael J.; Chalmers, Lisa; Horn, Alixis; Sloan, Andrew E. (2006).
"Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma".
Journal of Neuro-Oncology 82 (1): 81–3. DOI:10.1007/s11060-006-9241-y. PMID 16944309.
36. ^ Dall’oglio, Stefano; D’amico, Anna; Pioli, Fabio; Gabbani, Milena; Pasini, Felice; Passarin, Maria
Grazia; Talacchi, Andrea; Turazzi, Sergio et al. (2008). "Dose-intensity temozolomide after
concurrent chemoradiotherapy in operated high-grade gliomas". Journal of Neuro-Oncology 90
(3): 315–9. DOI:10.1007/s11060-008-9663-9. PMID 18688571.
37. ^ FDA Approves Drug for Treatment of Aggressive Brain Cancer
38. ^ Fulci, Giulia; Chiocca, Antonio (2007). "The status of gene therapy for brain tumors". Expert
Opinion on Biological Therapy 7 (2): 197–208. DOI:10.1517/14712598.7.2.197. PMC 2819130.
PMID 17250458. http://informahealthcare.com/doi/abs/10.1517/14712598.7.2.197.
39. ^ Tai, Chien-Kuo; Jun Wang, Wei; Chen, Thomas C.; Kasahara, Noriyuki (2005). "Single-Shot,
Multicycle Suicide Gene Therapy by Replication-Competent Retrovirus Vectors Achieves Long-
Term Survival Benefit in Experimental Glioma". Molecular Therapy 12 (5): 842–851.
DOI:10.1016/j.ymthe.2005.03.017. PMID 16257382.
http://www.nature.com/mt/journal/v12/n5/full/mt20051365a.html.
40. ^ http://www.Tocagen.com
41. ^ [1];Clinical Trials.gov (January 2011) "A Study of a Replication Competent Retrovirus
Administered to Subjects With Recurrent Glioblastoma (GBM)"
42. ^ ClinicalTrails.gov, a service of the U.S. National Institutes of Health,
http://clinicaltrials.gov/ct2/show/NCT01071837
43. ^ Kleber et al: Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell, 2008
Mar;13(3):235-48, http://www.ncbi.nlm.nih.gov/pubmed/18328427
44. ^ Ghebeh, H; Bakr, MM; Dermime, S (2008). "Cancer stem cell immunotherapy: the right bullet
for the right target". Hematology/oncology and stem cell therapy 1 (1): 1–2. PMID 20063521.
45. ^ Moviglia, GA; Carrizo, AG; Varela, G; Gaeta, CA; Paes De Lima, A; Farina, P; Molina, H (2008).
"Preliminary report on tumor stem cell/B cell hybridoma vaccine for recurrent glioblastoma
multiforme". Hematology/oncology and stem cell therapy 1 (1): 3–13. PMID 20063522.
46. ^ A prospective, randomized, open-label, phase III clinical trial of NovoTTF-100A versus best
standard of care chemotherapy in patients with recurrent glioblastoma. – Stupp et al. 28 (18):
LBA2007 – ASCO Meeting Abstracts. Meeting.ascopubs.org (2010-06-20). Retrieved on 2010-10-
19.
47. ^
http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=647437&version=HealthProfession
al&protocolsearchid=8237659
48. ^ http://www.nutritionandmetabolism.com/content/7/1/33
49. ^ Nieder, C; Adam, M; Molls, M; Grosu, A (2006). "Therapeutic options for recurrent high-grade
glioma in adult patients: Recent advances". Critical Reviews in Oncology/Hematology 60 (3):
181–93. DOI:10.1016/j.critrevonc.2006.06.007. PMID 16875833.
abc
50. ^ Krex, D.; Klink, B.; Hartmann, C.; Von Deimling, A.; Pietsch, T.; Simon, M.; Sabel, M.;
Steinbach, J. P. et al. (2007). "Long-term survival with glioblastoma multiforme". Brain 130 (Pt
10): 2596–606. DOI:10.1093/brain/awm204. PMID 17785346.
14

15. 51. ^ Martinez, Ramon; Schackert, Gabriele; Yaya-Tur, Ricard; Rojas-Marcos, Iñigo; Herman, James
G.; Esteller, Manel (2006). "Frequent hypermethylation of the DNA repair gene MGMT in long-
term survivors of glioblastoma multiforme". Journal of Neuro-Oncology 83 (1): 91–3.
