Cancer Management and Research Dovepress Malignant Gliomas: Current Perspectives in Diagnosis, Treatment, and Early Response Assessment Using Advanced Quantitative Imaging Methods

Malignant gliomas consist of glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, and some less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas. Malignant gliomas have high morbidity and mortality. Even with optimal treatment, median survival is only 12–15 months for glioblastomas and 2–5 years for anaplastic gliomas. However, recent advances in imaging and quantitative analysis of image data have led to earlier diagnosis of tumors and tumor response to therapy, providing oncologists with a greater time window for therapy management. In addition, improved understanding of tumor biology, genetics, and resistance mechanisms has enhanced surgical techniques, chemotherapy methods, and radiotherapy administration. After proper diagnosis and institution of appropriate therapy, there is now a vital need for quantitative methods that can sensitively detect malignant glioma response to therapy at early follow-up times, when changes in management of nonresponders can have its greatest effect. Currently, response is largely evaluated by measuring magnetic resonance contrast and size change, but this approach does not take into account the key biologic steps that precede tumor size reduction. Molecular imaging is ideally suited to measuring early response by quantifying cellular metabolism, proliferation, and apoptosis, activities altered early in treatment. We expect that successful integration of quantitative imaging biomarker assessment into the early phase of clinical trials could provide a novel approach for testing new therapies, and importantly, for facilitating patient management, sparing patients from weeks or months of toxicity and ineffective treatment. This review will present an overview of epidemiology, molecular pathogenesis and current advances in diagnoses, and management of malignant gliomas.

[1]  Axel Hoos,et al.  Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria , 2009, Clinical Cancer Research.

[2]  K. Herholz,et al.  Methyl-l-11C-Methionine PET as a Diagnostic Marker for Malignant Progression in Patients with Glioma , 2009, Journal of Nuclear Medicine.

[3]  Jochen Herms,et al.  Real-time imaging reveals the single steps of brain metastasis formation , 2010, Nature Medicine.

[4]  H. Duffau,et al.  Intra-Operative Direct Electrical Stimulations of the Central Nervous System: The Salpêtrière Experience With 60 Patients , 1999, Acta Neurochirurgica.

[5]  C. Meyer,et al.  Evaluation of the functional diffusion map as an early biomarker of time-to-progression and overall survival in high-grade glioma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  F. Soussaline,et al.  Brain tumor protein synthesis and histological grades: A study by positron emission tomography (PET) with C11-L-Methionine , 2004, Journal of Neuro-Oncology.

[7]  A. Friedman,et al.  The Addition of Bevacizumab to Standard Radiation Therapy and Temozolomide Followed by Bevacizumab, Temozolomide, and Irinotecan for Newly Diagnosed Glioblastoma , 2011, Clinical Cancer Research.

[8]  R. Timmerman,et al.  Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[10]  Erwin G. Van Meir,et al.  Detection of “oncometabolite” 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma , 2012, Journal of Molecular Medicine.

[11]  B A Kall,et al.  Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. , 1987, Mayo Clinic proceedings.

[12]  M. Gilbert Recurrent glioblastoma: a fresh look at current therapies and emerging novel approaches. , 2011, Seminars in oncology.

[13]  Paula D. Bos,et al.  Metastasis: from dissemination to organ-specific colonization , 2009, Nature Reviews Cancer.

[14]  Hans-Jakob Steiger,et al.  Multimodal metabolic imaging of cerebral gliomas: positron emission tomography with [18F]fluoroethyl-L-tyrosine and magnetic resonance spectroscopy. , 2005, Journal of neurosurgery.

[15]  H. Zaidi,et al.  Assessment of various strategies for 18F-FET PET-guided delineation of target volumes in high-grade glioma patients , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[16]  Akira Matsumura,et al.  Anti-vascular endothelial growth factor antibody and nimustine as combined therapy: effects on tumour growth and angiogenesis in human glioblastoma xenografts. , 2003, Neuro-oncology.

