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===Ion channels===
===Ion channels===
Furthermore, glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. It has been hypothesized that by upregulating these ion channels, glioblastoma tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids glioblastoma cells to change cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior, because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain.<ref>{{cite journal |doi=10.5402/2011/590249 |title=Ion Channels in Glioblastoma |year=2011 |last1=Molenaar |first1=Remco J. |journal=ISRN Neurology |volume=2011 |pages=1 |pmid=22389824 |pmc=3263536}}</ref>
Furthermore, glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. It has been hypothesized that by upregulating these ion channels, glioblastoma tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids glioblastoma cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior, because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain.<ref>{{cite journal |doi=10.5402/2011/590249 |title=Ion Channels in Glioblastoma |year=2011 |last1=Molenaar |first1=Remco J. |journal=ISRN Neurology |volume=2011 |pages=1 |pmid=22389824 |pmc=3263536}}</ref>


==Diagnosis==
==Diagnosis==

Revision as of 16:19, 9 February 2015

Glioblastoma
SpecialtyNeuro-oncology Edit this on Wikidata

Glioblastoma multiforme (GBM), WHO classification name "glioblastoma", also known as Grade IV Astrocytoma,[1] is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. GBM is a rare disease, with an incidence of 2–3 cases per 100,000 person life-years in Europe and North America.[2] It presents two variants: giant cell glioblastoma and gliosarcoma.

Treatment can involve chemotherapy, radiation and surgery. Median survival with standard-of-care radiation and chemotherapy with temozolomide is 15 months.[3] Median survival without treatment is 4½ months. Although no randomized controlled trials have been done, surgery remains the standard of care.[4]

Signs and symptoms

Main article: Brain tumor

Although common symptoms of the disease include seizure, nausea and vomiting, headache, memory loss, and hemiparesis, the single most prevalent symptom is a progressive memory, personality, or neurological deficit due to temporal and frontal lobe involvement. The kind of symptoms produced depends highly on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is an asymptomatic condition until it reaches an enormous size.

Risk factors

For unknown reasons, GBM occurs more commonly in males.[5] Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking,[6] consumption of cured meat,[7] or electromagnetic fields[8][9][10][11] as of yet. Alcohol consumption may be a possible risk factor.[12] Glioblastoma has been associated with the viruses SV40,[13] HHV-6,[14][15] and cytomegalovirus.[16] There also appears to be a small link between ionizing radiation and glioblastoma.[17] Some also believe that there may be a link between polyvinyl chloride (which is commonly used in construction) and glioblastoma.[18] A 2006 analysis links brain cancer to lead exposure in the work-place.[19] There is an association of brain tumor incidence and malaria, suggesting that the anopheles mosquito, the carrier of malaria, might transmit a virus or other agent that could cause glioblastoma[20] or that the immunosuppression associated with malaria could enhance viral replication. Also HHV-6 reactivates in response to hypersensitivity reactions from drugs and environmental chemicals.[21]

Other risk factors include:[22]

Pathogenesis

Glioblastoma multiforme tumors are characterized by the presence of small areas of necrotizing tissue that is surrounded by anaplastic cells. This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from Grade 3 astrocytomas, which do not have these features.

Molecular alterations

There are four subtypes of glioblastoma.[24] Ninety-seven percent of tumors in the 'classical' subtype carry extra copies of the epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of epidermal growth factor receptor (EGFR), whereas the gene TP53, which is often mutated in glioblastoma, is rarely mutated in this subtype.[25] In contrast, the proneural subtype often has high rates of alterations in TP53, and in PDGFRA, the gene encoding a-type platelet-derived growth factor receptor, and in IDH1, the gene encoding isocitrate dehydrogenase-1. The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding Neurofibromin 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types.[26] Many other genetic alterations have been described in glioblastoma, and the majority of them are clustered in three pathways, the P53, RB, and the PI3K/AKT.[27] Glioblastomas have alterations in 64-87%, 68-78% and 88% of these pathways, respectively.[2] Another important alteration is methylation of MGMT, a "suicide" DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. Since an MGMT enzyme can only repair one DNA alkylation due its suicide repair mechanism, reverse capacity is low and methylation of the MGMT gene promoter greatly affects DNA-repair capacity.[28][29] Indeed, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.[30]

GBMs usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Less than 10% form more slowly following degeneration of low-grade astrocytoma or anaplastic astrocytoma. These are called secondary GBMs and are more common in younger patients (mean age 45 versus 62 years).[31] The tumor may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid (CSF) (> 100 mg/dL), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may spread (rarely) to the spinal cord or cause meningeal gliomatosis. However, metastasis of GBM beyond the central nervous system is extremely unusual. About 50% of GBMs occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may rarely exhibit the classic infiltration across the corpus callosum, producing a butterfly (bilateral) glioma.

