Glioblastoma

from Wikipedia, the free encyclopedia
Classification according to ICD-10
C71 Malignant neoplasm of the brain
C71.0 Cerebrum, excluding lobes and ventricles
C71.1 Frontal lobes
C71.2 Temporal lobe
C71.3 Parietal lobes
C71.4 Occipital lobe
C71.5 Cerebral ventricle
C71.6 cerebellum
C71.7 Brain stem
C71.8 Brain, overlapping several areas
C71.9 Brain, unspecified
ICD-10 online (WHO version 2019)

The glioblastoma (also glioblastoma multiforme ) is the most common malignant brain tumor in adults. Glioblastoma has tissue similarities to the glial cells of the brain and is classified as grade IV according to the WHO classification of tumors of the central nervous system due to the very poor prognosis . Treatment consists of surgical reduction of the tumor mass, radiation and chemotherapy . A definitive cure cannot currently be achieved. The mean survival time is a few months without treatment and around 15 months with current therapy methods. Some sufferers survive longer, but only a few survive for several years. In some rare cases, those affected have even survived for over 20 years. The U87MG glioblastoma cell line was the first cancer cell line to have its genome completely sequenced .

Historical

The term glioblastoma multiforme was coined in 1926 by Percival Bailey and Harvey Cushing . The concept was based on the idea that the tumor develops from primitive precursors of glial cells (glioblasts), as well as the observation that the appearance with necrosis, hemorrhages and cysts can be very variable (multiform). The term Spongioblastoma multiforme , which was used by the pathologist Frank Burr Mallory as early as 1914, could not gain acceptance.

distribution

Glioblastomas are the most common malignant brain tumors in adults. Among the ( neuroepithelial ) tumors that arise from brain tissue, they account for around half of all cases. The tumor is most common in older adults between the ages of 60 and 70; the average age at diagnosis is 64 years. Men are affected significantly more often than women (ratio 1.7: 1). Data from the American brain tumor registry show that glioblastomas are at least twice as common in whites as in the black population. Compared to adults, glioblastomas in children are very rare. The incidence in Europe and North America has been found to be 2.9 to 3.5 new cases per year per 100,000 population and is lower in developing countries. The only established causal ( etiological ) environmental factor is currently exposure to ionizing radiation .

The majority of glioblastomas are sporadic cases with no evidence of heredity. However, in certain rare hereditary diseases , including Li-Fraumeni syndrome or Turcot syndrome , glioblastomas can occur more frequently in families.

Disease emergence

Glioblastomas can arise completely new ( de novo ) or through progressive dedifferentiation from less malignant astrocytomas . It is therefore not uncommon for astrocytomas that have been treated to manifest themselves as glioblastomas when they relapse . These so-called secondary glioblastomas are more likely to occur in younger patients and have a different spectrum of genetic changes than newly developed ones (see molecular pathology ). In an epidemiological study carried out in Switzerland, primary glioblastomas in the canton of Zurich were about twenty times more common than secondary ones .

localization

MRI with contrast agents of a glioblastoma in a 15-year-old boy; In the coronal incision, the space-occupying effect on the displacement of the midline ( falx cerebri ) can be clearly seen.

The glioblastoma starts from the white matter . By far its most common location is the cerebrum , where it can arise in all cerebral lobes, but prefers the frontal and temporal lobes . In the area of the cerebellum , brain stem and spinal cord glioblastomas are rare. Hemispheric glioblastomas often grow over the bar to the other side. Such tumors are called "butterfly gliomas". Glioblastoma growth is diffuse infiltrating.

Clinical manifestations

Because of the rapid growth, the symptoms usually develop quickly within a few weeks to months. The first symptoms can be persistent and unaccustomed headaches , but also new epileptic seizures. Focal neurological deficits such as paralysis , aphasia and visual disturbances can also occur depending on the location. After all, it is often noticeable personality changes, apathy or psychomotor slowdown that lead the patient to the doctor. Signs of intracranial pressure such as papillae , vomiting , somnolence and coma occur late and are prognostically unfavorable.