[17]  Gargi Chakraborty,et al.  Quantitative metrics of net proliferation and invasion link biological aggressiveness assessed by MRI with hypoxia assessed by FMISO-PET in newly diagnosed glioblastomas. , 2009, Cancer research.

[18]  M. Mrugala,et al.  Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. , 2009, Neurology.

[19]  D. Le Bihan Molecular diffusion, tissue microdynamics and microstructure. , 1995, NMR in biomedicine.

[20]  H. Engler,et al.  Positron emission tomography 11C‐methionine and survival in patients with low‐grade gliomas , 2001 .

[21]  G. Reifenberger,et al.  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 , 2010, Acta Neuropathologica.

[22]  K. Aldape,et al.  Biomarkers Classification and Therapeutic Decision-Making for Malignant Gliomas , 2012, Current Treatment Options in Oncology.

[23]  J. Mackey,et al.  Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  J. Rey,et al.  Allelic loss at 1 p is associated with tumor progression of meningiomas , 1994, Genes, chromosomes & cancer.

[25]  M. Walker,et al.  An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. , 1979, International journal of radiation oncology, biology, physics.

[26]  J. Villano,et al.  Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data. , 2012, Neuro-oncology.

[27]  P. Wen,et al.  Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. , 1999, Journal of neurosurgery.

[28]  J. Gillard,et al.  Imaging biomarkers of brain tumour margin and tumour invasion. , 2011, The British journal of radiology.

[29]  K. Hoang-Xuan,et al.  Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  L. Ellis,et al.  Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Winand N M Dinjens,et al.  Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  K. Flaherty,et al.  BRAF in Melanoma: Current Strategies and Future Directions , 2013, Clinical Cancer Research.

[33]  H. R. Arvinda,et al.  RETRACTED ARTICLE: Glioma grading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging , 2009, Journal of Neuro-Oncology.

[34]  Manuel Lopes,et al.  Intraoperative mapping of the subcortical language pathways using direct stimulations. An anatomo-functional study. , 2002, Brain : a journal of neurology.

[35]  M. Bergström,et al.  Positron emission tomography with ([11C]methyl)-L-methionine, [11C]D-glucose, and [68Ga]EDTA in supratentorial tumors. , 1985, Journal of computer assisted tomography.

[36]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[37]  Otto Muzik,et al.  Imaging proliferation in vivo with [F-18]FLT and positron emission tomography , 1998, Nature Medicine.

[38]  Marvin Bergsneider,et al.  Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[39]  Glyn Johnson,et al.  Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging. , 2002, Radiology.

[40]  W. Heiss,et al.  Patient-Tailored, Imaging-Guided, Long-Term Temozolomide Chemotherapy in Patients with Glioblastoma , 2010, Molecular imaging.

[41]  Timothy F Cloughesy,et al.  Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. , 2008, Neuro-oncology.

[42]  Susan Chang,et al.  Pseudoprogression and pseudoresponse: Challenges in brain tumor imaging , 2009, Current neurology and neuroscience reports.

[43]  Z L Gokaslan,et al.  A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. , 2001, Journal of neurosurgery.

[44]  P. Black,et al.  Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy. , 1998, Journal of neurosurgery.

[45]  A. Thiel,et al.  11C-methionine PET for differential diagnosis of low-grade gliomas , 1998, Neurology.

[46]  H. Engler,et al.  Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas. , 2001, Cancer.

[47]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[48]  T. Cloughesy,et al.  3′-Deoxy-3′-18F-Fluorothymidine PET and MRI for Early Survival Predictions in Patients with Recurrent Malignant Glioma Treated with Bevacizumab , 2012, The Journal of Nuclear Medicine.

[49]  N. Sanai Emerging operative strategies in neurosurgical oncology. , 2012, Current opinion in neurology.

[50]  Mauricio Castillo,et al.  Cerebral blood volume measurements and proton MR spectroscopy in grading of oligodendroglial tumors. , 2007, AJR. American journal of roentgenology.

[51]  Hong Wu,et al.  Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy , 2012, Journal of Neuro-Oncology.