DOI:10.1007/s11060-006-9292-0. PMID 17164975.
52. ^ University of California, Los Angeles Neuro-Oncology : How Our Patients Perform :
Glioblastoma Multiforme [GBM]. Neurooncology.ucla.edu. Retrieved on 2010-10-19.
53. ^ Shaw, E; Seiferheld, W; Scott, C; Coughlin, C; Leibel, S; Curran, W; Mehta, M (2003).
"Reexamining the radiation therapy oncology group (RTOG) recursive partitioning analysis
(RPA) for glioblastoma multiforme (GBM) patients". International Journal of Radiation
OncologyBiologyPhysics 57 (2): S135–6. DOI:10.1016/S0360-3016(03)00843-5 Winger MJ,
Macdonald DR, Cairncross JG. Supratentorial anaplastic gliomas in adults. The
prognostic importance of extent of resection and prior low-grade glioma. J
Neurosurg. Oct 1989;71(4):487-93. [Medline].
54. Black PM. Brain tumor. Part 2. N Engl J Med. May 30 1991;324(22):1555-64.
[Medline].
55. Black PM. Brain tumors. Part 1. N Engl J Med. May 23 1991;324(21):1471-6.
[Medline].
56. Rich JN, Hans C, Jones B, et al. Gene expression profiling and genetic markers in
glioblastoma survival. Cancer Res. May 15 2005;65(10):4051-8. [Medline]. [Full
Text].
57. Kleihues P, Burger PC, Cavenee WK. Glioblastoma. In: WHO Classification:
Pathology and genetics of tumors of the nervous system. ed. Lyon, France:
International Agency for Research on Cancers; 1997:16-24.
58. Watanabe K, Sato K, Biernat W, et al. Incidence and timing of p53 mutations
during astrocytoma progression in patients with multiple biopsies. Clin Cancer
Res. Apr 1997;3(4):523-30. [Medline].
59. Korkolopoulou P, Christodoulou P, Kouzelis K, Hadjiyannakis M, Priftis A,
Stamoulis G, et al. MDM2 and p53 expression in gliomas: a multivariate survival
analysis including proliferation markers and epidermal growth factor receptor. Br
J Cancer. 1997;75(9):1269-78. [Medline]. [Full Text].
60. Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in
diverse human tumour types. Nature. Dec 7 1989;342(6250):705-8. [Medline].
61. Watanabe K, Tachibana O, Sata K, et al. Overexpression of the EGF receptor and
p53 mutations are mutually exclusive in the evolution of primary and secondary
glioblastomas. Brain Pathol. Jul 1996;6(3):217-23; discussion 23-4. [Medline].
62. Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M. A functional p53-
responsive intronic promoter is contained within the human mdm2 gene. Nucleic
Acids Res. Jul 25 1995;23(14):2584-92. [Medline]. [Full Text].
63. Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged
epidermal growth factor receptor genes in human glioblastomas reveal deletions
of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad
Sci U S A. May 15 1992;89(10):4309-13. [Medline]. [Full Text].
15

16. 64. Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich
JN. Molecularly targeted therapy for malignant glioma. Cancer. Jul 1
2007;110(1):13-24. [Medline].
65. Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, et al.
Epidermal growth factor receptor variant III status defines clinically distinct
subtypes of glioblastoma. J Clin Oncol. Jun 1 2007;25(16):2288-94. [Medline].
[Full Text].
66. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al.
Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes
Dev. Nov 1 2007;21(21):2683-710. [Medline]. [Full Text].
67. Libermann TA, Nusbaum HR, Razon N, et al. Amplification, enhanced
expression and possible rearrangement of EGF receptor gene in primary human
brain tumours of glial origin. Nature. Jan 10-18 1985;313(5998):144-7.
[Medline].
68. von Deimling A, Louis DN, von Ammon K, et al. Association of epidermal
growth factor receptor gene amplification with loss of chromosome 10 in human
glioblastoma multiforme. J Neurosurg. Aug 1992;77(2):295-301. [Medline].
69. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, et
al. Structural alterations of the epidermal growth factor receptor gene in human
gliomas. Proc Natl Acad Sci U S A. Apr 1 1992;89(7):2965-9. [Medline]. [Full
Text].