Investigation methods

The diagnosis is initially supported by imaging procedures such as computed tomography (CT) or magnetic resonance imaging (MRT). On CT imaging with contrast agent , the glioblastoma appears irregularly shaped with strong contrast agent absorption at the edges (ring-shaped enhancement ). In the case of smaller tumors, this is configured in a ring shape, in the case of larger tumors it forms a garland-like formation. Significant edema typically forms around the tumor . The MRI findings are quite typical: the solid parts of the glioblastoma strongly enrich the contrast medium, on the other hand the recesses stand out due to the cystic parts and the bleeding. Ultimately, the diagnosis is confirmed neuropathologically on the tumor tissue obtained from a stereotactic brain biopsy or tumor resection . In individual cases, supplementary examinations such as electroencephalography and lumbar puncture are carried out, which are used to assess the tendency to seizures or to differentiate between brain abscesses and lymphomas for differential diagnosis .

pathology

Glioblastoma (Macroscopic Specimen). Coronal section of a formalin-fixed brain. The tumor appears as a gray-red, partly necrotic area of ​​the left temporal and frontal lobe. The tumor has also spread into the bars (center of the image, dark gray area).

The glioblastoma is characterized by its inhomogeneous and diverse (hence: multiforme ) appearance: the cut surface of the tumor often shows reddish hemorrhages and yellowish tissue deposits ( necroses ).

histology

Glioblastoma (histological specimen with typical line-shaped necroses and palisade-like arrangement of pleomorphic tumor cells around the necroses) ( hematoxylin-eosin staining )

In terms of fine tissue ( histologically ), these are cell-dense, astrocytically differentiated tumors that diffusely infiltrate the surrounding, reactively altered brain tissue. The tumor cells are fibrillar-astrocytic differentiated with multipolar fine processes or have a fattened cell differentiation with an inflated cytoplasm . Giant cells with bizarre nuclei or small-cell areas with less extensive cell bodies also occur. The cell nuclei are usually rich in chromatin and diverse (polymorphic). Mitotic and proliferative activity are increased.

According to the WHO classification of tumors of the central nervous system , the decisive factor for the diagnosis of glioblastoma (and the differentiation from anaplastic astrocytoma ) is, however, the detection of tumor necrosis (extensive or typically line-shaped with an increase in perifocal cell density) or highly pathological blood vessels.

variants

In Gliosarkomen is glioblastomas, in addition to the above-described astrocytic tumor proportions also in connective tissue sarcomatous have portions with spindle cell tumor cells. As giant cell glioblastomas glioblastomas are designated with a pronounced riesenzelligen component. Glioblastomas with oligodendroglial components, which may have a slightly more favorable prognosis, must also be distinguished.

Immunohistochemistry

Immunohistochemical staining of tumor cells for GFAP

Immunohistochemistry is in the tumor cells - as in those of other glial brain tumors - the glial fibrillary acidic protein ( glial fibrillary acidic protein , GFAP ) detectable, the differentiation from in most cases brain metastases allowed.

Molecular pathology

Immunohistochemical staining for p53 . Accumulation of (defective) p53 protein in the tumor cell nuclei of a secondary glioblastoma with mutation of the TP53 gene. The nuclei of affected blood vessel wall cells are unstained.
Immunohistochemical staining with an antibody directed against mutated IDH1 protein. Expression of mutated IDH1 protein in tumor cells of a secondary glioblastoma with a known mutation of the IDH1 gene (R132H). The nuclei of affected blood vessel wall cells are unstained.

The gene losses ( deletions ) that make up the glioblastoma affect in most cases the tumor suppressor gene TP53 ( chromosome 17 ), the retinoblastoma suppressor gene RB-1 ( chromosome 13 ) and deletions of chromosome 22 as well as the complete loss of the long arm of the chromosome 10 . These genetic damage are often combined. In the case of newly developed primary glioblastomas, which predominantly occur in older patients, there is more frequent loss of the PTEN gene or amplification of the EGFR gene. In secondary glioblastomas, which predominantly occur in middle age and which are the result of a gradual progression from less malignant (less malignant) astrocytomas, mutations of the TP53 gene are often present. In addition, point mutations in IDH1 and IDH2 genes coding for an isocitrate dehydrogenase are more common in this group, especially the R132H mutation in the IDH1 gene. The most common mutation (IDH-R132H) can be reliably detected by immunohistochemistry using a specific antibody. A mutation in the IDH gene is particularly relevant for the prognosis, since patients with an IDH mutation have a survival advantage over patients with the wild-type variant.