The tumor may take on a variety of appearances, depending on the amount of hemorrhage, necrosis, or its age. A CT scan will usually show an inhomogeneous mass with a hypodense center and a variable ring of enhancement surrounded by edema. Mass effect from the tumor and edema may compress the ventricles and cause hydrocephalus.

Glioblastoma stem-like cells

Cancer cells with stem cell-like properties have been found in glioblastomas (this may be a cause of their resistance to conventional treatments, and high recurrence rate).[32] A biomarker for cells in glioblastomas that exhibit cancer stem cell properties, the transcription factor Hes3, has been shown to regulate their number when placed in culture.[33]

Metabolism

The IDH1 gene encodes for the enzyme isocitrate dehydrogenase 1 and is frequently mutated in glioblastoma (primary GBM: 5%, secondary GBM >80%).[29] By producing very high concentrations of the "oncometabolite" D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1-enzyme it induces profound changes to the metabolism of IDH1-mutated glioblastoma, compared with IDH1 wild-type glioblastoma or healthy astrocytes. Among others, it increases the glioblastoma cells' dependence on glutamine or glutamate as an energy source.[34] It has been hypothesized that IDH1-mutated glioblastoma are in a very high demand for glutamate and use this amino acid and neurotransmitter as a chemotactic signal. Since healthy astrocytes excrete glutamate, IDH1-mutated glioblastoma cells do not favor dense tumor structures but instead migrate, invade and disperse into healthy parts of the brain where glutamate concentrations are higher. This may explain the invasive behaviour of these IDH1-mutated glioblastoma.[35]

Ion channels

Furthermore, glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. It has been hypothesized that by upregulating these ion channels, glioblastoma tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids glioblastoma cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior, because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain.[36]

Diagnosis

Image 1b. Sagittal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old boy.
Glioblastoma (histology slide)

When viewed with MRI, glioblastomas often appear as ring-enhancing lesions. The appearance is not specific, however, as other lesions such as abscess, metastasis, tumefactive multiple sclerosis, and other entities may have a similar appearance.[37] Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy or a craniotomy with tumor resection and pathologic confirmation. Because the tumor grade is based upon the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the lesion. Imaging of tumor blood flow using perfusion MRI and measuring tumor metabolite concentration with MR spectroscopy will add value to standard MRI in the diagnosis of glioblastoma by showing increased relative cerebral blood volume and increased choline peak respectively, but pathology remains the gold standard.[38]

In the diagnosis of glioblastoma it is important to distinguish primary glioblastoma from secondary glioblastoma. These tumors occur spontaneously (de novo) or have progressed from a lower-grade glioma, respectively.[39] Primary glioblastomas have a worse prognosis, different tumor biology may have a different response to therapy, which makes this a critical evaluation to determine patient prognosis and therapy.[28] Over 80% of secondary glioblastoma carries a mutation in IDH1, whereas this mutation is rare in primary glioblastoma (5-10%). Thus, IDH1 mutations may become a useful tool to distinguish primary and secondary glioblastomas in the future, since histopathologically they are very similar and the distinction without molecular biomarkers is unreliable.[40]

Treatment

It is very difficult to treat glioblastoma due to several complicating factors:[41]

  • The tumor cells are very resistant to conventional therapies.
  • The brain is susceptible to damage due to conventional therapy.
  • The brain has a very limited capacity to repair itself.
  • Many drugs cannot cross the blood–brain barrier to act on the tumor.

Treatment of primary brain tumors and brain metastases consists of both symptomatic and palliative therapies.

Symptomatic therapy

Supportive treatment focuses on relieving symptoms and improving the patient’s neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.