70. Duerr EM, Rollbrocker B, Hayashi Y, et al. PTEN mutations in gliomas and
glioneuronal tumors. Oncogene. Apr 30 1998;16(17):2259-64. [Medline].
71. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma.
Am J Pathol. May 2007;170(5):1445-53. [Medline]. [Full Text].
72. Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and
genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp
Neurol. Jun 2005;64(6):479-89. [Medline].
73. Dohrmann GJ, Farwell JR, Flannery JT. Glioblastoma multiforme in children. J
Neurosurg. Apr 1976;44(4):442-8. [Medline].
74. Farrell CJ, Plotkin SR. Genetic causes of brain tumors: neurofibromatosis,
tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. Nov
2007;25(4):925-46, viii. [Medline].
75. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain
tumors. Neurol Clin. Nov 2007;25(4):867-90, vii. [Medline].
76. Hardell L, Carlberg M, Söderqvist F, Mild KH, Morgan LL. Long-term use of
cellular phones and brain tumours: increased risk associated with use for > or =10
years. Occup Environ Med. Sep 2007;64(9):626-32. [Medline].
16

17. 77. Lahkola A, Auvinen A, Raitanen J, Schoemaker MJ, Christensen HC, Feychting
M, et al. Mobile phone use and risk of glioma in 5 North European countries. Int
J Cancer. Apr 15 2007;120(8):1769-75. [Medline].
78. Inskip PD, Tarone RE, Hatch EE, Wilcosky TC, Shapiro WR, Selker RG, et al.
Cellular-telephone use and brain tumors. N Engl J Med. Jan 11 2001;344(2):79-
86. [Medline].
79. Weintraub MI. Glioblastoma multiforme and the cellular telephone scare. J
Neurosurg. Jan 1994;80(1):169-70. [Medline].
80. Kan P, Simonsen SE, Lyon JL, Kestle JR. Cellular phone use and brain tumor: a
meta-analysis. J Neurooncol. Jan 2008;86(1):71-8. [Medline].
81. International Electromagnetic Field (EMF) Collaborative. Cellphones and Brain
Tumors: 15 Reasons for Concern. Science, Spin and the Truth Behind
Interphone. Available at http://www.radiationresearch.org/pdfs/reasons_us.pdf.
Accessed October 19, 2009.
82. Mukundan S, Holder C, Olson JJ. Neuroradiological assessment of newly
diagnosed glioblastoma. J Neurooncol. Sep 2008;89(3):259-69. [Medline].
83. Piroth MD, Holy R, Pinkawa M, et al. Prognostic impact of postoperative, pre-
irradiation (18)F-fluoroethyl-l-tyrosine uptake in glioblastoma patients treated
with radiochemotherapy. Radiother Oncol. May 2011;99(2):218-24. [Medline].
84. Russell DS, Rubinstein LJ. Pathology of tumors of the nervous system. 6th ed.
London, England: Edward Arnold; 1998:426-52.
85. Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P. Grading of astrocytomas.
A simple and reproducible method. Cancer. Nov 15 1988;62(10):2152-65.
[Medline].
86. Kim TS, Halliday AL, Hedley-Whyte ET, Convery K. Correlates of survival and
the Daumas-Duport grading system for astrocytomas. J Neurosurg. Jan
1991;74(1):27-37. [Medline].
87. Pedersen PH, Rucklidge GJ, Mork SJ, et al. Leptomeningeal tissue: a barrier
against brain tumor cell invasion. J Natl Cancer Inst. Nov 2 1994;86(21):1593-9.
[Medline].
88. Nagashima G, Suzuki R, Hokaku H, et al. Graphic analysis of microscopic tumor
cell infiltration, proliferative potential, and vascular endothelial growth factor
expression in an autopsy brain with glioblastoma. Surg Neurol. Mar
1999;51(3):292-9. [Medline].
89. Pompili A, Calvosa F, Caroli F, et al. The transdural extension of gliomas. J
Neurooncol. Jan 1993;15(1):67-74. [Medline].
90. Brat DJ, Prayson RA, Ryken TC, Olson JJ. Diagnosis of malignant glioma: role
of neuropathology. J Neurooncol. Sep 2008;89(3):287-311. [Medline].