The rare childhood glioblastomas differ in the pattern of genetic changes from the tumors occurring in adults: mutations in the H3F3A gene play a major role here. On the basis of genetic and epigenetic changes, a classification of glioblastomas into six subgroups was proposed in 2012.

treatment

Short-term clinical improvement can be achieved by treating the perifocal cerebral edema , which is practically always present, with corticosteroids . The neurosurgical operation with reduction of the main mass of the tumor (tumor reduction) can slow down the progression of the disease, but not prevent it permanently, since almost always individual tumor cells have already infiltrated the healthy brain tissue and therefore complete removal of the tumor is not possible. An innovative procedure in addition to the neurosurgical treatment of malignant brain tumors (e.g. glioblastoma) is fluorescence-assisted surgery with 5-aminolevulinic acid (5-ALA). About four hours before the operation, the patient receives an endogenous substance (5-ALA) as a drinking solution, which accumulates in the brain tumor and is converted into a fluorescent dye there. During the operation, this dye can be stimulated to glow (fluorescence) by blue-violet light (wavelength 410 to 440 nm), so that the tumor (dark blue) can be clearly differentiated from healthy brain tissue (pink). With this procedure, a largely complete removal of the tumors is much safer and more effective. This leads to an increase in the time it takes for these tumors to grow back (recurrence-free interval), which significantly improves the prognosis of this disease. The procedure was developed in 2004 in Düsseldorf and Munich and is used in many German clinics. To extend the recurrence-free and absolute survival time, the operation is practically always followed by radiation and often chemotherapy , in particular patients with evidence of epigenetic changes (hypermethylation) of the promoter of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) from chemotherapy with cytostatic drug benefit. For patients with newly diagnosed glioblastoma and methylated MGMT promoters, a combination of CCNU and temozolomide as well as radiation therapy has been used in first-line therapy since 2017. Other chemotherapeutic agents that are used, among other things, in the event of a relapse are nitrosoureas , vinca alkaloids , fotemustine and cytosine arabinoside , whereby various treatment schemes are in use. It is still unclear which patients can benefit from local chemotherapy with implantation of carmustine bound to polymers .

Another method of glioblastoma treatment is tumor therapy fields . Weak alternating electrical fields in a medium frequency range (200 kHz for glioblastoma) are directed onto the diseased area of ​​the body via external electrodes. The aim is to inhibit the growth of cancerous tumors. They are a supplement to the Stupp protocol for the initial diagnosis.

Clinical studies

The development of new forms of treatment for glioblastoma is the subject of intensive research. In February 2013, 257 clinical trials were registered as active or in preparation on Clinicaltrials.gov, a registry of the United States National Library of Medicine . Tyrosine kinase receptors , such as the receptors for epidermal growth factor (EGFR) and platelet derived growth factor (PDGF), represent potential target molecules for new therapeutic approaches.

Treatment with bevacizumab , an antibody that neutralizes vascular endothelial growth factor (VEGF) , in combination with the topoisomerase inhibitor irinotecan did not improve overall survival in clinical studies , although individual patient groups may respond favorably to this treatment.

The therapy in a clinical study with APG101 , a fully human CD95-Fc fusion protein that prevents the binding of the CD95 ligand to the CD95 receptor, represents a novel treatment approach. It is based on findings from the German Cancer Research Center and the University Hospital Heidelberg , according to which the binding of the CD95 ligand to the CD95 receptor in glioblastoma cells stimulates the invasive growth and migration of tumor cells. A blockade of this binding by APG101 should therefore lead to a reduction in the invasive growth and migration of these cells. A phase I study with 34 healthy volunteers to investigate the safety and tolerability of APG101 showed that the substance was well tolerated. The potential effectiveness of APG101 was investigated in a randomized, controlled, phase II clinical trial in patients with GBM who had relapsed disease. Patient recruitment is complete. A total of 83 patients were treated as part of the clinical trial. The primary endpoint of the study, a doubling of the number of patients with progression-free survival after six months, was exceeded. No serious drug-related side effects were observed during treatment with APG101, which lasted up to two years.