  • Historically, around 90% of patients with glioblastoma underwent anticonvulsant treatment, although it has been estimated that only approximately 40% of patients required this treatment. Recently, it has been recommended that neurosurgeons not administer anticonvulsants prophylactically, and should wait until a seizure occurs before prescribing this medication.[42] Those receiving phenytoin concurrent with radiation may have serious skin reactions such as erythema multiforme and Stevens–Johnson syndrome.
  • Corticosteroids, usually dexamethasone given 4 to 8 mg every 4 to 6 h, can reduce peritumoral edema (through rearrangement of the blood–brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.

Palliative therapy

Palliative treatment usually is conducted to improve quality of life and to achieve a longer survival time. It includes surgery, radiation therapy, and chemotherapy. A maximally feasible resection with maximal tumor-free margins is usually performed along with external beam radiation and chemotherapy. Gross total resection of tumor is associated with a better prognosis.

Surgery

Surgery is the first stage of treatment of glioblastoma. An average GBM tumor contains 1011 cells, which is on average reduced to 109 cells after surgery (a reduction of 99%). It is used to take a section for a pathological diagnosis, to remove some of the symptoms of a large mass pressing against the brain, to remove disease before secondary resistance to radiotherapy and chemotherapy, and to prolong survival.

The greater the extent of tumor removal, the better. Removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed.[43] The chances of near-complete initial removal of the tumor can be greatly increased if the surgery is guided by a fluorescent dye known as 5-aminolevulinic acid.[44] GBM cells are widely infiltrative through the brain at diagnosis, and so despite a "total resection" of all obvious tumor, most people with GBM later develop recurrent tumors either near the original site or at more distant "satellite lesions" within the brain. Other modalities, including radiation, are used after surgery in an effort to suppress and slow recurrent disease.

Radiotherapy

After surgery, radiotherapy is the mainstay of treatment for people with glioblastoma. A pivotal clinical trial carried out in the early 1970s showed that among 303 GBM patients randomized to radiation or nonradiation therapy, those who received radiation had a median survival more than double those who did not.[45] Subsequent clinical research has attempted to build on the backbone of surgery followed by radiation. On average, radiotherapy after surgery can reduce the tumor size to 107 cells. Whole brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy.[46] A total radiation dose of 60–65 Gy has been found to be optimal for treatment.[47]

GBM tumors are well known to contain zones of tissue exhibiting hypoxia which are highly resistant to radiotherapy. Various approaches to chemotherapy radiosensitizers have been pursued with limited success to date. Newer research approaches are currently being studied, including preclinical and clinical investigations into the use of an oxygen diffusion-enhancing compound such as trans sodium crocetinate (TSC) as radiosensitizers[48] and a clinical trial is currently underway.[49]

Boron neutron capture therapy has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.

Chemotherapy

Most of studies show no benefit from the addition of chemotherapy. However, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived a median of 14.6 months as opposed to 12.1 months for the group receiving radiation alone.[50] This treatment regime is now standard for most cases of glioblastoma where the person is not enrolled in a clinical trial.[51][52] Temozolomide seems to work by sensitizing the tumor cells to radiation.[53]

High doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses.[54]

Antiangiogenic therapy with medications such as bevacizumab slow tumor growth but do not affect overall survival.[55]

Gene transfer

Gene transfer is a promising approach for fighting cancers including brain cancer.[56] Unlike current conventional cancer treatments such as chemotherapy and radiation therapy, gene transfer has the potential to selectively kill cancer cells while leaving healthy cells unharmed. Over the past two decades significant advances have been made in gene transfer technology and the field has matured to the point of clinical and commercial feasibility. Advances include vector (gene delivery vehicle) construction, vector producer cell efficiency and scale-up processes, preclinical models for target diseases and regulatory guidance regarding clinical trial design including endpoint definitions and measurements. In one such approach, researchers at UCLA in 2005 reported a long-term survival benefit in an experimental brain tumor animal model.[57] Subsequently, in preparation for human clinical trials, this technology was further developed by Tocagen, and is currently under clinical investigation in a Phase I/II trial for the potential treatment of recurrent high grade glioma including glioblastoma multiforme (GBM) and anaplastic astrocytoma.[58]

MicroRNA

RNA interference, usually micro-RNA, is being studied in tissue culture and pathology specimens. MicroRNA-screening of plasma is used to determine the prognosis of glioblastoma.[59][60]

