Skip to main content

Advertisement

SpringerLink
Log in

Refined brain tumor diagnostics and stratified therapies: the requirement for a multidisciplinary approach

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Individualized therapies are popular current concepts in oncology and first steps towards stratified medicine have now been taken in neurooncology through implementation of stratified therapeutic approaches. Knowledge about the molecular basis of brain tumors has expanded greatly in recent years and a few molecular alterations are studied routinely because of their clinical relevance. However, no single targeted agent has yet been fully approved for the treatment of glial brain tumors. In this review, we argue that multidisciplinary and integrated approaches are essential for translational research and the development of new treatments for patients with malignant gliomas, and we present a conceptual framework in which to place the components of such an interdisciplinary approach. We believe that this ambitious goal can be best realized through strong cooperation of brain tumor centers with local hospitals and physicians; such an approach enables close dialogue between expert subspecialty clinicians and local therapists to consider all aspects of this increasingly complex set of diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ahluwalia MS (2011) American Society of Clinical Oncology 2011 CNS tumors update. Expert Rev Anticancer Ther 11:1495–1497

    Article  PubMed  Google Scholar 

  2. Alexiou GA, Tsiouris S, Voulgaris S, Kyritsis AP, Fotopoulos AD (2012) Glioblastoma multiforme imaging: the role of nuclear medicine. Curr Radiopharm 5:308–313

    Article  PubMed  CAS  Google Scholar 

  3. Ananthnarayan S, Bahng J, Roring J, Nghiemphu P, Lai A, Cloughesy T, Pope WB (2008) Time course of imaging changes of GBM during extended bevacizumab treatment. J Neurooncol 88:339–347

    Article  PubMed  Google Scholar 

  4. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602

    Article  PubMed  CAS  Google Scholar 

  5. Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG (2008) Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 67:878–887

    Article  PubMed  CAS  Google Scholar 

  6. Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK (2010) Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28:2817–2823

    Article  PubMed  CAS  Google Scholar 

  7. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95

    Article  PubMed  CAS  Google Scholar 

  8. Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP (2007) CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67:4010–4015

    Article  PubMed  CAS  Google Scholar 

  9. Bettstetter M, Dechant S, Ruemmele P, Vogel C, Kurz K, Morak M, Keller G, Holinski-Feder E, Hofstaedter F, Dietmaier W (2008) MethyQESD, a robust and fast method for quantitative methylation analyses in HNPCC diagnostics using formalin-fixed and paraffin-embedded tissue samples. Lab Invest 88:1367–1375

    Article  PubMed  CAS  Google Scholar 

  10. Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH, Turski A, Azodi Y, Yang Y, Doucette T, Colman H, Sulman EP, Lang FF, Rao G, Copray S, Vaillant BD, Aldape KD (2011) The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25:2594–2609

    Article  PubMed  CAS  Google Scholar 

  11. Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ (2005) Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer 5:899–904

    Article  PubMed  CAS  Google Scholar 

  12. Bradley DP, Tessier JJ, Lacey T, Scott M, Jurgensmeier JM, Odedra R, Mills J, Kilburn L, Wedge SR (2009) Examining the acute effects of cediranib (RECENTIN, AZD2171) treatment in tumor models: a dynamic contrast-enhanced MRI study using gadopentate. Magn Reson Imaging 27:377–384

    Article  PubMed  CAS  Google Scholar 

  13. Brandes AA, Stupp R, Hau P, Lacombe D, Gorlia T, Tosoni A, Mirimanoff RO, Kros JM, van den Bent MJ (2010) EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma. Eur J Cancer 46:348–354

    Article  PubMed  CAS  Google Scholar 

  14. Butowski N, Chang SM, Lamborn KR, Polley MY, Parvataneni R, Hristova-Kazmierski M, Musib L, Nicol SJ, Thornton DE, Prados MD (2010) Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study. Neuro Oncol 12:608–613

    Article  PubMed  CAS  Google Scholar 

  15. Butowski N, Chang SM, Lamborn KR, Polley MY, Pieper R, Costello JF, Vandenberg S, Parvataneni R, Nicole A, Sneed PK, Clarke J, Hsieh E, Costa BM, Reis RM, Hristova-Kazmierski M, Nicol SJ, Thornton DE, Prados MD (2011) Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma. Neuro Oncol 13:1331–1338

    Article  PubMed  CAS  Google Scholar 

  16. Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, Iafrate AJ, Louis DN (2007) Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 13:2038–2045