17

18. 91. Caccamo DV, Rubenstein LJ. Tumors: Applications of immunohistochemical
methods. In: Neuropathology: The diagnostic approach. St Louis, Mo: Mosby-
Year Book; 1997:193-218.
92. Lampl Y, Eshel Y, Gilad R, Sarova-Pinchas I. Glioblastoma multiforme with
bone metastase and cauda equina syndrome. J Neurooncol. Apr 1990;8(2):167-
72. [Medline].
93. Hulbanni S, Goodman PA. Glioblastoma multiforme with extraneural metastases
in the absence of previous surgery. Cancer. Mar 1976;37(3):1577-83. [Medline].
94. Hoffman HJ, Duffner PK. Extraneural metastases of central nervous system
tumors. Cancer. Oct 1 1985;56(7 Suppl):1778-82. [Medline].
95. Barnard RO, Geddes JF. The incidence of multifocal cerebral gliomas. A
histologic study of large hemisphere sections. Cancer. Oct 1 1987;60(7):1519-31.
[Medline].
96. Batzdorf U, Malamud N. The Problem of Multicentric Gliomas. J Neurosurg.
Feb 1963;20:122-36. [Medline].
97. Pasquier B, Pasquier D, N'Golet A, Panh MH, Couderc P. Extraneural metastases
of astrocytomas and glioblastomas: clinicopathological study of two cases and
review of literature. Cancer. Jan 1 1980;45(1):112-25. [Medline].
98. Preusser M, de Ribaupierre S, Wohrer A, et al. Current concepts and
management of glioblastoma. Ann Neurol. Jul 2011;70(1):9-21. [Medline].
99. Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G,
et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. Apr 12
2007;356(15):1527-35. [Medline]. [Full Text].
100. Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, et al.
Abbreviated course of radiation therapy in older patients with glioblastoma
multiforme: a prospective randomized clinical trial. J Clin Oncol. May 1
2004;22(9):1583-8. [Medline]. [Full Text].
101. Glantz M, Chamberlain M, Liu Q, Litofsky NS, Recht LD. Temozolomide
as an alternative to irradiation for elderly patients with newly diagnosed
malignant gliomas. Cancer. May 1 2003;97(9):2262-6. [Medline].
102. Scott J, Tsai YY, Chinnaiyan P, Yu HH. Effectiveness of radiotherapy for
elderly patients with glioblastoma. Int J Radiat Oncol Biol Phys. Sep 1
2011;81(1):206-10. [Medline].
103. [Best Evidence] Stupp R, Hegi ME, Mason WP, van den Bent MJ,
Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in
a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet
Oncol. May 2009;10(5):459-66. [Medline].
18

19. 104. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N
Engl J Med. Mar 10 2005;352(10):987-96. [Medline]. [Full Text].
105. Chamberlain MC, Kormanik PA. Practical guidelines for the treatment of
malignant gliomas. West J Med. Feb 1998;168(2):114-20. [Medline]. [Full Text].
106. Shapiro WR, Green SB, Burger PC, et al. Randomized trial of three
chemotherapy regimens and two radiotherapy regimens and two radiotherapy
regimens in postoperative treatment of malignant glioma. Brain Tumor
Cooperative Group Trial 8001. J Neurosurg. Jul 1989;71(1):1-9. [Medline].
107. Wernicke AG, Edgar MA, Lavi E, et al. Prostate-specific membrane
antigen as a potential novel vascular target for treatment of glioblastoma
multiforme. Arch Pathol Lab Med. Nov 2011;135(11):1486-9. [Medline].
108. Barker FG, Prados MD, Chang SM, et al. Radiation response and survival
time in patients with glioblastoma multiforme. J Neurosurg. Mar
1996;84(3):442-8. [Medline].
109. Leibel SA, Scott CB, Loeffler JS. Contemporary approaches to the
treatment of malignant gliomas with radiation therapy. Semin Oncol. Apr
1994;21(2):198-219. [Medline].
110. Liang BC, Thornton AF Jr, Sandler HM, Greenberg HS. Malignant
astrocytomas: focal tumor recurrence after focal external beam radiation therapy.
J Neurosurg. Oct 1991;75(4):559-63. [Medline].
111. Buatti J, Ryken TC, Smith MC, Sneed P, Suh JH, Mehta M, et al.
Radiation therapy of pathologically confirmed newly diagnosed glioblastoma in
adults. J Neurooncol. Sep 2008;89(3):313-37. [Medline].
112. Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr,
Mealey J Jr, et al. Evaluation of BCNU and/or radiotherapy in the treatment of
anaplastic gliomas. A cooperative clinical trial. J Neurosurg. Sep
1978;49(3):333-43. [Medline].
113. Halperin EC, Bruger PC. Conventional external beam radiotherapy for
central nervous system malignancies. In: Frank BD, ed. Symposium on Neuro-
Oncology. Vol 3. 4th ed. New York, NY: Neurologic Clinics; 1985:867-82.
114. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma.
Neurology. Sep 1980;30(9):907-11. [Medline].
115. Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in
malignant glioma: standard of care and future directions. J Clin Oncol. Sep 10
2007;25(26):4127-36. [Medline].
116. Chi AS, Wen PY. Inhibiting kinases in malignant gliomas. Expert Opin
Ther Targets. Apr 2007;11(4):473-96. [Medline].
19

20. 117. Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of
integrating this novel treatment modality with chemoradiation for solid cancers. J
Clin Oncol. Sep 10 2007;25(26):4033-42. [Medline]. [Full Text].
118. Rodrigus P. Motexafin gadolinium: a possible new radiosensitiser. Expert
Opin Investig Drugs. Jul 2003;12(7):1205-10. [Medline].
119. Butowski NA, Sneed PK, Chang SM. Diagnosis and treatment of recurrent
high-grade astrocytoma. J Clin Oncol. Mar 10 2006;24(8):1273-80. [Medline].
120. Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of
fractionated stereotactic reirradiation in recurrent gliomas: long-term results in
172 patients treated in a single institution. J Clin Oncol. Dec 1
2005;23(34):8863-9. [Medline].
121. Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC,
et al. The American Society for Therapeutic Radiology and Oncology (ASTRO)
evidence-based review of the role of radiosurgery for malignant glioma. Int J
Radiat Oncol Biol Phys. Sep 1 2005;63(1):47-55. [Medline].
122. Kornblith PL. The role of cytotoxic chemotherapy in the treatment of
malignant brain tumors. Surg Neurol. Dec 1995;44(6):551-2. [Medline].
123. Kornblith PL, Walker M. Chemotherapy for malignant gliomas [published
erratum appears in J Neurosurg 1988 Oct;69(4):645]. J Neurosurg. Jan
1988;68(1):1-17. [Medline].
124. Lesser GJ, Grossman S. The chemotherapy of high-grade astrocytomas.
Semin Oncol. Apr 1994;21(2):220-35. [Medline].
125. Levin VA. Chemotherapy of primary brain tumors. In: Frank BD, ed.
Symposium on Neuro-Oncology. Vol 3. 4th ed. New York, NY: Neurologic
Clinics; 1985:855-66.
126. Levin VA, Silver P, Hannigan J, et al. Superiority of post-radiotherapy
adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over
BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol
Phys. Feb 1990;18(2):321-4. [Medline].
127. Fadul CE, Wen PY, Kim L, Olson JJ. Cytotoxic chemotherapeutic
management of newly diagnosed glioblastoma multiforme. J Neurooncol. Sep
2008;89(3):339-57. [Medline].
128. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of
radiation therapy with and without adjuvant chemotherapy for malignant gliomas
in adults. Cancer. Apr 15 1993;71(8):2585-97. [Medline].
129. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic
review and meta-analysis of individual patient data from 12 randomised trials.
Lancet. Mar 23 2002;359(9311):1011-8. [Medline].
130. Westphal M, Ram Z, Riddle V, Hilt D, Bortey E. Gliadel wafer in initial
surgery for malignant glioma: long-term follow-up of a multicenter controlled
20

21. trial. Acta Neurochir (Wien). Mar 2006;148(3):269-75; discussion 275.
[Medline].
131. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M.
MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J
Med. Mar 10 2005;352(10):997-1003. [Medline]. [Full Text].
132. Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al.
Correlation of O6-methylguanine methyltransferase (MGMT) promoter
methylation with clinical outcomes in glioblastoma and clinical strategies to
modulate MGMT activity. J Clin Oncol. Sep 1 2008;26(25):4189-99. [Medline].