Also gene therapy methods are being tested in clinical trials.

Another experimental approach is treatment with nanoparticles . These consist of an iron oxide core and a shell that is supposed to facilitate the penetration of the iron oxide particles into the cancer cells. The particles are directly into the tumor injected . The tumor , which has been enriched with iron oxide particles, which form a ferrofluid , is heated to over 46 ° C with alternating magnetic fields in several passes . In the animal model, the survival times were significantly improved. Study results in humans have been available since September 2010, and the therapy has been available since mid-2011.

In another research approach, as with other cancers, parvoviruses were used . Apart from a phase I / II study on 18 patients with glioblastomas from 2012, no further data have been published so far. A comparable approach is treatment with genetically modified, attenuated poliovirus ( PVS-RIPO ), which is still in an early experimental stage.

forecast

Glioblastoma is extremely difficult to treat. As a rule, a final cure has not yet been possible. Treatment with surgery, subsequent radiation and chemotherapy can, according to current studies, extend the mean survival time by a few months and alleviate symptoms. A 2003 study divided the prognosis into three groups based on the age of the patient, the type of treatment, and the Karnofsky Index (KPS) using Recursive Partitioning Analysis (RPA ).

RPA class definition Mean survival time 1 year survival rate 3 year survival rate 5 year survival rate
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 neurological function
V + VI Age ≥ 50, KPS ≥ 70, surgical removal with poor neurological function 7.5 months 28% 1 % 0%
Age ≥ 50, KPS ≥ 70, without surgery
Age ≥ 50, KPS <70

Because of the diffuse infiltration of the brain tissue by tumor cells, a relapse often occurs within months after treatment . Nevertheless, individual patients can live with glioblastoma for several years in relatively good health. The identification of clinical and molecular factors characteristic of such long-term survivors is the subject of intense research.