    Article  PubMed  CAS  Google Scholar 

  17. Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D, Buckner J, Fink K, Souhami L, Laperierre N, Mehta M, Curran W (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24:2707–2714

    Article  PubMed  CAS  Google Scholar 

  18. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479

    Article  PubMed  CAS  Google Scholar 

  19. Cairncross JG, Wang M, Shaw EG, Jenkins RB, Scheithauer BW, Brachman D, Buckner JC, Fink KL, Souhami L, Laperriere N, Curran WJ and Mehta MP (2012) Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study. J Clin Oncol 30:ASCO MEETING ABSTRACTS (suppl; abstr 2008b)

  20. Camelo-Piragua S, Jansen M, Ganguly A, Kim JC, Louis DN, Nutt CL (2010) Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol 119:509–511

    Article  PubMed  Google Scholar 

  21. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  CAS  Google Scholar 

  22. Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H, Lasorella A, Aldape K, Califano A, Iavarone A (2010) The transcriptional network for mesenchymal transformation of brain tumours. Nature 463:318–325

    Article  PubMed  CAS  Google Scholar 

  23. Chamberlain MC, Cloughsey T, Reardon DA, Wen PY (2012) A novel treatment for glioblastoma: integrin inhibition. Expert Rev Neurother 12:421–435

    Article  PubMed  CAS  Google Scholar 

  24. Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J, Hess K, Aldape K, Lamborn KR, Kuhn J, Dancey J, Prados MD (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361

    Article  PubMed  CAS  Google Scholar 

  25. Chinot OL, de La Motte Rouge T, Moore N, Zeaiter A, Das A, Phillips H, Modrusan Z, Cloughesy T (2011) AVAglio: Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme. Adv Ther 28:334–340

    Article  PubMed  CAS  Google Scholar 

  26. Christians A, Hartmann C, Benner A, Meyer J, von Deimling A, Weller M, Wick W, Weiler M (2012) Prognostic value of three different methods of MGMT promoter methylation analysis in a prospective trial on newly diagnosed glioblastoma. PLoS ONE 7:e33449

    Article  PubMed  CAS  Google Scholar 

  27. Cooper LA, Gutman DA, Chisolm C, Appin C, Kong J, Rong Y, Kurc T, Van Meir EG, Saltz JH, Moreno CS, Brat DJ (2012) The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. Am J Pathol 180:2108–2119

    Article  PubMed  CAS  Google Scholar 

  28. de Groot JF, Gilbert MR, Aldape K, Hess KR, Hanna TA, Ictech S, Groves MD, Conrad C, Colman H, Puduvalli VK, Levin V, Yung WK (2008) Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma. J Neurooncol 90:89–97

    Article  PubMed  CAS  Google Scholar 

  29. Decleves X, Amiel A, Delattre JY, Scherrmann JM (2006) Role of ABC transporters in the chemoresistance of human gliomas. Curr Cancer Drug Targets 6:433–445

    Article  PubMed  CAS  Google Scholar 

  30. Del Vecchio CA, Li G, Wong AJ (2012) Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev Vaccines 11:133–144

    Article  PubMed  CAS  Google Scholar 

  31. Del Vecchio CA, Wong AJ (2010) Rindopepimut, a 14-mer injectable peptide vaccine against EGFRvIII for the potential treatment of glioblastoma multiforme. Curr Opin Mol Ther 12:741–754

    PubMed  Google Scholar 

  32. Delic S, Lottmann N, Jetschke K, Reifenberger G, Riemenschneider MJ (2012) Identification and functional validation of CDH11, PCSK6 and SH3GL3 as novel glioma invasion-associated candidate genes. Neuropathol Appl Neurobiol 38:201–212

    Article  PubMed  CAS  Google Scholar 

  33. Den RB, Kamrava M, Sheng Z, Werner-Wasik M, Dougherty E, Marinucchi M, Lawrence YR, Hegarty S, Hyslop T, Andrews DW, Glass J, Friedman DP, Green MR, Camphausen K, Dicker AP (2012) A Phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas. Int J Radiat Oncol Biol Phys 85:321–328

    Article  PubMed  CAS  Google Scholar 

  34. Dhermain FG, Hau P, Lanfermann H, Jacobs AH, van den Bent MJ (2010) Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. Lancet Neurol 9:906–920

    Article  PubMed  Google Scholar 

  35. Drappatz J, Norden AD, Wong ET, Doherty LM, Lafrankie DC, Ciampa A, Kesari S, Sceppa C, Gerard M, Phan P, Schiff D, Batchelor TT, Ligon KL, Young G, Muzikansky A, Weiss SE, Wen PY (2010) Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 78:85–90