[52]  M. Berger,et al.  Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. , 2005, Journal of the National Cancer Institute.

[53]  N. Bleehen,et al.  Radiotherapy in high grade gliomas , 1989, British Journal of Cancer.

[54]  J. Slattery,et al.  Chemotherapy response criteria in malignant glioma , 1997, Neurology.

[55]  Benedick A Fraass,et al.  Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  Timothy D Johnson,et al.  Functional diffusion map as an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  A. Friedman,et al.  Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas , 2008, Clinical Cancer Research.

[58]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  R. Hawkins,et al.  Use of thallium-201 SPECT to quantitate malignancy grade of gliomas. , 1989, Journal of neurosurgery.

[60]  Darell D. Bigner,et al.  Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma , 2007, Clinical Cancer Research.

[61]  F. Lieberman,et al.  Comparison of Proton Magnetic Resonance Spectroscopy with Fluorine‐18 2‐Fluoro‐Deoxyglucose Positron Emission Tomography for Assessment of Brain Tumor Progression , 2012, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[62]  P. Gutin,et al.  Intensity modulated radiotherapy in high grade gliomas: Clinical and dosimetric results. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Ricardo J. Komotar,et al.  Discriminating radiation necrosis from tumor progression in gliomas: a systematic review what is the best imaging modality? , 2013, Journal of Neuro-Oncology.

[64]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[65]  G. Reifenberger,et al.  Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. , 1994, The American journal of pathology.

[66]  M. Mehta,et al.  Stereotactic radiosurgery for glioblastoma multiforme: report of a prospective study evaluating prognostic factors and analyzing long-term survival advantage. , 1994, International journal of radiation oncology, biology, physics.

[67]  K. Aldape,et al.  Absence of IDH1-R132H mutation predicts rapid progression of nonenhancing diffuse glioma in older adults. , 2012, Annals of diagnostic pathology.

[68]  G. Fuller,et al.  The significance of lack of MR contrast enhancement of supratentorial brain tumors in adults: histopathological evaluation of a series. , 1998, Surgical neurology.

[69]  M. Castillo,et al.  Clinical applications of proton MR spectroscopy. , 1996, AJNR. American journal of neuroradiology.

[70]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[71]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. , 2013, Neuro-oncology.

[72]  D. Kondziolka,et al.  Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case–control study , 2012, Journal of Neuro-Oncology.

[73]  T. Cloughesy,et al.  PTEN-Mediated Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors , 2007, Clinical Cancer Research.

[74]  Qimin He,et al.  3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. , 2003, Cancer research.

[75]  M J Gleason,et al.  Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  Thomas K Lewellen,et al.  18F-FDG PET of gliomas at delayed intervals: improved distinction between tumor and normal gray matter. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[77]  T. Maehara,et al.  Glioma surgery using a multimodal navigation system with integrated metabolic images. , 2009, Journal of neurosurgery.

[78]  T. Batchelor,et al.  Antiangiogenic Therapy for Glioblastoma , 2012, Cancer journal.

[79]  A. Narayana,et al.  Bevacizumab in the treatment of high-grade gliomas: an overview , 2011, Angiogenesis.

[80]  P. Robbins,et al.  Stereotactic Biopsy Of 100 Intracerebral Lesions At Sir Charles Gairdner Hospital , 1994, Pathology.

[81]  H. Atkins,et al.  Thallium-201 brain tumor imaging: a comparative study with pathologic correlation. , 1987, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[82]  Mark Muzi,et al.  Positron emission tomography imaging of brain tumors. , 2003, Neuroimaging clinics of North America.

[83]  R L Ehman,et al.  Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. , 1988, Radiology.

[84]  Tadashi Nariai,et al.  Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. , 2005, Journal of neurosurgery.

[85]  A. Kaye,et al.  The EGFRvIII variant in glioblastoma multiforme , 2009, Journal of Clinical Neuroscience.

[86]  T K Lewellen,et al.  Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. , 1996, International journal of radiation oncology, biology, physics.