literature

Web links

Commons : Glioblastoma  - Collection of Images, Videos and Audio Files

Individual evidence

  1. ^ Derek R. Johnson, Brian Patrick O'Neill (2011): Glioblastoma survival in the United States before and during the temozolomide era. In: Journal of Neuro-Oncology , 107 (2): pp. 359-364. doi: 10.1007 / s11060-011-0749-4 . PMID 22045118 .
  2. ↑ D. Krex, B. Klink, C. Hartmann, A. von Deimling, T. Pietsch, M. Simon, M. Sabel, JP Steinbach et al. (2007): Long-term survival with glioblastoma multiforme. Brain 130 (10): pp. 2596-2606. doi: 10.1093 / brain / awm204 .
  3. ↑ S. Fukushima, Y. Narita, Y. Miyakita, M. Ohno, T. Takizawa, Y. Takusagawa, M. Mori, K. Ichimura, H. Tsuda, S. Shibui: A case of more than 20 years survival with glioblastoma, and development of cavernous angioma as a delayed complication of radiotherapy. In: Neuropathology: official journal of the Japanese Society of Neuropathology. Volume 33, number 5, October 2013, pp. 576-581, doi: 10.1111 / neup.12022 , PMID 23406431 .
  4. ^ FW Floeth, KJ Langen, G. Reifenberger, F. Weber: Tumor-free survival of 7 years after gene therapy for recurrent glioblastoma. Neurology 2003; 61: pp. 270-271.
  5. ^ Bailey, Cushing: Tumors of the Glioma Group. JB Lippincott, Philadelphia, 1926.
  6. ↑ Mallory: Principles of pathologic histology. Saunders Philadelphia, 1925.
  7. ↑ CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2006 full text (PDF; 14 kB)
  8. ↑ WK Cavenee et al .: glioblastoma , in: WHO Classification of Tumors. Lyon, IARC Press, 2000.
  9. ↑ American Brain Cancer Registry
  10. ↑ a b H. Ohgaki, P. Kleihues: Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005, 64 (6): 479-89; PMID 15977639 .
  11. ↑ T. Homma, T. Fukushima et al. a .: Correlation among pathology, genotype, and patient outcomes in glioblastoma. In: Journal of Neuropathology & Experimental Neurology , Volume 65, Number 9, September 2006, pp. 846-854. doi: 10.1097 / 01.jnen.0000235118.75182.94 . PMID 16957578 .
  12. ↑ ME Velasco, D. Dahl u. a .: Immunohistochemical localization of glial fibrillary acidic protein in human glial neoplasms. In: Cancer . Volume 45, Number 3, February 1980, pp. 484-494, ISSN  0008-543X . PMID 6243508 .
  13. ↑ D. Capper, H. Zentgraf, J. Balss, C. Hartmann, A. von Deimling: Monoclonal antibody specific for IDH1 R132H mutation . In: Acta Neuropathol . . 118, No. 5, November 2009, pp. 599-601. doi : 10.1007 / s00401-009-0595-z . PMID 19798509 .
  14. ↑ H. Ohgaki, P. Dessen et al. a .: Genetic pathways to glioblastoma: a population-based study. In: Cancer Research . Volume 64, Number 19, October 2004, pp. 6892-6899. doi: 10.1158 / 0008-5472.CAN-04-1337 . PMID 15466178 .
  15. ↑ T. Watanabe, S. Nobusawa et al. a .: IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. In: The American Journal of Pathology . Volume 174, Number 4, April 2009, pp. 1149-1153. doi: 10.2353 / ajpath.2009.080958 . PMID 19246647 . PMC 2671348 (free full text).
  16. ^ DW Parsons, S. Jones et al. a .: An integrated genomic analysis of human glioblastoma multiforme. In: Science. Volume 321, Number 5897, September 2008, pp. 1807-1812. doi: 10.1126 / science.1164382 . PMID 18772396 . PMC 2820389 (free full text).
  17. ↑ Preusser M , Wöhrer A, Stary S, Höftberger R, Streubel B, Hainfellner JA. Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens. J Neuropathol Exp Neurol. 2011 Aug; 70 (8): 715-23. doi: 10.1097 / NEN.0b013e31822713f0 .
  18. ↑ Capper D1, S. Weissert, J. Balss, A. Habel, J. Meyer, D. Jäger, U. Ackermann, C. Tessmer, A. Korshunov, H. Zentgraf, C. Hartmann, A. von Deimling: Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain pathol. 2010 Jan; 20 (1): pp. 245-254. doi: 10.1111 / j.1750-3639.2009.00352.x .
  19. ↑ glioblastoma. Retrieved August 13, 2020 .