    Article  PubMed  CAS  Google Scholar 

  36. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042

    Article  PubMed  CAS  Google Scholar 

  37. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037

    Article  PubMed  CAS  Google Scholar 

  38. Einstein DB, Wessels B, Bangert B, Fu P, Nelson AD, Cohen M, Sagar S, Lewin J, Sloan A, Zheng Y, Williams J, Colussi V, Vinkler R, Maciunas R (2012) Phase II trial of radiosurgery to magnetic resonance spectroscopy-defined high-risk tumor volumes in patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys 84:668–674

    Article  PubMed  Google Scholar 

  39. Ewelt C, Floeth FW, Felsberg J, Steiger HJ, Sabel M, Langen KJ, Stoffels G, Stummer W (2011) Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence. Clin Neurol Neurosurg 113:541–547

    Article  PubMed  Google Scholar 

  40. Felsberg J, Erkwoh A, Sabel MC, Kirsch L, Fimmers R, Blaschke B, Schlegel U, Schramm J, Wiestler OD, Reifenberger G (2004) Oligodendroglial tumors: refinement of candidate regions on chromosome arm 1p and correlation of 1p/19q status with survival. Brain Pathol 14:121–130

    Article  PubMed  CAS  Google Scholar 

  41. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564

    Article  PubMed  CAS  Google Scholar 

  42. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740

    Article  PubMed  CAS  Google Scholar 

  43. Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, Morton RF, Jaeckle KA, Scheithauer BW, Dancey J, Hidalgo M, Walsh DJ (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304

    Article  PubMed  CAS  Google Scholar 

  44. Happold C, Roth P, Wick W, Schmidt N, Florea AM, Silginer M, Reifenberger G and Weller M (2012) Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. J Neurochem [Epub ahead of print]

  45. Haroun RI, Brem H (2000) Local drug delivery. Curr Opin Oncol 12:187–193

    Article  PubMed  CAS  Google Scholar 

  46. Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, Westphal M, Schackert G, Meyermann R, Pietsch T, Reifenberger G, Weller M, Loeffler M, von Deimling A (2010) Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 120:707–718

    Article  PubMed  Google Scholar 

  47. Hau P, Jachimczak P, Bogdahn U (2009) Treatment of malignant gliomas with TGF-beta2 antisense oligonucleotides. Expert Rev Anticancer Ther 9:1663–1674

    Article  PubMed  CAS  Google Scholar 

  48. Hau P, Jachimczak P, Schlaier J, Bogdahn U (2011) TGF-beta2 signaling in high-grade gliomas. Curr Pharm Biotechnol 12:2150–2157

    Article  PubMed  CAS  Google Scholar 

  49. Hau P, Jachimczak P, Schlingensiepen R, Stauder G, Bogdahn U, Schlingensiepen K et al (2007) Inhibition of TGF-beta2 with AP 12009 in recurrent malignant glioma: from preclinical to Phase I/II studies. Oligonucleotides 17:201–212

    Article  PubMed  CAS  Google Scholar 

  50. Hau P, Stupp R, Hegi ME (2007) MGMT methylation status: the advent of stratified therapy in glioblastoma? Dis Markers 23:97–104

    Article  PubMed  CAS  Google Scholar 

  51. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003

    Article  PubMed  CAS  Google Scholar 

  52. Heimberger AB, Sun W, Hussain SF, Dey M, Crutcher L, Aldape K, Gilbert M, Hassenbusch SJ, Sawaya R, Schmittling B, Archer GE, Mitchell DA, Bigner DD, Sampson JH (2008) Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study. Neuro Oncol 10:98–103

    Article  PubMed  CAS  Google Scholar 

  53. Hewitt RE (2011) Biobanking: the foundation of personalized medicine. Curr Opin Oncol 23:112–119

    Article  PubMed  Google Scholar 

  54. Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, Fitch-Bruhns M, Lazetic S, Park IK, Sato A, Satyal S, Wang X, Clarke MF, Lewicki J, Gurney A (2009) DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5:168–177

    Article  PubMed  CAS  Google Scholar 

  55. Holdhoff M, Ye X, Blakeley JO, Blair L, Burger PC, Grossman SA, Diaz LA Jr (2012) Use of personalized molecular biomarkers in the clinical care of adults with glioblastomas. J Neurooncol 110:279–285