Protein therapeutics - APG101

APG101 is a soluble CD95-Fc fusion protein that blocks the CD95 ligand from binding to the CD95 receptor. As demonstrated by Kleber et al., the binding of the CD95 ligand to its cognate receptor stimulates the invasive growth of glioblastoma cells.[61] Thus, the inhibition of this interaction through APG101 reduces tumor cell growth and migration. A randomized, double-blind, placebo-controlled phase I study with 34 healthy volunteers to examine the safety and tolerability of APG101 has shown that it is well tolerated.[62] The efficacy of APG101 was tested in a randomized controlled phase II trial with patients suffering from GBM. The study was initiated at the end of 2009 and first results were released in 2012. A total of 83 patients with first or second relapse of GBM were enrolled in the successful trial. The primary goal of doubling the number of patients reaching progression-free survival at six months (PFS6) was substantially exceeded.[63] No drug-related serious adverse events were observed during treatment with APG101 for up to two years.[64]

Immunotherapy

Relapse of glioblastoma is attributed to the recurrence and persistence of tumor stem cells.[65] In a small trial, a tumor B-cell hybridoma vaccine against tumor stem cells elicited a specific tumor immune reaction thus enhancing immune response to the disease.[66] Larger trials, including tests of different EGFR signaling patterns and their relationship to tumor stem cells being conducted by John A. Boockvar's lab at Weill Cornell Medical College, are in progress to further assess this approach to treating glioblastoma.

Prognosis

The median survival time from the time of diagnosis without any treatment is 3 months, but with treatment survival of 1–2 years is common. Increasing age (> 60 years of age) carries a worse prognostic risk. Death is usually due to cerebral edema or increased intracranial pressure.[67]

A good initial Karnofsky Performance Score (KPS) and MGMT methylation are associated with longer survival.[67] A DNA test can be conducted on glioblastomas to determine whether or not the promoter of the MGMT gene is methylated. Patients with a methylated MGMT promoter have been associated with significantly greater long-term benefit than patients with an unmethylated MGMT promoter.[68] This DNA characteristic is intrinsic to the patient and currently cannot be altered externally. Another positive prognostic marker for glioblastoma patients is mutation of the IDH1 gene,[2] which can be tested by DNA-based methods or by immunohistochemistry using an antibody against the most common mutation, namely IDH1-R132H.[69]

More prognostic power can be obtained by combining the mutational status of IDH1 and the methylation status of MGMT into a two-gene predictor. Patients with both IDH1 mutations and MGMT methylation have the longest survival, patients with an IDH1 mutation or MGMT methylation an intermediate survival and patients without either genetic event have the shortest survival.[70]

Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy.[67] However, much remains unknown about why some patients survive longer with glioblastoma. Age of under 50 is linked to longer survival in glioblastoma multiforme, as is 98%+ resection and use of temozolomide chemotherapy and better Karnofsky performance scores. A recent study confirms that younger age is associated with a much better prognosis, with a small fraction of patients under 40 years of age achieving a population-based cure. The population-based cure is thought to occur when a population's risk of death returns to that of the normal population, and in GBM, this is thought to occur after 10 years.[71]

UCLA Neuro-Oncology publishes real-time survival data for patients with this diagnosis.[72] They are the only institution in the United States that shows how their patients are performing. They also show a listing of chemotherapy agents used to treat GBM tumors. Despite a poor prognosis, there is a small number of survivors who have been GBM free for more than 10–20 years.

According to a 2003 study, glioblastoma multiforme prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.[73]

Recursive partitioning analysis
(RPA) class		 Definition Historical Median Survival Time Historical 1-Year Survival Historical 3-Year Survival Historical 5-Year Survival
III Age < 50, KPS ≥ 90 17.1 months 70% 20% 14%
IV Age < 50, KPS < 90 11.2 months 46% 7% 4%
Age > 50, KPS ≥ 70, surgical removal with good neurologic function
V + VI Age ≥ 50, KPS ≥ 70, surgical removal with poor neurologic function 7.5 months 28% 1% 0%
Age ≥ 50, KPS ≥ 70, no surgical removal
Age ≥ 50, KPS < 70

History

The term glioblastoma multiforme was introduced in 1926 by Percival Bailey and Harvey Cushing, based on the idea that the tumor originates from primitive precursors of glial cells (glioblasts), and the highly variable appearance due to the presence of necrosis, hemorrhage and cysts (multiform).[74]