133. Broniscer A, Gururangan S, MacDonald TJ, Goldman S, Packer RJ,
Stewart CF, et al. Phase I trial of single-dose temozolomide and continuous
administration of o6-benzylguanine in children with brain tumors: a pediatric
brain tumor consortium report. Clin Cancer Res. Nov 15 2007;13(22 Pt 1):6712-
8. [Medline]. [Full Text].
134. Kaiser MG, Parsa AT, Fine RL, Hall JS, Chakrabarti I, Bruce JN. Tissue
distribution and antitumor activity of topotecan delivered by intracerebral clysis
in a rat glioma model. Neurosurgery. Dec 2000;47(6):1391-8; discussion 1398-9.
[Medline].
135. Bruce JN, Falavigna A, Johnson JP, et al. Intracerebral clysis in a rat
glioma model. Neurosurgery. Mar 2000;46(3):683-91. [Medline].
136. Lopez KA, Waziri AE, Canoll PD, Bruce JN. Convection-enhanced
delivery in the treatment of malignant glioma. Neurol Res. Jul 2006;28(5):542-8.
[Medline].
137. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety
and efficacy of intraoperative controlled delivery by biodegradable polymers of
chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment
Group. Lancet. Apr 22 1995;345(8956):1008-12. [Medline].
138. Bota DA, Desjardins A, Quinn JA, Affronti ML, Friedman HS. Interstitial
chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of
malignant gliomas. Ther Clin Risk Manag. Oct 2007;3(5):707-15. [Medline].
[Full Text].
139. FDA. Avastin Approval History. U.S. Food and Drug Administration.
Available at
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf.
Accessed 5/7/09.
140. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA,
Quinn JA, et al. Phase II trial of bevacizumab and irinotecan in recurrent
malignant glioma. Clin Cancer Res. Feb 15 2007;13(4):1253-9. [Medline]. [Full
Text].
21

22. 141. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA,
Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma
multiforme. J Clin Oncol. Oct 20 2007;25(30):4722-9. [Medline].
142. Cloughesy TF, Prados MD, Wen PY. A phase II, randomized, non-
comparative clinical trial of the effect of bevacizumab (BV) alone or in
combinationwith irinotecan (CPT) on 6-month progressionfree survival (PFS6) in
recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol.
2008;26:Suppl:91s.
143. Rich JN, Rasheed BK, Yan H. EGFR mutations and sensitivity to
gefitinib. N Engl J Med. Sep 16 2004;351(12):1260-1; author reply 1260-1.
[Medline].
144. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL. Phase
II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. Jan 1 2004;22(1):133-
42. [Medline]. [Full Text].
145. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ.
Molecular determinants of the response of glioblastomas to EGFR kinase
inhibitors. N Engl J Med. Nov 10 2005;353(19):2012-24. [Medline]. [Full Text].
146. Fulci G, Chiocca EA. The status of gene therapy for brain tumors. Expert
Opin Biol Ther. Feb 2007;7(2):197-208. [Medline]. [Full Text].
147. Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS,
Herndon JE 2nd, et al. Salvage radioimmunotherapy with murine iodine-131-
labeled antitenascin monoclonal antibody 81C6 for patients with recurrent
primary and metastatic malignant brain tumors: phase II study results. J Clin
Oncol. Jan 1 2006;24(1):115-22. [Medline].
148. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB,
Fiveash JB, et al. Phase I single-dose study of intracavitary-administered iodine-
131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol. Aug 1
2006;24(22):3644-50. [Medline].
149. Ferguson S, Lesniak MS. Convection enhanced drug delivery of novel
therapeutic agents to malignant brain tumors. Curr Drug Deliv. Apr
2007;4(2):169-80. [Medline].
150. Quang TS, Brady LW. Radioimmunotherapy as a novel treatment
regimen: (125)I-labeled monoclonal antibody 425 in the treatment of high-grade
brain gliomas. Int J Radiat Oncol Biol Phys. Mar 1 2004;58(3):972-5. [Medline].
151. Rich JN, Bigner DD. Development of novel targeted therapies in the
treatment of malignant glioma. Nat Rev Drug Discov. May 2004;3(5):430-46.
[Medline]. [Full Text].
152. Ammirati M, Vick N, Liao YL, et al. Effect of the extent of surgical
resection on survival and quality of life in patients with supratentorial
glioblastomas and anaplastic astrocytomas. Neurosurgery. Aug 1987;21(2):201-
6. [Medline].