    Article  PubMed  CAS  Google Scholar 

  56. Hummel R, Maurer J, Haier J (2011) MicroRNAs in brain tumors: a new diagnostic and therapeutic perspective? Mol Neurobiol 44:223–234

    Article  PubMed  CAS  Google Scholar 

  57. Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, Greenman C, Edkins S, Bignell G, Davies H, O’Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Richardson D, Shepherd R, Small A, Solomon H, Tofts C, Varian J, West S, Widaa S, Yates A, Easton DF, Riggins G, Roy JE, Levine KK, Mueller W, Batchelor TT, Louis DN, Stratton MR, Futreal PA, Wooster R (2006) A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res 66:3987–3991

    Article  PubMed  CAS  Google Scholar 

  58. Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP (2009) IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 11:341–347

    Article  PubMed  CAS  Google Scholar 

  59. Iwamoto FM, Lamborn KR, Robins HI, Mehta MP, Chang SM, Butowski NA, Deangelis LM, Abrey LE, Zhang WT, Prados MD, Fine HA (2010) Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro Oncol 12:855–861

    Article  PubMed  CAS  Google Scholar 

  60. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610–622

    Article  PubMed  CAS  Google Scholar 

  61. Jennings MT, Iyengar S (2001) The molecular genetics of therapeutic resistance in malignant astrocytomas. Am J Pharmacogenomics 1:93–99

    Article  PubMed  CAS  Google Scholar 

  62. Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677

    Article  PubMed  CAS  Google Scholar 

  63. Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP (2009) Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119–2123

    Article  PubMed  CAS  Google Scholar 

  64. Khasraw M, Simeonovic M, Grommes C (2012) Bevacizumab for the treatment of high-grade glioma. Expert Opin Biol Ther 12:1101–1111

    Article  PubMed  CAS  Google Scholar 

  65. Kim TM, Huang W, Park R, Park PJ, Johnson MD (2011) A developmental taxonomy of glioblastoma defined and maintained by MicroRNAs. Cancer Res 71:3387–3399

    Article  PubMed  CAS  Google Scholar 

  66. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro Oncol 1:44–51

    PubMed  CAS  Google Scholar 

  67. Kreisl TN, Kotliarova S, Butman JA, Albert PS, Kim L, Musib L, Thornton D, Fine HA (2010) A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol 12:181–189

    Article  PubMed  CAS  Google Scholar 

  68. Kreisl TN, McNeill KA, Sul J, Iwamoto FM, Shih J, Fine HA (2012) A phase I/II trial of vandetanib for patients with recurrent malignant glioma. Neuro Oncol 14:1519–1526

    Article  PubMed  CAS  Google Scholar 

  69. Kros JM, Gorlia T, Kouwenhoven MC, Zheng PP, Collins VP, Figarella-Branger D, Giangaspero F, Giannini C, Mokhtari K, Mork SJ, Paetau A, Reifenberger G, van den Bent MJ (2007) Panel review of anaplastic oligodendroglioma from European Organization for Research and Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome. J Neuropathol Exp Neurol 66:545–551

    Article  PubMed  CAS  Google Scholar 

  70. Lalezari S, Chou AP, Tran A, Solis OE, Khanlou N, Chen W, Li S, Carrillo JA, Chowdhury R, Selfridge J, Sanchez DE, Wilson RW, Zurayk M, Lalezari J, Lou JJ, Ormiston L, Ancheta K, Hanna R, Miller P, Piccioni D, Ellingson BM, Buchanan C, Mischel PS, Nghiemphu PL, Green R, Wang HJ, Pope WB, Liau LM, Elashoff RM, Cloughesy TF, Yong WH, Lai A (2013) Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome. Neuro Oncol 15:370–381

    Article  PubMed  CAS  Google Scholar 

  71. Lamszus K, Kunkel P, Westphal M (2003) Invasion as limitation to anti-angiogenic glioma therapy. Acta Neurochir Suppl 88:169–177

    PubMed  CAS  Google Scholar 

  72. Lindemann C, Hackmann O, Delic S, Schmidt N, Reifenberger G, Riemenschneider MJ (2011) SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. Acta Neuropathol 122:241–251

    Article  PubMed  CAS  Google Scholar 

  73. Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J, Junker M, Oefner PJ, Bogdahn U, Wischhusen J, Spang R, Storch A, Beier CP (2010) Transcriptional profiles of CD133+ and CD133− glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res 70:2030–2040