[87]  J. Frahm,et al.  Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra. , 1993, Radiology.

[88]  J. Buckner,et al.  The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. , 2007, Neuro-oncology.

[89]  James M Provenzale,et al.  Correlation of relative permeability and relative cerebral blood volume in high-grade cerebral neoplasms. , 2006, AJR. American journal of roentgenology.

[90]  C. Claussen,et al.  Simultaneous Mr/pet Imaging of the Human Brain: Feasibility Study 1 , 2022 .

[91]  Roland Kreis,et al.  Development of the human brain: In vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy , 1993, Magnetic resonance in medicine.

[92]  M. Nikiforova,et al.  1p/19q testing has no significance in the workup of glioblastomas , 2013, Neuropathology and applied neurobiology.

[93]  S. Berlangieri,et al.  Correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in gliomas using 18F-fluoromisonidazole, 18F-FDG PET, and immunohistochemical studies. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[94]  Glyn Johnson,et al.  Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. , 2003, AJNR. American journal of neuroradiology.

[95]  Ying Lu,et al.  Analysis of the spatial characteristics of metabolic abnormalities in newly diagnosed glioma patients , 2002, Journal of magnetic resonance imaging : JMRI.

[96]  I. Kanno,et al.  Clinical positron emission tomography for brain tumors: comparison of fludeoxyglucose F 18 and L-methyl-11C-methionine. , 1996, AJNR. American journal of neuroradiology.

[97]  F. O’Sullivan,et al.  Regional Hypoxia in Glioblastoma Multiforme Quantified with [18F]Fluoromisonidazole Positron Emission Tomography before Radiotherapy: Correlation with Time to Progression and Survival , 2008, Clinical Cancer Research.

[98]  M. Berger,et al.  The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. , 1999, Surgical neurology.

[99]  M. Sasaki,et al.  Carbon-11-methionine PET in focal cortical dysplasia: a comparison with fluorine-18-FDG PET and technetium-99m-ECD SPECT. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[100]  P. Gardner,et al.  What are the limits of endoscopic sinus surgery?: the expanded endonasal approach to the skull base. , 2009, The Keio journal of medicine.

[101]  Karl Herholz,et al.  Use of 11C-methionine PET to monitor the effects of temozolomide chemotherapy in malignant gliomas , 2006, European Journal of Nuclear Medicine and Molecular Imaging.

[102]  A. Brandes,et al.  MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[103]  W Cramer,et al.  On the Origin of Cancer* , 1938, British medical journal.

[104]  R. Stupp,et al.  Should biomarkers be used to design personalized medicine for the treatment of glioblastoma? , 2010, Future oncology.

[105]  Susan M. Chang,et al.  Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[106]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[107]  J. Engh,et al.  Endoneurosurgical resection of intraventricular and intraparenchymal lesions using the port technique. , 2013, World neurosurgery.

[108]  D. Nam,et al.  Expression of VEGF and brain specific angiogenesis inhibitor-1 in glioblastoma: prognostic significance. , 2004, Oncology reports.

[109]  E. Weltman,et al.  Radiosurgical Boost for Primary High-grade Gliomas , 2002, Journal of Neuro-Oncology.

[110]  S. Cha,et al.  Update on brain tumor imaging: from anatomy to physiology. , 2006, AJNR. American journal of neuroradiology.

[111]  W. Mason,et al.  Phase III Trial of Bevacizumab Added to Standard Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma: Final Progression-Free Survival and Preliminary Overall Survival Results from AVAglio (PL02.002) , 2013 .

[112]  Tracy T Batchelor,et al.  AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. , 2007, Cancer cell.

[113]  F. Davis,et al.  Epidemiology of brain tumors. , 2000, Current opinion in neurology.

[114]  R. Sevick,et al.  How often are nonenhancing supratentorial gliomas malignant? A population study , 2002, Neurology.

[115]  A. Brandes,et al.  Treatment options for recurrent glioblastoma: pitfalls and future trends , 2009, Expert review of anticancer therapy.

