Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor. Although clinical presentation and brain imaging might be suggestive, histopathological evaluation by means of a brain biopsy is routinely performed to establish the diagnosis. A serum marker indicative of GBM may simplify the diagnostic work-up of patients suspected to having a brain tumor. We prospectively examined 113 patients with newly diagnosed single supratentorial or infratentorial space-occupying brain lesions. Glial fibrillary acidic protein (GFAP) levels were determined from venous blood samples via a prototype ELISA assay prior to any invasive procedures. Serum levels of GFAP were correlated with histopathological findings and MRI parameters. GFAP values were significantly higher in GBM patients (n = 33) compared to all other tumors (p < 0.001). A GFAP serum concentration of ≥0.01 µg/L revealed a sensitivity of 85 % and a specificity of 70 % for differentiating GBM from other entities. By applying a GFAP cut-off point of 0.20 µg/L, specificity was maximized (99 %), but sensitivity dropped to 27 %. In GBM patients, serum GFAP values were significantly correlated with tumor volume. GBM patients with high GFAP levels showed more in vivo GFAP expression as well as more necrosis and perilesional edema compared to GBM patients having low or non-detectable GFAP levels. GFAP serum concentrations differentiated between patients with GBM and patients with cerebral mass lesions of other entities with a moderate diagnostic accuracy. Serum GFAP levels in GBM patients were positively correlated with tumor volume and histopathological tumor characteristics.
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Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899
Okonogi N, Shirai K, Oike T, Murata K, Noda SE, Suzuki Y, Nakano T (2015) Topics in chemotherapy, molecular-targeted therapy, and immunotherapy for newly-diagnosed glioblastoma multiforme. Anticancer Res 35:1229–1235
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
Eng LF (1985) Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes. J Neuroimmunol 8:203–214
Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 25:1439–1451
Brommeland T, Rosengren L, Fridlund S, Hennig R, Isaksen V (2007) Serum levels of glial fibrillary acidic protein correlate to tumour volume of high-grade gliomas. Acta Neurol Scand 116:380–384
Gallego Perez-Larraya J, Paris S, Idbaih A, Dehais C, Laigle-Donadey F, Navarro S, Capelle L, Mokhtari K, Marie Y, Sanson M, Hoang-Xuan K, Delattre JY, Mallet A (2014) Diagnostic and prognostic value of preoperative combined GFAP, IGFBP-2, and YKL-40 plasma levels in patients with glioblastoma. Cancer 120:3972–3980
Jung CS, Foerch C, Schanzer A, Heck A, Plate KH, Seifert V, Steinmetz H, Raabe A, Sitzer M (2007) Serum GFAP is a diagnostic marker for glioblastoma multiforme. Brain 130:3336–3341
Jung CS, Unterberg AW, Hartmann C (2011) Diagnostic markers for glioblastoma. Histol Histopathol 26:1327–1341
Diaz-Arrastia R, Wang KK, Papa L, Sorani MD, Yue JK, Puccio AM, McMahon PJ, Inoue T, Yuh EL, Lingsma HF, Maas AI, Valadka AB, Okonkwo DO, Manley GT (2014) Acute biomarkers of traumatic brain injury: relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. J Neurotrauma 31:19–25
Foerch C, Niessner M, Back T, Bauerle M, De Marchis GM, Ferbert A, Grehl H, Hamann GF, Jacobs A, Kastrup A, Klimpe S, Palm F, Thomalla G, Worthmann H, Sitzer M (2012) Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke. Clin Chem 58:237–245
Nduom EK, Yang C, Merrill MJ, Zhuang Z, Lonser RR (2013) Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms. J Neurosurg 119:427–433