    Article  PubMed  CAS  Google Scholar 

  74. Louis DN (2006) Molecular pathology of malignant gliomas. Annu Rev Pathol 1:97–117

    Article  PubMed  CAS  Google Scholar 

  75. Louis DN (2012) The next step in brain tumor classification: “Let us now praise famous men”… or molecules? Acta Neuropathol 124:761–762

    Article  PubMed  Google Scholar 

  76. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) (2007) WHO classification of tumours of the central nervous system, 4th edn. IARC Press, Lyon

    Google Scholar 

  77. Lu C, Shervington A (2008) Chemoresistance in gliomas. Mol Cell Biochem 312:71–80

    Article  PubMed  CAS  Google Scholar 

  78. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O’Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474–478

    Article  PubMed  CAS  Google Scholar 

  79. Maintz D, Fiedler K, Koopmann J, Rollbrocker B, Nechev S, Lenartz D, Stangl AP, Louis DN, Schramm J, Wiestler OD, von Deimling A (1997) Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol 56:1098–1104

    Article  PubMed  CAS  Google Scholar 

  80. Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R (2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 13:916–926

    Article  PubMed  CAS  Google Scholar 

  81. Malzkorn B, Wolter M, Riemenschneider MJ, Reifenberger G (2011) Unraveling the glioma epigenome: from molecular mechanisms to novel biomarkers and therapeutic targets. Brain Pathol 21:619–632

    Article  PubMed  CAS  Google Scholar 

  82. Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Demuth T, Ross KR, Berens T, Coons SW, Watts G, Trent JM, Wei JS, Giese A, Berens ME (2001) Glioma cell motility is associated with reduced transcription of proapoptotic and proliferation genes: a cDNA microarray analysis. J Neurooncol 53:161–176

    Article  PubMed  CAS  Google Scholar 

  83. Masui K, Cloughesy TF, Mischel PS (2012) Review: molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies. Neuropathol Appl Neurobiol 38:271–291

    Article  PubMed  CAS  Google Scholar 

  84. Matsusue E, Fink JR, Rockhill JK, Ogawa T, Maravilla KR (2010) Distinction between glioma progression and post-radiation change by combined physiologic MR imaging. Neuroradiology 52:297–306

    Article  PubMed  Google Scholar 

  85. Mikkelsen T, Brodie C, Finniss S, Berens ME, Rennert JL, Nelson K, Lemke N, Brown SL, Hahn D, Neuteboom B, Goodman SL (2009) Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 124:2719–2727

    Article  PubMed  CAS  Google Scholar 

  86. Mueller W, Hartmann C, Hoffmann A, Lanksch W, Kiwit J, Tonn J, Veelken J, Schramm J, Weller M, Wiestler OD, Louis DN, von Deimling A (2002) Genetic signature of oligoastrocytomas correlates with tumor location and denotes distinct molecular subsets. Am J Pathol 161:313–319

    Article  PubMed  CAS  Google Scholar 

  87. Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF, de Tribolet N, Regli L, Wick W, Kouwenhoven MC, Hainfellner JA, Heppner FL, Dietrich PY, Zimmer Y, Cairncross JG, Janzer RC, Domany E, Delorenzi M, Stupp R, Hegi ME (2008) Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26:3015–3024

    Article  PubMed  CAS  Google Scholar 

  88. Nabors LB, Supko JG, Rosenfeld M, Chamberlain M, Phuphanich S, Batchelor T, Desideri S, Ye X, Wright J, Gujar S, Grossman SA (2011) Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma. Neuro Oncol 13:1324–1330

    Article  PubMed  CAS  Google Scholar 

  89. Neyns B, Sadones J, Chaskis C, Dujardin M, Everaert H, Lv S, Duerinck J, Tynninen O, Nupponen N, Michotte A, De Greve J (2011) Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol 103:491–501

    Article  PubMed  CAS  Google Scholar 

  90. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522

    Article  PubMed  CAS  Google Scholar 

  91. Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453

    Article  PubMed  CAS  Google Scholar 

  92. Ohka F, Natsume A, Motomura K, Kishida Y, Kondo Y, Abe T, Nakasu Y, Namba H, Wakai K, Fukui T, Momota H, Iwami K, Kinjo S, Ito M, Fujii M, Wakabayashi T (2011) The global DNA methylation surrogate LINE-1 methylation is correlated with MGMT promoter methylation and is a better prognostic factor for glioma. PLoS ONE 6:e23332