[116]  Tao Jiang,et al.  Understanding high grade glioma: molecular mechanism, therapy and comprehensive management. , 2013, Cancer letters.

[117]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[118]  Heinrich Lanfermann,et al.  Increased choline levels coincide with enhanced proliferative activity of human neuroepithelial brain tumors , 2002, NMR in biomedicine.

[119]  Wei Chen,et al.  Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[120]  D. Louis,et al.  Survey of treatment recommendations for anaplastic oligodendroglioma. , 2007, Neuro-oncology.

[121]  John A Butman,et al.  Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[122]  E. Alexander,et al.  Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. , 1978, Journal of neurosurgery.

[123]  B. Beuthien-Baumann,et al.  3-O-methyl-6-18F-fluoro-L-dopa, a new tumor imaging agent: investigation of transport mechanism in vitro. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[124]  A. Brandes,et al.  Correlations between O6-methylguanine DNA methyltransferase promoter methylation status, 1p and 19q deletions, and response to temozolomide in anaplastic and recurrent oligodendroglioma: a prospective GICNO study. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[125]  P. Salunke,et al.  Molecular markers of glioma: an update on recent progress and perspectives , 2012, Journal of Cancer Research and Clinical Oncology.

[126]  Geoffrey S Young,et al.  Advanced MRI of adult brain tumors. , 2007, Neurologic clinics.

[127]  Branislav Jeremic,et al.  L-(methyl-11C) methionine positron emission tomography for target delineation in resected high-grade gliomas before radiotherapy. , 2005, International journal of radiation oncology, biology, physics.

[128]  Napoleone Ferrara,et al.  Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. , 2005, Biochemical and biophysical research communications.

[129]  S. Goldman,et al.  Prognostic value positron emission tomography with [18F]fluoro-2-deoxy-D-glucose in the low-grade glioma. , 1996, Neurosurgery.

[130]  Robert Jeraj,et al.  RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[131]  R M Weisskoff,et al.  Relative cerebral blood volume maps corrected for contrast agent extravasation significantly correlate with glioma tumor grade, whereas uncorrected maps do not. , 2006, AJNR. American journal of neuroradiology.

[132]  A. Gregory Sorensen,et al.  Angiogenesis in brain tumours , 2007, Nature Reviews Neuroscience.

[133]  O. Warburg [Origin of cancer cells]. , 1956, Oncologia.

[134]  P. Gutin,et al.  Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. , 1986, Journal of neurosurgery.

[135]  Heinrich Lanfermann,et al.  1H MRSI and progression-free survival in patients with WHO grades II and III gliomas , 2010, Neurological research.

[136]  Maria Werner-Wasik,et al.  Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. , 2004, International journal of radiation oncology, biology, physics.

[137]  R. Mirimanoff,et al.  Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. , 2009, The Lancet. Oncology.

[138]  A. Alavi,et al.  PET imaging for differentiating recurrent brain tumor from radiation necrosis. , 2005, Radiologic clinics of North America.

[139]  M. Castillo,et al.  Proton MR spectroscopy in neoplastic and non-neoplastic brain disorders. , 1998, Magnetic resonance imaging clinics of North America.

[140]  Seung-Koo Lee,et al.  Diffusion tensor and perfusion imaging of brain tumors in high-field MR imaging. , 2012, Neuroimaging clinics of North America.

[141]  P. Wen,et al.  An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma , 2009, Journal of Neuro-Oncology.

[142]  Matthias Hofmann,et al.  Hybrid PET/MRI of Intracranial Masses: Initial Experiences and Comparison to PET/CT , 2010, The Journal of Nuclear Medicine.

[143]  Wolfgang A. Weber,et al.  O-(2-[18F]Fluoroethyl)-l-tyrosine and l-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study , 2000, European Journal of Nuclear Medicine.

[144]  J van de Geijn,et al.  The imaging revolution and radiation oncology: use of CT, ultrasound, and NMR for localization, treatment planning and treatment delivery. , 1985, International journal of radiation oncology, biology, physics.