22

23. 153. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et
al. A multivariate analysis of 416 patients with glioblastoma multiforme:
prognosis, extent of resection, and survival. J Neurosurg. Aug 2001;95(2):190-8.
[Medline].
154. Keles GE, Anderson B, Berger MS. The effect of extent of resection on
time to tumor progression and survival in patients with glioblastoma multiforme
of the cerebral hemisphere. Surg Neurol. Oct 1999;52(4):371-9. [Medline].
155. Sanai N, Berger MS. Glioma extent of resection and its impact on patient
outcome. Neurosurgery. Apr 2008;62(4):753-64; discussion 264-6. [Medline].
156. Fadul C, Wood J, Thaler H, et al. Morbidity and mortality of craniotomy
for excision of supratentorial gliomas. Neurology. Sep 1988;38(9):1374-9.
[Medline].
157. Ryken TC, Frankel B, Julien T, Olson JJ. Surgical management of newly
diagnosed glioblastoma in adults: role of cytoreductive surgery. J Neurooncol.
Sep 2008;89(3):271-86. [Medline].
158. Ciric I, Rovin R, Cozzens JW. Role of surgery in the treatment of
malignant cerebral gliomas. In: Malignant Cerebral Glioma. Park Ridge, Ill:
American Association of Neurological Surgeons; 1990:141-53.
159. El Hindy N, Bachmann HS, Lambertz et al. Association of the CC
genotype of the regulatory BCL2 promoter polymorphism (-938C>A) with better
2-year survival in patients with glioblastoma multiforme. J Neurosurg. Jun
2011;114(6):1631-9. [Medline].
160. Coffey RJ, Lunsford LD, Taylor FH. Survival after stereotactic biopsy of
malignant gliomas. Neurosurgery. Mar 1988;22(3):465-73. [Medline].
161. Jakola AS, Unsgard G, Solheim O. Quality of life in patients with
intracranial gliomas: the impact of modern image-guided surgery. J Neurosurg.
Jun 2011;114(6):1622-30. [Medline].
162. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant
prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology.
May 23 2000;54(10):1886-93. [Medline]. [Full Text].
163. Scott JN, Rewcastle NB, Brasher PM, et al. Long-term glioblastoma
multiforme survivors: a population-based study. Can J Neurol Sci. Aug
1998;25(3):197-201. [Medline].
164. Sneed PK, Prados MD, McDermott MW, et al. Large effect of age on the
survival of patients with glioblastoma treated with radiotherapy and
brachytherapy boost. Neurosurgery. May 1995;36(5):898-903; discussion 903-4.
[Medline].
165. Salmon I, Dewitte O, Pasteels JL, et al. Prognostic scoring in adult
astrocytic tumors using patient age, histopathological grade, and DNA histogram
type. J Neurosurg. May 1994;80(5):877-83. [Medline].
23

24. 166. Li J, Wang M, Won M, et al. Validation and simplification of the
Radiation Therapy Oncology Group recursive partitioning analysis classification
for glioblastoma. Int J Radiat Oncol Biol Phys. Nov 1 2011;81(3):623-30.
[Medline].
167. Kaur G, Bloch O, Jian BJ, et al. A critical evaluation of cystic features in
primary glioblastoma as a prognostic factor for survival. J Neurosurg. Oct
2011;115(4):754-9. [Medline].
168. Bouvier-Labit C, Chinot O, Ochi C, Gambarelli D, Dufour H, Figarella-
Branger D. Prognostic significance of Ki67, p53 and epidermal growth factor
receptor immunostaining in human glioblastomas. Neuropathol Appl Neurobiol.
Oct 1998;24(5):381-8. [Medline].
169. Bullard DE, Bigner DD. Applications of monoclonal antibodies in the
diagnosis and treatment of primary brain tumors. J Neurosurg. Jul 1985;63(1):2-
16. [Medline].
170. Burger PC, Green SB. Patient age, histologic features, and length of
survival in patients with glioblastoma multiforme. Cancer. May 1
1987;59(9):1617-25. [Medline].
171. Burger PC, Heinz ER, Shibata T, Kleihues P. Topographic anatomy and
CT correlations in the untreated glioblastoma multiforme. J Neurosurg. May
1988;68(5):698-704. [Medline].