Research

A 2014 investigation made a screening of various drugs for anti-glioblastoma activity and identified 22 drugs with potent anti-glioblastoma activity, including the combination of irinotecan and statins.[75]

Laboratory research using genetically engineered stem cells to target glioblastomas in mice was reported in 2014 to show promise.[76]

A Tumor Treating Fields device was approved by the U.S. Food and Drug Administration (FDA) in April 2011 on the basis of clinical trials that appeared to demonstrate efficacy in the treatment of recurring glioblastoma multiforme (GBM).[77]

See also

References

  1. ^ "Glioblastoma and Malignant Astrocytoma" (PDF). American Brain Tumour Association (ABTA). Retrieved 4 September 2014. Glioblastoma or glioblastoma multiforme ("multiforme" is no longer part of the WHO designation, though glioblastoma is still often abbreviated "GBM") is the highest grade glioma (grade IV) tumor, is the most malignant form of astrocytoma, and is synonymous with a grade IV glioma.
  2. ^ a b c Bleeker, Fonnet E.; Molenaar, Remco J.; Leenstra, Sieger (2012). "Recent advances in the molecular understanding of glioblastoma". Journal of Neuro-Oncology. 108 (1): 11–27. doi:10.1007/s11060-011-0793-0. PMC 3337398. PMID 22270850.
  3. ^ Johnson, Derek R.; O'Neill, Brian Patrick (2011). "Glioblastoma survival in the United States before and during the temozolomide era". Journal of Neuro-Oncology. 107 (2): 359–64. doi:10.1007/s11060-011-0749-4. PMID 22045118.
  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.
  5. ^ Ohgaki, Hiroko; Kleihues, Paul (2005). "Population-Based Studies on Incidence, Survival Rates, and Genetic Alterations in Astrocytic and Oligodendroglial Gliomas". Journal of Neuropathology & Experimental Neurology. 64 (6): 479–89. PMID 15977639.
  6. ^ Zheng, Tongzhang; Cantor, Kenneth P.; Zhang, Yawei; Chiu, Brian C. H.; Lynch, Charles F. (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.
  7. ^ Wheeler, Lamar; Huncharek, Michael; Kupelnick, Bruce (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. PMID 14533876.
  8. ^ 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.
  9. ^ 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.
  10. ^ Kan, Peter; Simonsen, Sara E.; Lyon, Joseph L.; Kestle, John R. W. (2007). "Cellular phone use and brain tumor: A meta-analysis". Journal of Neuro-Oncology. 86 (1): 71–8. doi:10.1007/s11060-007-9432-1. PMID 17619826.
  11. ^ Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell (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.
  12. ^ Baglietto, Laura; Giles, Graham G.; English, Dallas R.; Karahalios, Amalia; Hopper, John L.; Severi, Gianluca (2011). "Alcohol consumption and risk of glioblastoma; evidence from the Melbourne collaborative cohort study". International Journal of Cancer. 128 (8): 1929. doi:10.1002/ijc.25770.
  13. ^ Vilchez, Regis A; Kozinetz, Claudia A; Arrington, Amy S; Madden, Charles R; Butel, Janet S (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.
  14. ^ Crawford, JR; Santi, MR; Thorarinsdottir, HK; Cornelison, R; Rushing, EJ; Zhang, H; Yao, K; Jacobson, S; MacDonald, TJ (2009). "Detection of human herpesvirus-6 variants in pediatric brain tumors: Association of viral antigen in low grade gliomas". Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 46 (1): 37–42. doi:10.1016/j.jcv.2009.05.011. PMC 2749001. PMID 19505845.
  15. ^ Chi, J.; Gu, B.; Zhang, C.; Peng, G.; Zhou, F.; Chen, Y.; Zhang, G.; Guo, Y.; et al. (2012). "Human Herpesvirus 6 Latent Infection in Patients with Glioma". Journal of Infectious Diseases. 206 (9): 1394–8. doi:10.1093/infdis/jis513. PMID 22962688.
  16. ^ "Target acquired", The Economist, May 29th, 2008