[145]  A. Waldman,et al.  Low-grade gliomas: do changes in rCBV measurements at longitudinal perfusion-weighted MR imaging predict malignant transformation? , 2008, Radiology.

[146]  K. Ericson,et al.  FDG-PET on irradiated brain tumor: ten years' summary , 2006, Acta Radiologica.

[147]  D L McShan,et al.  A quantitative assessment of the addition of MRI to CT-based, 3-D treatment planning of brain tumors. , 1992, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[148]  K. Wallner,et al.  Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. , 1989, International journal of radiation oncology, biology, physics.

[149]  T. Todo,et al.  Extended field stereotactic radiosurgery for recurrent glioblastoma , 2012, Cancer.

[150]  J. Kirkpatrick,et al.  Stereotactic radiosurgery and bevacizumab for recurrent glioblastoma multiforme. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[151]  B. Munch‐Petersen,et al.  Human thymidine kinase 1. Regulation in normal and malignant cells. , 1995, Advances in enzyme regulation.

[152]  B. Miller A review of chemical issues in 1H NMR spectroscopy: N‐acetyl‐l‐aspartate, creatine and choline , 1991, NMR in biomedicine.

[153]  A. Falini,et al.  Anatomical and biochemical investigation of primary brain tumours , 2001, European Journal of Nuclear Medicine.

[154]  J. Brown,et al.  Therapeutic targets in radiotherapy. , 2001, International journal of radiation oncology, biology, physics.

[155]  R. Blasberg,et al.  “Facilitated” Amino Acid Transport is Upregulated in Brain Tumors , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[156]  R. Maciunas,et al.  Optimal cutoff levels of F-18 fluorodeoxyglucose uptake in the differentiation of low-grade from high-grade brain tumors with PET. , 1995, Radiology.

[157]  R. Arceci Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma , 2010 .

[158]  N. Saito,et al.  Role of Gamma Knife Radiosurgery in Neurosurgery: Past and Future Perspectives , 2010 .

[159]  K. Ichimura Molecular pathogenesis of IDH mutations in gliomas , 2012, Brain Tumor Pathology.

[160]  Mustafa Khasraw,et al.  Advances in the Treatment of Malignant Gliomas , 2010, Current oncology reports.

[161]  R. McLendon,et al.  A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. , 2011, Journal of the National Comprehensive Cancer Network : JNCCN.

[162]  O. Witte,et al.  Positron emission tomography with injection of methionine as a prognostic factor in glioma. , 2001, Journal of neurosurgery.

[163]  B. Weber,et al.  Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[164]  Mitchel S. Berger,et al.  Magnetic Resonance of 2-Hydroxyglutarate in IDH1-Mutated Low-Grade Gliomas , 2012, Science Translational Medicine.

[165]  Mark Muzi,et al.  True tracers: comparing FDG with glucose and FLT with thymidine. , 2005, Nuclear medicine and biology.

[166]  Cuthbert Dukes,et al.  Origin of Cancer , 1938 .

[167]  Elke Hattingen,et al.  Prognostic value of choline and creatine in WHO grade II gliomas , 2008, Neuroradiology.

[168]  T. Seike,et al.  Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis , 2010, Clinical & Experimental Metastasis.

[169]  Timothy F Cloughesy,et al.  Clinical trial end points for high-grade glioma: the evolving landscape. , 2011, Neuro-oncology.

[170]  M. Wyss,et al.  Early metabolic responses in temozolomide treated low-grade glioma patients , 2009, Journal of Neuro-Oncology.

[171]  A. Lassman Success at Last: A Molecular Factor That Informs Treatment , 2013, Current Oncology Reports.

[172]  W Vaalburg,et al.  Radiolabeled amino acids: basic aspects and clinical applications in oncology. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[173]  D. Langleben,et al.  PET in differentiation of recurrent brain tumor from radiation injury. , 2000, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[174]  P. Keegan,et al.  FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. , 2009, The oncologist.

[175]  Patrick Y Wen,et al.  End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald's Criteria. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[176]  R. McLendon,et al.  Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. , 2011, Neuro-oncology.