    Article  PubMed  CAS  Google Scholar 

  93. Okada Y, Hurwitz EE, Esposito JM, Brower MA, Nutt CL, Louis DN (2003) Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas. Cancer Res 63:413–416

    PubMed  CAS  Google Scholar 

  94. Pafundi DH, Laack NN, Youland RS, Parney IF, Lowe VJ, Giannini C, Kemp BJ, Grams MP, Morris JM, Hoover JM, Hu LS, Sarkaria JN and Brinkmann DH (2013) Biopsy validation of 18F-DOPA PET and biodistribution in gliomas for neurosurgical planning and radiotherapy target delineation: results of a prospective pilot study. Neuro Oncol 2013 Mar 3 [Epub ahead of print]

  95. Pan E, Yu D, Yue B, Potthast L, Chowdhary S, Smith P, Chamberlain M (2012) A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. J Neurooncol 110:111–118

    Article  PubMed  CAS  Google Scholar 

  96. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  97. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173

    Article  PubMed  CAS  Google Scholar 

  98. Piroth MD, Pinkawa M, Holy R, Klotz J, Schaar S, Stoffels G, Galldiks N, Coenen HH, Kaiser HJ, Langen KJ, Eble MJ (2012) Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study. Strahlenther Onkol 188:334–339

    Article  PubMed  CAS  Google Scholar 

  99. Plate KH, Scholz A, Dumont DJ (2012) Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathol 124:763–775

    Article  PubMed  Google Scholar 

  100. Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF (2006) MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66:1258–1260

    Article  PubMed  CAS  Google Scholar 

  101. Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M, Fedoroff A, Sneed PK, Berger MS, McDermott MW, Parsa AT, Vandenberg S, James CD, Lamborn KR, Stokoe D, Haas-Kogan DA (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584

    Article  PubMed  CAS  Google Scholar 

  102. Rampling R, Sanson M, Gorlia T, Lacombe D, Lai C, Gharib M, Taal W, Stoffregen C, Decker R, van den Bent MJ (2012) A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054). Neuro Oncol 14:344–350

    Article  PubMed  CAS  Google Scholar 

  103. Rao SA, Santosh V, Somasundaram K (2010) Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma. Mod Pathol 23:1404–1417

    Article  PubMed  CAS  Google Scholar 

  104. Reardon DA, Dresemann G, Taillibert S, Campone M, van den Bent M, Clement P, Blomquist E, Gordower L, Schultz H, Raizer J, Hau P, Easaw J, Gil M, Tonn J, Gijtenbeek A, Schlegel U, Bergstrom P, Green S, Weir A, Nikolova Z (2009) Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma. Br J Cancer 101:1995–2004

    Article  PubMed  CAS  Google Scholar 

  105. Reardon DA, Egorin MJ, Desjardins A, Vredenburgh JJ, Beumer JH, Lagattuta TF, Gururangan S, Herndon JE 2nd, Salvado AJ, Friedman HS (2009) Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer 115:2188–2198

    Article  PubMed  CAS  Google Scholar 

  106. Reardon DA, Egorin MJ, Quinn JA, Rich JN, Gururangan S, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE 2nd, Dowell JM, Badruddoja MA, McLendon RE, Lagattuta TF, Kicielinski KP, Dresemann G, Sampson JH, Friedman AH, Salvado AJ, Friedman HS (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368

    Article  PubMed  CAS  Google Scholar 

  107. Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26:5610–5617

    Article  PubMed  CAS  Google Scholar 

  108. Reardon DA, Nabors LB, Stupp R, Mikkelsen T (2008) Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin Investig Drugs 17:1225–1235

    Article  PubMed  CAS  Google Scholar 

  109. Reardon DA, Neyns B, Weller M, Tonn JC, Nabors LB, Stupp R (2011) Cilengitide: an RGD pentapeptide alphanubeta3 and alphanubeta5 integrin inhibitor in development for glioblastoma and other malignancies. Future oncol 7:339–354

    Article  PubMed  CAS  Google Scholar 

  110. Reifenberger G, Louis DN (2003) Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol 62:111–126

    PubMed  CAS  Google Scholar 

  111. Riemenschneider MJ, Buschges R, Wolter M, Reifenberger J, Bostrom J, Kraus JA, Schlegel U, Reifenberger G (1999) Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res 59:6091–6096

    PubMed  CAS  Google Scholar 

  112. Riemenschneider MJ, Hegi ME, Reifenberger G (2010) MGMT promoter methylation in malignant gliomas. Target Oncol 5:161–165