  17. ^ Cavenee, WK (2000). "High-grade gliomas with chromosome 1p loss". Journal of neurosurgery. 92 (6): 1080–1. doi:10.3171/jns.2000.92.6.1080. PMID 10839286.
  18. ^ http://www.brain-cancer-net.org/pvc-poly-vinyl-chloride.htm[full citation needed]
  19. ^ 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.
  20. ^ 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.
  21. ^ Pritchett, Joshua C.; Nanau, Radu M.; Neuman, Manuela G. (2012). "The Link between Hypersensitivity Syndrome Reaction Development and Human Herpes Virus-6 Reactivation". International Journal of Hepatology. 2012: 1. doi:10.1155/2012/723062. PMC 3362035. PMID 22666603.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Glioblastoma multiforme at Mount Sinai
  23. ^ [1]
  24. ^ Verhaak, Roel G. W.; Hoadley, Katherine A.; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D.; Miller, C. Ryan; Ding, Li; et al. (January 2010). "Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1". Cancer Cell. 17 (1): 98–110. doi:10.1016/j.ccr.2009.12.020. PMC 2818769. PMID 20129251.
  25. ^ Hayden, Erika Check (2010). "Genomics boosts brain-cancer work". Nature. 463 (7279): 278. doi:10.1038/463278a. PMID 20090720.
  26. ^ Kuehn, Bridget M. (2010). "Genomics Illuminates a Deadly Brain Cancer". JAMA. 303 (10): 925–7. doi:10.1001/jama.2010.236. PMID 20215599.
  27. ^ Bleeker, FE; Lamba, S; Zanon, C; Molenaar, RJ; Hulsebos, TJ; Troost, D; van Tilborg, AA; Vandertop, WP; Leenstra, S; van Noorden, CJ; Bardelli, A (26 September 2014). "Mutational profiling of kinases in glioblastoma". BMC cancer. 14: 718. PMID 25256166.
  28. ^ a b Molenaar, RJ; Verbaan, D; Lamba, S; Zanon, C; Jeuken, JW; Boots-Sprenger, SH; Wesseling, P; Hulsebos, TJ; Troost, D; van Tilborg, AA; Leenstra, S; Vandertop, WP; Bardelli, A; van Noorden, CJ; Bleeker, FE (September 2014). "The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone". Neuro-oncology. 16 (9): 1263–73. PMID 24510240.
  29. ^ a b Molenaar, RJ; Radivoyevitch, T; Maciejewski, JP; van Noorden, CJ; Bleeker, FE (28 May 2014). "The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation". Biochimica et biophysica acta. 1846 (2): 326–341. PMID 24880135.
  30. ^ Hegi, Monika E.; Diserens, Annie-Claire; Gorlia, Thierry; Hamou, Marie-France; De Tribolet, Nicolas; Weller, Michael; Kros, Johan M.; Hainfellner, Johannes A.; et al. (2005). "MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma". New England Journal of Medicine. 352 (10): 997–1003. doi:10.1056/NEJMoa043331. PMID 15758010.
  31. ^ 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.
  32. ^ 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.
  33. ^ Park, Deric M.; Jung, Jinkyu; Masjkur, Jimmy; Makrogkikas, Stylianos; Ebermann, Doreen; Saha, Sarama; Rogliano, Roberta; Paolillo, Nicoletta; Pacioni, Simone; McKay, Ron D.; Poser, Steve; Androutsellis-Theotokis, Andreas (2013). "Hes3 regulates cell number in cultures from glioblastoma multiforme with stem cell characteristics". Scientific Reports. 3: 1095. Bibcode:2013NatSR...3E1095P. doi:10.1038/srep01095. PMC 3566603. PMID 23393614.
  34. ^ van Lith, SA; Navis, AC; Verrijp, K; Niclou, SP; Bjerkvig, R; Wesseling, P; Tops, B; Molenaar, R; van Noorden, CJ; Leenders, WP (August 2014). "Glutamate as chemotactic fuel for diffuse glioma cells: are they glutamate suckers?". Biochimica et biophysica acta. 1846 (1): 66–74. PMID 24747768.
  35. ^ van Lith, SA; Molenaar, R; van Noorden, CJ; Leenders, WP (December 2014). "Tumor cells in search for glutamate: an alternative explanation for increased invasiveness of IDH1 mutant gliomas". Neuro-oncology. 16 (12): 1669–70. PMID 25074540.
  36. ^ Molenaar, Remco J. (2011). "Ion Channels in Glioblastoma". ISRN Neurology. 2011: 1. doi:10.5402/2011/590249. PMC 3263536. PMID 22389824.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  37. ^ 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.