[177]  D. Louis,et al.  Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? , 2013, Nature Reviews Clinical Oncology.

[178]  R. Barnard,et al.  The classification of tumours of the central nervous system. , 1982, Neuropathology and applied neurobiology.

[179]  J. Herman,et al.  Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[180]  Dieta Brandsma,et al.  Incidence of early pseudo‐progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide , 2008, Cancer.

[181]  P. Hecke,et al.  Gadolinium-enhanced MRI of intracranial lesions. A review of indications and results. , 1991, Clinical imaging.

[182]  D. Kondziolka,et al.  Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. , 1997, Neurosurgery.

[183]  A. Jackson,et al.  Comparative study into the robustness of compartmental modeling and model‐free analysis in DCE‐MRI studies , 2006, Journal of magnetic resonance imaging : JMRI.

[184]  E. Winer,et al.  CNS metastases in breast cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[185]  Tarik Tihan,et al.  Volumetric extent of resection and residual contrast enhancement on initial surgery as predictors of outcome in adult patients with hemispheric anaplastic astrocytoma. , 2006, Journal of neurosurgery.

[186]  T. Tamiya,et al.  11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[187]  Paul S Mischel,et al.  MR imaging correlates of survival in patients with high-grade gliomas. , 2005, AJNR. American journal of neuroradiology.

[188]  Hans Clevers,et al.  Wnt/β-Catenin Signaling and Disease , 2012, Cell.

[189]  C. Degueldre,et al.  Preoperative evaluation of 54 gliomas by PET with fluorine-18-fluorodeoxyglucose and/or carbon-11-methionine. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[190]  B. Radotra,et al.  Quantitation of angiogenesis and its correlation with vascular endothelial growth factor expression in astrocytic tumors. , 2004, Analytical and quantitative cytology and histology.

[191]  W. Koch,et al.  Positron Emission Tomography with O-(2-[18F]fluoroethyl)-l-tyrosine versus Magnetic Resonance Imaging in the Diagnosis of Recurrent Gliomas , 2005, Neurosurgery.

[192]  L. Chin,et al.  Gamma Knife Stereotactic Radiosurgery for Patients with Glioblastoma Multiforme , 2002, Neurosurgery.

[193]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[194]  P. Gutin,et al.  Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches , 2011, Radiation oncology.

[195]  P. Kleihues,et al.  Genetic pathways to primary and secondary glioblastoma. , 2007, The American journal of pathology.

[196]  Fred H. Hochberg,et al.  Assumptions in the radiotherapy of glioblastoma , 1980, Neurology.

[197]  R. Board,et al.  The use of systemic therapies for the treatment of brain metastases in metastatic melanoma: opportunities and unanswered questions. , 2013, Cancer treatment reviews.

[198]  L. Mariani,et al.  Frequent BRAF Gain in Low‐Grade Diffuse Gliomas with 1p/19q Loss , 2012, Brain pathology.

[199]  L. Wiens,et al.  Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[200]  Karl-Josef Langen,et al.  O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. , 2005, Brain : a journal of neurology.

[201]  Wei Chen,et al.  18F-FDOPA PET imaging of brain tumors: comparison study with 18F-FDG PET and evaluation of diagnostic accuracy. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[202]  Allan H Friedman,et al.  Phase II trial of gefitinib in recurrent glioblastoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[203]  B. Drayer,et al.  Differentiating recurrent tumor from radiation necrosis: time for re-evaluation of positron emission tomography? , 1998, AJNR. American journal of neuroradiology.

[204]  E. Shaw,et al.  Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[205]  D. Hwang,et al.  Prediction of Pathology and Survival by FDG PET in Gliomas , 2003, Journal of Neuro-Oncology.

[206]  Matthew J. Oborski,et al.  Distinguishing pseudoprogression from progression in high-grade gliomas: a brief review of current clinical practice and demonstration of the potential value of 18F-FDG PET. , 2013, Clinical nuclear medicine.