Yung WK, Luna M, Borit A (1985) Vimentin and glial fibrillary acidic protein in human brain tumors. J Neurooncol 3:35–38
Lyubimova NV, Toms MG, Popova EE, Bondarenko YV, Krat VB, Kushlinskii NE (2011) Neurospecific proteins in the serum of patients with brain tumors. Bull Exp Biol Med 150:732–734
Larsson IM, Wallin E, Kristofferzon ML, Niessner M, Zetterberg H, Rubertsson S (2014) Post-cardiac arrest serum levels of glial fibrillary acidic protein for predicting neurological outcome. Resuscitation 85:1654–1661
Mayer CA, Brunkhorst R, Niessner M, Pfeilschifter W, Steinmetz H, Foerch C (2013) Blood levels of glial fibrillary acidic protein (GFAP) in patients with neurological diseases. PLoS One 8:e62101
Kleihues P, Burger PC, Scheithauer BW (1993) The new WHO classification of brain tumours. Brain Pathol 3:255–268
Harter PN, Bunz B, Dietz K, Hoffmann K, Meyermann R, Mittelbronn M (2010) Spatio-temporal deleted in colorectal cancer (DCC) and netrin-1 expression in human foetal brain development. Neuropathol Appl Neurobiol 36:623–635
Wang K, Wang YY, Ma J, Wang JF, Li SW, Jiang T, Dai JP (2014) Prognostic value of MGMT promoter methylation and TP53 mutation in glioblastomas depends on IDH1 mutation. Asian Pac J Cancer Prev 15:10893–10898
Weller M, Tabatabai G, Kastner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bahr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Husing J, Reifenberger G, Wick W (2015) MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin Cancer Res 21(9):2057–2064
Weise LM, Harter PN, Eibach S, Braczynski AK, Dunst M, Rieger J, Bahr O, Hattingen E, Steinbach JP, Plate KH, Seifert V, Mittelbronn M (2014) Confounding factors in diagnostics of MGMT promoter methylation status in glioblastomas in stereotactic biopsies. Stereotact Funct Neurosurg 92:129–139
Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J (1996) The ABCs of measuring intracerebral hemorrhage volumes. Stroke 27:1304–1305
Papa L, Silvestri S, Brophy GM, Giordano P, Falk JL, Braga CF, Tan CN, Ameli NJ, Demery JA, Dixit NK, Mendes ME, Hayes RL, Wang KK, Robertson CS (2014) GFAP out-performs S100beta in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. J Neurotrauma 31:1815–1822
Petzold A (2015) Glial fibrillary acidic protein is a body fluid biomarker for glial pathology in human disease. Brain Res 1600:17–31
Lyubimova NV, Toms MG, Fu RG, Bondarenko YV (2013) Biochemical markers of brain tumours. Klin Lab Diagn 71–72:40–72
Wilhelmsson U, Eliasson C, Bjerkvig R, Pekny M (2003) Loss of GFAP expression in high-grade astrocytomas does not contribute to tumor development or progression. Oncogene 22:3407–3411
Brunkhorst R, Pfeilschifter W, Foerch C (2010) Astroglial proteins as diagnostic markers of acute intracerebral hemorrhage-pathophysiological background and clinical findings. Transl Stroke Res 1:246–251
Noreen F, Roosli M, Gaj P, Pietrzak J, Weis S, Urfer P, Regula J, Schar P, Truninger K (2014) Modulation of age- and cancer-associated DNA methylation change in the healthy colon by aspirin and lifestyle. J Natl Cancer Inst 106(7):dju161
Kiviniemi A, Gardberg M, Frantzen J, Parkkola R, Vuorinen V, Pesola M, Minn H (2015) Serum levels of GFAP and EGFR in primary and recurrent high-grade gliomas: correlation to tumor volume, molecular markers, and progression-free survival. J Neurooncol 124:237–245
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Tichy, J., Spechtmeyer, S., Mittelbronn, M. et al. Prospective evaluation of serum glial fibrillary acidic protein (GFAP) as a diagnostic marker for glioblastoma. J Neurooncol 126, 361–369 (2016). https://doi.org/10.1007/s11060-015-1978-8
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DOI: https://doi.org/10.1007/s11060-015-1978-8