  38. ^ Weerakkody, Yuranga; Gaillard, Frank. "Glioblastoma". Radiopaedia.org. Retrieved 13 September 2014.
  39. ^ Bleeker, FE; Molenaar, RJ; Leenstra, S (May 2012). "Recent advances in the molecular understanding of glioblastoma". Journal of neuro-oncology. 108 (1): 11–27. PMID 22270850.
  40. ^ . PMID 24880135. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  41. ^ Lawson, H. Christopher; Sampath, Prakash; Bohan, Eileen; Park, Michael C.; Hussain, Namath; Olivi, Alessandro; Weingart, Jon; Kleinberg, Lawrence; Brem, Henry (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.
  42. ^ Stevens, Glen H. J. (2006). "Antiepileptic therapy in patients with central nervous system malignancies". Current Neurology and Neuroscience Reports. 6 (4): 311–8. doi:10.1007/s11910-006-0024-9. PMID 16822352.
  43. ^ 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.
  44. ^ Stummer, Walter; Pichlmeier, Uwe; Meinel, Thomas; Wiestler, Otmar Dieter; Zanella, Friedhelm; Reulen, Hans-Jürgen; 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. {{cite journal}}: |first7= has generic name (help)
  45. ^ 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.
  46. ^ Showalter, Timothy N.; Andrel, Jocelyn; Andrews, David W.; Curran, Walter J.; Daskalakis, Constantine; Werner-Wasik, Maria (2007). "Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression". International Journal of Radiation Oncology*Biology*Physics. 69 (3): 820–4. doi:10.1016/j.ijrobp.2007.03.045. PMID 17499453.
  47. ^ Fulton, DS; Urtasun, RC; Scott-Brown, I; Johnson, ES; Mielke, B; Curry, B; Huyser-Wierenga, D; Hanson, J; Feldstein, M (1992). "Increasing radiation dose intensity using hyperfractionation in patients with malignant glioma. Final report of a prospective phase I-II dose response study". Journal of Neuro-Oncology. 14 (1): 63–72. doi:10.1007/BF00170946. PMID 1335044.
  48. ^ Sheehan, Jason P; Shaffrey, Mark E; Gupta, Brinda; Larner, James; Rich, Jeremy N; Park, Deric M (2010). "Improving the radiosensitivity of radioresistant and hypoxic glioblastoma". Future Oncology. 6 (10): 1591–601. doi:10.2217/fon.10.123. PMID 21062158.
  49. ^ Clinical trial number NCT01465347 for "Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) With Concomitant Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM)" at ClinicalTrials.gov
  50. ^ 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): 987–96. doi:10.1056/NEJMoa043330. PMID 15758009.
  51. ^ 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 (1): 37–52. doi:10.1017/S1748232105000054. ISBN 978-0-521-86253-0.
  52. ^ "Temozolomide Plus Radiation Helps Brain Cancer – National Cancer Institute". Retrieved 2007-09-15.[dead link]
  53. ^ 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.
  54. ^ Dall’Oglio, Stefano; d’Amico, Anna; Pioli, Fabio; Gabbani, Milena; Pasini, Felice; Passarin, Maria Grazia; Talacchi, Andrea; Turazzi, Sergio; Maluta, Sergio (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.
  55. ^ Khasraw, M; Ameratunga, MS; Grant, R; Wheeler, H; Pavlakis, N (Sep 22, 2014). "Antiangiogenic therapy for high-grade glioma". The Cochrane database of systematic reviews. 9: CD008218. doi:10.1002/14651858.CD008218.pub3. PMID 25242542.
  56. ^ Fulci, Giulia; Chiocca, E 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.
  57. ^ Tai, C; Wang, W; Chen, T; Kasahara, N (2005). "Single-Shot, Multicycle Suicide Gene Therapy by Replication-Competent Retrovirus Vectors Long-Term Survival Benefit in Experimental Glioma". Molecular Therapy. 12 (5): 842–51. doi:10.1016/j.ymthe.2005.03.017. PMID 16257382.
  58. ^ Clinical trial number NCT01156584 for "A Study of a Retroviral Replicating Vector Administered to Subjects With Recurrent Malignant Glioma" at ClinicalTrials.gov