172. Burger PC, Scheithauer BW. Tumors of the central nervous system. In:
Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology;
1994.
173. Burger PC, Vogel FS, Green SB, Strike TA. Glioblastoma multiforme and
anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer.
Sep 1 1985;56(5):1106-11. [Medline].
174. Devaux BC, O'Fallon JR, Kelly PJ. Resection, biopsy, and survival in
malignant glial neoplasms. A retrospective study of clinical parameters, therapy,
and outcome. J Neurosurg. May 1993;78(5):767-75. [Medline].
175. Dropcho EJ, Soong SJ. The prognostic impact of prior low grade histology
in patients with anaplastic gliomas: a case-control study. Neurology. Sep
1996;47(3):684-90. [Medline].
176. Giordana MT, Bradac GB, Pagni CA, et al. Primary diffuse
leptomeningeal gliomatosis with anaplastic features. Acta Neurochir (Wien).
1995;132(1-3):154-9. [Medline].
177. Glantz MJ, Hoffman JM, Coleman RE, et al. Identification of early
recurrence of primary central nervous system tumors by
[18F]fluorodeoxyglucose positron emission tomography. Ann Neurol. Apr
1991;29(4):347-55. [Medline].
178. Greenberg MS. Tumor: Primary brain tumors. In: Handbook of
Neurosurgery. 4th ed. Lakeland, Fla: Greenberg Graphics; 1997:244-311.
24

25. 179. Herholz K, Pietrzyk U, Voges J, et al. Correlation of glucose consumption
and tumor cell density in astrocytomas. A stereotactic PET study. J Neurosurg.
Dec 1993;79(6):853-8. [Medline].
180. Lang FF, Miller DC, Koslow M, Newcomb EW. Pathways leading to
glioblastoma multiforme: a molecular analysis of genetic alterations in 65
astrocytic tumors. J Neurosurg. Sep 1994;81(3):427-36. [Medline].
181. Lantos PL, VandenBerg SR, Kleihues P. Tumors of the nervous system.
In: Graham DI, Lantos PL, eds. Greenfield's Neuropathology. 6th ed. London,
England: Edward Arnold; 1998:583-879.
182. Macdonald DR, Cascino TL, Schold SC, Cairncross JG. Response criteria
for phase II studies of supratentorial malignant glioma. J Clin Oncol. Jul
1990;8(7):1277-80. [Medline].
183. Mahaley MS, Mettlin C, Natarajan N, et al. National survey of patterns of
care for brain-tumor patients. J Neurosurg. Dec 1989;71(6):826-36. [Medline].
184. Newcomb EW, Cohen H, Lee SR, et al. Survival of patients with
glioblastoma multiforme is not influenced by altered expression of p16, p53,
EGFR, MDM2 or Bcl-2 genes. Brain Pathol. Oct 1998;8(4):655-67. [Medline].
185. Ohgaki H, Watanabe K, Peraud A, et al. A case history of glioma
progression. Acta Neuropathol (Berl). May 1999;97(5):525-32. [Medline].
186. Patronas NJ, Di Chiro G, Kufta C, et al. Prediction of survival in glioma
patients by means of positron emission tomography. J Neurosurg. Jun
1985;62(6):816-22. [Medline].
187. Shiras A, Bhosale A, Shepal V, Shukla R, Baburao VS, Prabhakara K, et
al. A unique model system for tumor progression in GBM comprising two
developed human neuro-epithelial cell lines with differential transforming
potential and coexpressing neuronal and glial markers. Neoplasia. Nov-Dec
2003;5(6):520-32. [Medline]. [Full Text].
188. van den Bent MJ, Hegi ME, Stupp R. Recent developments in the use of
chemotherapy in brain tumours. Eur J Cancer. Mar 2006;42(5):582-8. [Medline].
189. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. Jul 31
2008;359(5):492-507. [Medline]. [Full Text].
190. Wood JR, Green SB, Shapiro WR. The prognostic importance of tumor
size in malignant gliomas: a computed tomographic scan study by the Brain
Tumor Cooperative Group. J Clin Oncol. Feb 1988;6(2):338-43. [Medline].
191. Zulch KJ. Brain Tumors: their biology and pathology. 3rd ed. Berlin,
Germany: Springer-Verlag; 1986
192. Robbin &Cortan, Pathologic Basis Of Disease,8th edition
25