  20. ↑ J. Schwartzentruber, A. Korshunov, XY Liu, DT Jones, E. Pfaff, K. Jacob, D. Sturm, AM Fontebasso, DA Quang, M. Tönjes, V. Hovestadt, S. Albrecht, M. Kool, A . Nantel, C. Konermann, A. Lindroth, N. Jäger, T. Rausch, M. Ryzhova, Jan Korbel , T. Hielscher, P. Hauser, M. Garami, A. Klekner, L. Bognar, M. Ebinger, MU Schuhmann, W. Scheurlen, A. Pekrun, MC Frühwald, W. Roggendorf, C. Kramm, M. Dürken, J. Atkinson, P. Lepage, A. Montpetit, M. Zakrzewska, K. Zakrzewski, PP Liberski, Z . Dong, P. Siegel, AE Kulozik, M. Zapatka, A. Guha, D. Malkin, J. Felsberg, G. Reifenberger, A. von Deimling, K. Ichimura, VP Collins, H. Witt, T. Milde, O. Witt, C. Zhang, P. Castelo-Branco, P. Lichter, D. Faury, U. Tabori, C. Plass, J. Majewski, SM Pfister, N. Jabado: Driver mutations in histone H3.3 and chromatin remodeling genes in pediatric glioblastoma. In: Nature . Volume 482, Number 7384, February 2012, pp. 226-231. doi: 10.1038 / nature10833 . PMID 22286061 .
  21. ↑ D. Sturm, H. Witt, V. Hovestadt, DA Khuong-Quang, DT Jones, C. Konermann, E. Pfaff, M. Tönjes, M. Sill, S. Bender, M. Kool, M. Zapatka, N Becker, M. Zucknick, T. Hielscher, XY Liu, AM Fontebasso, M. Ryzhova, S. Albrecht, K. Jacob, M. Wolter, M. Ebinger, MU Schuhmann, T. van Meter, MC Frühwald, H. Hauch, A. Pekrun, B. Radlwimmer, T. Niehues, G. von Komorowski, M. Dürken, AE Kulozik, J. Madden, A. Donson, NK Foreman, R. Drissi, M. Fouladi, W. Scheurlen, A von Deimling, C. Monoranu, W. Roggendorf, C. Herold-Mende, A. Unterberg, CM Kramm, J. Felsberg, C. Hartmann, B. Wiestler, W. Wick, T. Milde, O. Witt, AM Lindroth, J. Schwartzentruber, D. Faury, A. Fleming, M. Zakrzewska, PP Liberski, K. Zakrzewski, P. Hauser, M. Garami, A. Klekner, L. Bognar, S. Morrissy, F. Cavalli, MD Taylor, P. van Sluis, J. Koster, R. Versteeg, R. Volckmann, T. Mikkelsen, K. Aldape, G. Reifenberger, VP Collins, J. Majewski, A. Korshunov, P. Lichter, C. Plass, N. Jabado, SM Pfister: Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma. In: Cancer Cell . Volume 22, Number 4, October 2012, pp. 425-437. doi: 10.1016 / j.ccr.2012.08.024 . PMID 23079654 .
  22. ↑ B. Pakrah-Bodingbauer, M. Loyoddin, S. Oberndorfer, G. Kleinpeter: Value of 5-aminolevulinic acid (5-ALA) supported glioma surgery. (PDF; 1.6 MB) In: J Neurol Neurochir Psychiatr. Volume 10, Number 2, 2009, pp. 22-25.
  23. ^ R. Stupp, WP Mason et al. a .: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. In: The New England journal of medicine . Volume 352, Number 10, March 2005, pp. 987-996. doi: 10.1056 / NEJMoa043330 . PMID 15758009 .
  24. ↑ Ulrich Herrlinger, Theophilos Tzaridis, Frederic Mack, Joachim Steinbach, Uwe Schlegel: ACTR-58. PHASE III TRIAL OF CCNU / TEMOZOLOMIDE (TMZ) COMBINATION THERAPY VS. STANDARD TMZ THERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED GLIOBLASTOMA PATIENTS: THE CeTeg / NOA-09 trial . In: Neuro-Oncology . tape 19 , suppl_6, November 2017, ISSN  1522-8517 , p. vi13-vi14 , doi : 10.1093 / neuonc / nox168.049 .
  25. ↑ J. Perry, A. Chambers et al. a .: Gliadel wafers in the treatment of malignant glioma: a systematic review. In: Current Oncology Volume 14, Number 5, October 2007, pp. 189-194. PMID 17938702 . PMC 2002480 (free full text).
  26. ↑ Roger Stupp, Sophie Taillibert, Andrew Kanner, William Read, David M. Steinberg: Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial . In: JAMA . tape 318 , no. 23 , December 19, 2017, ISSN  0098-7484 , p. 2306 , doi : 10.1001 / jama.2017.18718 , PMID 29260225 , PMC 5820703 (free full text) - ( jamanetwork.com [accessed July 6, 2020]).
  27. ↑ [1] Query at clinicaltrials.gov on February 24, 2013.