  59. ^ Møller, Heidi G.; Rasmussen, Andreas P.; Andersen, Hjalte H.; Johnsen, Kasper B.; Henriksen, Michael; Duroux, Meg (2012). "A Systematic Review of MicroRNA in Glioblastoma Multiforme: Micro-modulators in the Mesenchymal Mode of Migration and Invasion". Molecular Neurobiology. 47 (1): 131–44. doi:10.1007/s12035-012-8349-7. PMC 3538124. PMID 23054677.
  60. ^ Niyazi, Maximilian; Zehentmayr, Franz; Niemöller, Olivier M; Eigenbrod, Sabina; Kretzschmar, Hans; Osthoff, Klaus-Schulze; Tonn, Jörg-Christian; Atkinson, Mike; Mörtl, Simone; Belka, Claus (2011). "MiRNA expression patterns predict survival in glioblastoma". Radiation Oncology. 6: 153. doi:10.1186/1748-717X-6-153. PMC 3235977. PMID 22074483.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  61. ^ Kleber, Susanne; Sancho-Martinez, Ignacio; Wiestler, Benedict; Beisel, Alexandra; Gieffers, Christian; Hill, Oliver; Thiemann, Meinolf; Mueller, Wolf; et al. (2008). "Yes and PI3K Bind CD95 to Signal Invasion of Glioblastoma". Cancer Cell. 13 (3): 235–48. doi:10.1016/j.ccr.2008.02.003. PMID 18328427.
  62. ^ Tuettenberg, Jochen; Seiz, Marcel; Debatin, Klaus-Michael; Hollburg, Wiebke; Von Staden, Michael; Thiemann, Meinolf; Hareng, Barbara; Fricke, Harald; Kunz, Claudia (2012). "Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients". International Immunopharmacology. 13 (1): 93–100. doi:10.1016/j.intimp.2012.03.004. PMID 22446296.
  63. ^ Apogenix drug candidate APG101 reaches primary goal inPhase II brain cancer trial, http://www.pharmatopics.com/2012/03/apogenix-drug-candidate-apg101-reaches-primary-goal-in-phase-ii-brain-cancer-trial/[full citation needed]
  64. ^ APG101 ExceedsExpectations with Controlled Phase II Clinical Trial in Treatment of RecurrentGlioblastoma, http://apogenix.com/fileadmin/media/pdf/press_releases_english/120726_Secondary_Endpoints_GBM_en_final.pdf[full citation needed]
  65. ^ 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.
  66. ^ 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.
  67. ^ a b c 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 (10): 2596–606. doi:10.1093/brain/awm204.
  68. ^ 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.
  69. ^ M. Preusser, A. Wöhrer, S. Stary, R. Höftberger, B. Streubel, J. A. Hainfellner: Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens. In: J Neuropathol Exp Neurol. 2011 Aug;70(8), S. 715–723. doi:10.1097/NEN.0b013e31822713f0
  70. ^ Molenaar, Remco J. (2014). "The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone". Neuro-Oncology. doi:10.1093/neuonc/nou005. PMID 24510240.
  71. ^ Smoll, Nicolas R.; Schaller, Karl; Gautschi, Oliver P. (2012). "The Cure Fraction of Glioblastoma Multiforme". Neuroepidemiology. 39 (1): 63–9. doi:10.1159/000339319. PMID 22776797.
  72. ^ University of California, Los Angeles Neuro-Oncology : How Our Patients Perform : Glioblastoma Multiforme [GBM]. Neurooncology.ucla.edu. Retrieved on 2010-10-19.
  73. ^ Shaw, E.G; 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 Oncology*Biology*Physics. 57 (2): S135–6. doi:10.1016/S0360-3016(03)00843-5.
  74. ^ Bailey & Cushing: Tumors of the Glioma Group JB Lippincott, Philadelphia, 1926.[page needed]
  75. ^ Jiang PF (Jan 2014). "Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs". J Transl Med. 12. doi:10.1186/1479-5876-12-13. PMC 3898565. PMID 24433351.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  76. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/stem.1874, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/stem.1874 instead.
  77. ^ http://www.cancer.gov/clinicaltrials/search/view?cdrid=647437&version=HealthProfessional&protocolsearchid=8237659
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