    Article  PubMed  Google Scholar 

  113. Riemenschneider MJ, Jeuken JW, Wesseling P, Reifenberger G (2010) Molecular diagnostics of gliomas: state of the art. Acta Neuropathol 120:567–584

    Article  PubMed  CAS  Google Scholar 

  114. Riemenschneider MJ, Mueller W, Betensky RA, Mohapatra G, Louis DN (2005) In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation. Am J Pathol 167:1379–1387

    Article  PubMed  CAS  Google Scholar 

  115. Riemenschneider MJ, Reifenberger G (2009) Astrocytic tumors. Recent Results Cancer Res 171:3–24

    Article  PubMed  Google Scholar 

  116. Riemenschneider MJ, Reifenberger G (2009) Molecular neuropathology of gliomas. Int J Mol Sci 10:184–212

    Article  PubMed  CAS  Google Scholar 

  117. Riemenschneider MJ, Reifenberger G (2010) Molecular neuropathology of low-grade gliomas and its clinical impact. Adv Tech Stand Neurosurg 35:35–64

    Article  PubMed  CAS  Google Scholar 

  118. Riemenschneider MJ, Reifenberger G (2009) Novel insights into the pathogenesis of gliomas based on large-scale molecular profiling approaches. Curr Opin Neurol 22:619–624

    Article  PubMed  CAS  Google Scholar 

  119. Sahm F, Capper D, Jeibmann A, Habel A, Paulus W, Troost D, von Deimling A (2012) Addressing diffuse glioma as a systemic brain disease with single-cell analysis. Arch Neurol 69:523–526

    Article  PubMed  Google Scholar 

  120. Sana J, Hajduch M, Michalek J, Vyzula R, Slaby O (2011) MicroRNAs and glioblastoma: roles in core signalling pathways and potential clinical implications. J Cell Mol Med 15:1636–1644

    Article  PubMed  CAS  Google Scholar 

  121. Sarkaria JN, Galanis E, Wu W, Dietz AB, Kaufmann TJ, Gustafson MP, Brown PD, Uhm JH, Rao RD, Doyle L, Giannini C, Jaeckle KA, Buckner JC (2010) Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. Clin Cancer Res 16:5573–5580

    Article  PubMed  CAS  Google Scholar 

  122. Scaringi C, Minniti G, Caporello P, Enrici RM (2012) Integrin inhibitor cilengitide for the treatment of glioblastoma: a brief overview of current clinical results. Anticancer Res 32:4213–4223

    PubMed  CAS  Google Scholar 

  123. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405

    Article  PubMed  CAS  Google Scholar 

  124. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B, Jachimczak P (2006) Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. Cytokine Growth Factor Rev 17:129–139

    Article  PubMed  CAS  Google Scholar 

  125. Schlingensiepen R, Goldbrunner M, Szyrach MN, Stauder G, Jachimczak P, Bogdahn U, Schulmeyer F, Hau P, Schlingensiepen KH (2005) Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 15:94–104

    Article  PubMed  CAS  Google Scholar 

  126. Seidel S, Garvalov BK, Wirta V, von Stechow L, Schanzer A, Meletis K, Wolter M, Sommerlad D, Henze AT, Nister M, Reifenberger G, Lundeberg J, Frisen J, Acker T (2010) A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 133:983–995

    Article  PubMed  Google Scholar 

  127. Specenier P (2012) Bevacizumab in glioblastoma multiforme. Expert Rev Anticancer Ther 12:9–18

    Article  PubMed  CAS  Google Scholar 

  128. Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, Pietsch T, Hicking C, Tonn JC, Diserens AC, Pica A, Hermisson M, Krueger S, Picard M, Weller M (2010) Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28:2712–2718

    Article  PubMed  CAS  Google Scholar 

  129. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  130. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tonjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Fruhwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Durken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, Pfister SM (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437

    Article  PubMed  CAS  Google Scholar 

  131. Tabatabai G, Tonn JC, Stupp R, Weller M (2011) The role of integrins in glioma biology and anti-glioma therapies. Curr Pharm Des 17:2402–2410

    Article  PubMed  CAS  Google Scholar 

  132. Toedt G, Barbus S, Wolter M, Felsberg J, Tews B, Blond F, Sabel MC, Hofmann S, Becker N, Hartmann C, Ohgaki H, von Deimling A, Wiestler OD, Hahn M, Lichter P, Reifenberger G, Radlwimmer B (2011) Molecular signatures classify astrocytic gliomas by IDH1 mutation status. Int J Cancer 128:1095–1103

