Glioblastoma multiforme

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Glioblastoma multiforme
Classification and external resources

Coronal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old male.
ICD-10 C71
ICD-9 191
ICD-O: M9440/3
OMIM 137800
DiseasesDB 29448
eMedicine neuro/147 med/2692
MeSH D005909

Glioblastoma multiforme (GBM), WHO classification name "glioblastoma", 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 rare, with incidence of 2–3 cases per 100,000 in Europe and North America. 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.[1] Median survival without treatment is 4½ months. Although no randomized controlled trials have been done, surgery remains the standard of care.[2]

Signs and symptoms

Main article: Brain tumor

Although common symptoms of the disease include seizure, nausea and vomiting, headache, 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.

Causes

For unknown reasons, GBM occurs more commonly in males.[3] Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking,[4] consumption of cured meat,[5] or electromagnetic fields.[6][7][8][9] Alcohol consumption may be a possible risk factor.[10] Glioblastoma has been associated with the viruses SV40,[11] HHV-6,[12][13] and cytomegalovirus.[14] There also appears to be a small link between ionizing radiation and glioblastoma.[15] Some also believe that there may be a link between polyvinyl chloride (which is commonly used in construction) and glioblastoma.[16] A 2006 analysis links brain cancer to lead exposure in the work-place.[17] 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[18] or that the immunosuppression associated with malaria could enhance viral replication. Also HHV-6 reactivates in response to hypersensitivty reactions from drugs and environmental chemicals.[19]

Other risk factors include:[20]

  • Sex: male (slightly more common in men than women)
  • Age: over 50 years old
  • Ethnicity: Caucasians, Asians
  • Having a low-grade astrocytoma (brain tumor), which often, given enough time, develops into a higher-grade tumor
  • Having one of the following genetic disorders is associated with an increased incidence of gliomas:

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.

There are four subtypes of glioblastoma.[21] 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.[22] 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 IDHl, the gene encoding isocitrate dehydrogenase-1. The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding Neurofibromatosis type 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types.[23] 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. Glioblastomas have alterations in 64-87%, 68-78% and 88% of these pathways, respectively.[24] Another important alteration is methylation of MGMT, a DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. Indeed, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.[25]

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).[26] 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.

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 reoccurrence rate).[27]

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.[28]

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.[29]

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.[30] 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 may add value to standard MRI in the diagnosis of glioblastoma, but pathology remains the gold standard.[citation needed]

Treatment

It is very difficult to treat glioblastoma due to several complicating factors:[31]

  • 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.[32] 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.[33] 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.[34] 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.[35] 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.[36] A total radiation dose of 60–65 Gy has been found to be optimal for treatment.[37]

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[38] and a clinical trial is currently underway.[39]

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

Chemotherapy

In other cancers where radiation can prolong survival or even cure tumors, the addition of chemotherapy to radiation improves survival over radiation treatment alone. Examples include cervical cancer, throat cancer and others. Because of this, several large clinical trials took place in which it was hoped survival of GBM patients might be improved with the addition of chemotherapy to radiation. Most of these studies showed 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.[40] This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial.[41][42] Temozolomide seems to work by sensitizing the tumor cells to radiation.[43]

High doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses.[44]

The U.S. Food and Drug Administration approved Avastin (bevacizumab) to treat patients with glioblastoma at progression after standard therapy based on the results of two studies that showed Avastin reduced tumor size in some glioblastoma patients. In the first study, 28% of glioblastoma patients had tumor shrinkage, 38% survived for at least one year, and 43% survived for at least six months without their disease progressing.[45] Unlike the case for colon cancer, lung cancer and other cancers where bevacizumab acts by potentiating chemotherapy, the studies leading to approval showed that in GBM, the addition of chemotherapy to bevacizumab did not improve on results from bevacizumab alone. Bevacizumab reduces brain edema and consequent symptoms, and it may be that the benefit from this drug is due to its action against edema rather than any action against the tumor itself. Some patients with brain edema do not actually have any active tumor remaining, but rather develop the edema as a late effect of prior radiation treatment. This type of edema is difficult to distinguish from that due to tumor, and both may coexist. Both respond to bevacizumab.[citation needed]