  28. ↑ IK Mellinghoff, MY Wang, I. Vivanco, DA Haas-Kogan, S. Zhu, EQ Dia, KV Lu, K. Yoshimoto, JH Huang, DJ Chute, BL Riggs, S. Horvath, LM Liau, WK Cavenee, PN Rao, R. Beroukhim, TC Peck, JC Lee, WR Sellers, D. Stokoe, M. Prados, TF Cloughesy, CL Sawyers, PS Mischel: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. In: The New England Journal of Medicine . Volume 353, Number 19, November 2005, pp. 2012-2024. doi: 10.1056 / NEJMoa051918 . PMID 16282176 .
  29. ↑ DA Reardon, MJ Egorin, JA Quinn, JN Rich, JN Rich, S. Gururangan, I. Gururangan, JJ Vredenburgh, A. Desjardins, S. Sathornsumetee, JM Provenzale, JE Herndon, JM Dowell, MA Badruddoja, RE McLendon, TF Lagattuta, KP Kicielinski, G. Dresemann, JH Sampson, AH Friedman, AJ Salvado, HS Friedman: Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. In: Journal of Clinical Oncology . Volume 23, Number 36, December 2005, pp. 9359-9368. doi: 10.1200 / JCO.2005.03.2185 . PMID 16361636 .
  30. ↑ S. Sathornsumetee, Y. Cao, JE Marcello, JE Herndon, RE McLendon, A. Desjardins, HS Friedman, MW Dewhirst, JJ Vredenburgh, JN Rich: tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients Treated with bevacizumab and irinotecan. In: Journal of clinical oncology. Volume 26, Number 2, January 2008, pp. 271-278. doi: 10.1200 / JCO.2007.13.3652 . PMID 18182667 .
  31. ^ S. Kleber, I. Sancho-Martinez et al. a .: Yes and PI3K bind CD95 to signal invasion of glioblastoma. In: Cancer cell. Volume 13, Number 3, March 2008, pp. 235-248. doi: 10.1016 / j.ccr.2008.02.003 . PMID 18328427 .
  32. ↑ Tuettenberg et al .: Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients. In: International Immunopharmacology Number 13, May 2012, pp. 93-100
  33. ↑ Apogenix drug candidate APG101 reaches primary goal in Phase II brain cancer trial, http://www.pharmatopics.com/2012/03/apogenix-drug-candidate-apg101-reaches-primary-goal-in-phase-ii-brain -cancer-trial /
  34. ↑ P. Dent, A. Yacoub et al. a .: Searching for a cure: gene therapy for glioblastoma. In: Cancer Biology and Therapy . Volume 7, Number 9, September 2008, pp. 1335-1340, ISSN  1555-8576 . PMID 18708757 . (Review).
  35. ↑ K. Maier-Hauff, R. Rothe u. a .: Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme. In: Journal of neuro-oncology. Volume 81, Number 1, January 2007, pp. 53-60, ISSN  0167-594X . doi: 10.1007 / s11060-006-9195-0 . PMID 16773216 .
  36. ↑ A. Jordan, R. Scholz u. a .: The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. In: Journal of neuro-oncology. Volume 78, Number 1, May 2006, pp. 7-14, ISSN  0167-594X . doi: 10.1007 / s11060-005-9059-z . PMID 16314937 .
  37. ↑ Announcement of clinical study results. MagForce AG Berlin, September 21, 2010.
  38. ↑ Nanotherm therapy for relapses of brain tumors. ( Memento of the original from September 23, 2015 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Charité Universitätsmedizin Berlin, July 7, 2011 @1@ 2Template: Webachiv / IABot / www.charite.de
  39. ↑ Viruses against cancer: Malignant brain tumors completely regress after therapy with parvoviruses. German Cancer Research Center, press release of May 3, 2010 (PDF file; 39 kB)
  40. ^ Antonio Marchini, Serena Bonifati et al. a .: Oncolytic parvoviruses: from basic virology to clinical applications. In: Virology Journal. 12, 2015, p. 6, doi: 10.1186 / s12985-014-0223-y .
  41. ↑ EG Shawl, W. Seiferheld, C. Scott a. a .: Re-examining the radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) for glioblastoma multiforme (GBM) patients . In: International Journal of Radiation Oncology - Biology - Physics . 57, No. 2, 2003, pp. 135-136. doi : 10.1016 / S0360-3016 (03) 00843-5 .
  42. ↑ D. Krex, B. Klink et al. a .: Long-term survival with glioblastoma multiforme. In: Brain. Volume 130, 2007, pp. 2596-2606. doi: 10.1093 / brain / awm204 . PMID 17785346 . (Review).
This version was added to the list of articles worth reading on October 25, 2008 .