    Article  PubMed  CAS  Google Scholar 

  133. van den Bent MJ (2010) Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician’s perspective. Acta Neuropathol 120:297–304

    Article  PubMed  Google Scholar 

  134. van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T (2006) Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715–2722

    Article  PubMed  CAS  Google Scholar 

  135. van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P, Frenay M, Tijssen CC, Lacombe D, Idbaih A, van Marion R, Kros JM, Dinjens WN, Gorlia T, Sanson M (2010) IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res 16:1597–1604

    Article  PubMed  CAS  Google Scholar 

  136. van den Bent MJ, Hoang-Xuan K, Brandes AA, Kros JM, Kouwenhoven MCM, Taphoorn MJB, Delattre JY, Bernsen HJJB, Frenay M, Tijssen C, Grisold W, Sipos L, Enting RH, Dinjens WNM, French P, Vecht CJ, Allgeier A, Lacombe DA and Gorlia T (2012) Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD). J Clin Oncol 30:ASCO MEETING ABSTRACTS (suppl; abstr 2)

  137. van den Bent MJ, Looijenga LH, Langenberg K, Dinjens W, Graveland W, Uytdewilligen L, Sillevis Smitt PA, Jenkins RB, Kros JM (2003) Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features. Cancer 97:1276–1284

    Article  PubMed  Google Scholar 

  138. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  PubMed  CAS  Google Scholar 

  139. Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6:425–436

    Article  PubMed  CAS  Google Scholar 

  140. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259

    Article  PubMed  CAS  Google Scholar 

  141. Vultur A, Villanueva J, Herlyn M (2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res 17:1658–1663

    Article  PubMed  CAS  Google Scholar 

  142. Walter F, la Fougere C, Belka C, Niyazi M (2012) Technical issues of [(18)F]FET-PET imaging for radiation therapy planning in malignant glioma patients—a review. Front Oncol 2:130

    Article  PubMed  CAS  Google Scholar 

  143. Weber MA, Henze M, Tuttenberg J, Stieltjes B, Meissner M, Zimmer F, Burkholder I, Kroll A, Combs SE, Vogt-Schaden M, Giesel FL, Zoubaa S, Haberkorn U, Kauczor HU, Essig M (2010) Biopsy targeting gliomas: do functional imaging techniques identify similar target areas? Invest Radiol 45:755–768

    Article  PubMed  Google Scholar 

  144. Weller M (2013) Assessing the MGMT status in glioblastoma: one step forward, two steps back? Neuro Oncol 15:253–254

    Article  PubMed  Google Scholar 

  145. Wick A, Dorner N, Schafer N, Hofer S, Heiland S, Schemmer D, Platten M, Weller M, Bendszus M, Wick W (2011) Bevacizumab does not increase the risk of remote relapse in malignant glioma. Ann Neurol 69:586–592

    Article  PubMed  Google Scholar 

  146. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880

    Article  PubMed  CAS  Google Scholar 

  147. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M (2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13:707–715

    Article  PubMed  CAS  Google Scholar 

  148. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA (2010) Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 28:1168–1174

    Article  PubMed  CAS  Google Scholar 

  149. Yang I, Aghi MK (2009) New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol 6:648–657

    Article  PubMed  Google Scholar 

  150. Ye F, Gao Q, Cai MJ (2010) Therapeutic targeting of EGFR in malignant gliomas. Expert Opin Ther Targets 14:303–316

    Article  PubMed  CAS  Google Scholar 

  151. Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL, Louis DN (2009) MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 15:4622–4629

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuropathology, Regensburg University Hospital, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany

    Markus J. Riemenschneider

  2. Department of Pathology, Pathology Service and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    David N. Louis

  3. Department of Neurology, University Hospital Zurich, Zurich, Switzerland

    Michael Weller

  4. Department of Neurology, University of Regensburg, Regensburg, Germany

    Peter Hau

  5. Wilhelm Sander-NeuroOncology Unit, Regensburg University Hospital, Regensburg, Germany

    Markus J. Riemenschneider & Peter Hau

Authors
  1. Markus J. Riemenschneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David N. Louis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Weller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Hau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus J. Riemenschneider.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Riemenschneider, M.J., Louis, D.N., Weller, M. et al. Refined brain tumor diagnostics and stratified therapies: the requirement for a multidisciplinary approach. Acta Neuropathol 126, 21–37 (2013). https://doi.org/10.1007/s00401-013-1127-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-013-1127-4

Keywords

Search

Navigation