In a letter to the editor of the New England Journal of Medicine on September 5, 2013, researchers from the Karolinska Institute in Stockholm, Sweden described "remarkably high" rates of survival using valganciclovir in 50 glioblastoma patients compared to 137 contemporary controls. Of these 50 patients, those with the best results "...received at least 6 months of therapy and thereafter received continuous treatment...."[46] These results support the conclusions of the HCMV (human cytomegalovirus) and Glioma Symposium which convened in Washington, DC on April 17, 2011. A summary of this symposium concludes that "...HCMV could serve as a novel target for a variety of therapeutic strategies...." and that "...existing evidence supports an oncomodulatory role for the HCMV in malignant gliomas...."[47]

Gene transfer

Gene transfer is a promising approach for fighting cancers including brain cancer.[48] 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.[49] 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.[50]

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.[51][52]

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.[53] 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.[54] 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.[55] No drug-related serious adverse events were observed during treatment with APG101 for up to two years.[56]

Immunotherapy

Relapse of glioblastoma is attributed to the recurrence and persistence of tumor stem cells.[57] 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.[58] 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.[59]

A good initial Karnofsky Performance Score (KPS) and MGMT methylation are associated with longer survival.[59] 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.[60] This DNA characteristic is intrinsic to the patient and currently cannot be altered externally.

Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy.[59] 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.[61]

UCLA Neuro-Oncology publishes real-time survival data for patients with this diagnosis.[62] 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.

According to a 2003 study, glioblastoma multiforme prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.[63]

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).[64]

References

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  3. ↑ 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. 
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  34. ↑ 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. 
  35. ↑ 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. 
  36. ↑ 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. 
  37. ↑ 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 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. 
  38. ↑ 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. 
  39. ↑ ClinicalTrials.gov NCT01465347 Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) With Concomitant Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM)
  40. ↑ 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. 
  41. ↑ 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. 
  42. ↑ "Temozolomide Plus Radiation Helps Brain Cancer – National Cancer Institute". Retrieved 2007-09-15. 
  43. ↑ 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. 
  44. ↑ 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. 
  45. ↑ "FDA Approves Drug for Treatment of Aggressive Brain Cancer" (Press release). Food and Drug Administration. May 8, 2009. Retrieved August 14, 2013. 
  46. ↑ Soderberg-Naucler C, Rahbar A, & Stragliotto G. Survival in Patients with Glioblastoma receiving Valganciclovir. New England Journal of Medicine 2013;369:10-11.
  47. ↑ Dziurynski K et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro-Oncology 2012;14:246-255.
  48. ↑ 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. 
  49. ↑ 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. 
  50. ↑ ClinicalTrials.gov NCT01156584 A Study of a Retroviral Replicating Vector Administered to Subjects With Recurrent Malignant Glioma
  51. ↑ 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. 
  52. ↑ Niyazi, Maximilian; Zehentmayr, Franz; Niemöller, Olivier M; Eigenbrod, Sabina; Kretzschmar, Hans; Osthoff, Klaus-Schulze; Tonn, Jörg-Christian; Atkinson, Mike et al. (2011). "MiRNA expression patterns predict survival in glioblastoma". Radiation Oncology 6: 153. doi:10.1186/1748-717X-6-153. PMC 3235977. PMID 22074483. 
  53. ↑ 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. 
  54. ↑ Tuettenberg, Jochen; Seiz, Marcel; Debatin, Klaus-Michael; Hollburg, Wiebke; Von Staden, Michael; Thiemann, Meinolf; Hareng, Barbara; Fricke, Harald et al. (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. 
  55. ↑ 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/[]
  56. ↑ 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[]
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  58. ↑ 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. 
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  60. ↑ 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. 
  61. ↑ 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. 
  62. ↑ University of California, Los Angeles Neuro-Oncology : How Our Patients Perform : Glioblastoma Multiforme [GBM]. Neurooncology.ucla.edu. Retrieved on 2010-10-19.
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  64. ↑ Bailey & Cushing: Tumors of the Glioma Group JB Lippincott, Philadelphia, 1926.

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Nervous tissue tumors/NS neoplasm/Neuroectodermal tumor (ICD-O 9350–9589) (C70–C72, D32–D33, 191–192/225)
Endocrine/
Sellar (9350–9379)
Sellar:
Other:
CNS
(9380–9539)
Neuroepithelial
(brain tumors,
spinal tumors)
Glioma
Astrocyte
Oligodendrocyte
Ependyma
Choroid plexus
Multiple/unknown
Mature
neuron
PNET
Primitive
Meningiomas
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Hematopoietic
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Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis).

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