[207]  Habib Zaidi,et al.  [(18)F]Fluoroethyltyrosine- positron emission tomography-guided radiotherapy for high-grade glioma , 2008, Radiation oncology.

[208]  I. Yamamoto,et al.  Cerebral haemodynamics in patients with hydrocephalus after subarachnoid haemorrhage due to ruptured aneurysm , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[209]  E. Krenning,et al.  Somatostatin receptor scintigraphy in the follow-up of patients with differentiated thyroid cancer , 2001, Journal of endocrinological investigation.

[210]  V. Sturm,et al.  Glucose consumption and methionine uptake in low-grade gliomas after iodine-125 brachytherapy , 1996, European Journal of Nuclear Medicine.

[211]  G. Reifenberger,et al.  The WHO Classification of Tumors of the Nervous System , 2002, Journal of neuropathology and experimental neurology.

[212]  O. Witte,et al.  Radiation necrosis or recurrence. , 1996, Journal of neurosurgery.

[213]  N. Dorward,et al.  Clinical Validation of True Frameless Stereotactic Biopsy: Analysis of the First 125 Consecutive Cases , 2001, Neurosurgery.

[214]  Mitchel S Berger,et al.  Functional outcome after language mapping for glioma resection. , 2008, The New England journal of medicine.

[215]  H. Lanfermann,et al.  Cerebral gliomas: diffusional kurtosis imaging analysis of microstructural differences. , 2010, Radiology.

[216]  Karl Herholz,et al.  18F-fluoro-L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[217]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[218]  M. J. van den Bent,et al.  Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[219]  P. J. Hoopes,et al.  Central nervous system tumors. , 1995, Seminars in veterinary medicine and surgery.

[220]  P. Brastianos,et al.  Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis , 2011, Journal of Neuro-Oncology.

[221]  J. Helpern,et al.  MRI quantification of non‐Gaussian water diffusion by kurtosis analysis , 2010, NMR in biomedicine.

[222]  M. Schocke,et al.  ADC histograms predict response to anti-angiogenic therapy in patients with recurrent high-grade glioma , 2011, Neuroradiology.

[223]  G. Barnett,et al.  The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery , 2001, International journal of cancer.

[224]  V. Heinemann,et al.  Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. , 2006, Breast.

[225]  M. J. van den Bent,et al.  Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[226]  Matthew S. Brown,et al.  Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. , 2009, Radiology.

[227]  Mark Muzi,et al.  [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: clinical outcomes and patterns of failure. , 2006, International journal of radiation oncology, biology, physics.

[228]  W P Dillon,et al.  Radiation injury of the brain. , 1991, AJNR. American journal of neuroradiology.

[229]  Paul S Mischel,et al.  Will kinase inhibitors make it as glioblastoma drugs? , 2012, Current topics in microbiology and immunology.

[230]  Jill S Barnholtz-Sloan,et al.  Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[231]  M. Senda,et al.  Clinical impact of 11C-methionine PET on expected management of patients with brain neoplasm , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[232]  Paul S Mischel,et al.  Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[233]  Thomas Czech,et al.  Brain tumour imaging with PET: a comparison between [18F]fluorodopa and [11C]methionine , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[234]  M Schwaiger,et al.  The value of F-18-fluorodeoxyglucose PET for the 3-D radiation treatment planning of malignant gliomas. , 1998, International journal of radiation oncology, biology, physics.

[235]  A. Jacobs,et al.  Neuroimaging in patients with gliomas. , 2008, Seminars in neurology.

[236]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[237]  L. Deangelis Anaplastic glioma: how to prognosticate outcome and choose a treatment strategy. [corrected]. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[238]  H. Duffau,et al.  Usefulness of intraoperative electrical subcortical mapping during surgery for low-grade gliomas located within eloquent brain regions: functional results in a consecutive series of 103 patients. , 2003, Journal of neurosurgery.

[239]  W. Nyhan,et al.  The uptake of a variety of amino acids into nuclear proteins of tumors and other tissues. , 1959, Cancer research.