Extent of tumor removal and molecular markers in cerebral glioblastoma: a combined prognostic factors study in a surgical series of 105 patients

Clinical article

View More View Less
  • 1 Department of Neurosurgery INM—IRCCS Neuromed, Pozzilli (Isernia), University of Rome “Sapienza;” and Department of Neurological Sciences—
  • 2 Neurosurgery and
  • 3 Neuroradiology, and
  • 4 Department of Psychology, Sapienza University of Rome, Italy
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

Object

In this paper, the authors' goal was to evaluate the prognostic value of YKL-40 expression as a prognostic factor for glioblastomas and to compare its validity to the already known MGMT.

Methods

Between January 2002 and January 2007, 105 patients were treated for cerebral glioblastoma. The extent of removal was classified in 4 groups. YKL-40 expression was evaluated by a semiquantitative immunohistochemical staining scale (0, no staining; 1, mild expression; and 2, strong expression). MGMT promoter methylation status was analyzed with methylation-specific polymerase chain reaction. All patients received adjuvant radiotherapy and chemotherapy. Kaplan-Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS), and to compare these parameters between the subgroups stratified by extent of surgical removal, MGMT methylation, and YKL-40 expression. The log-rank test was used to determine statistical significance. A multivariate regression analysis was applied to extent of removal, YKL-40 expression, and MGMT status to check their specific statistical power and to test the independence of the variables.

Results

There were 55 men and 50 women with a mean age of 58 years. Extent of surgical removal is reported. The MGMT promoter was methylated in 48 patients and nonmethylated in 57. Analysis of YKL-40 expression is reported. The median PFS was 10.7 months (14.9 months in the gross-total removal subgroup) (p < 0.0001), and the median OS was 12.5 months (17.4 months in the gross-total removal group) (p < 0.0001). In the univariate analysis, OS was significantly correlated to the extent of resection (p < 0.0001), MGMT status (p < 0.0001), and YKL-40 (p < 0.0001). Multivariate analysis showed that all 3 factors reached statistical significance with respect to patient survival. In particular, surgical removal contributed more than the 2 other factors to the survival prediction (β = −0.6254). Interestingly, YKL-40 (β = −0.3867) contributed more than MGMT (β = −0.1705) to the predicted survival.

Conclusions

The extent of removal is the most important factor influencing the OS of patients harboring glioblastomas. When biological aggressiveness is taken into account, YKL-40 expression was found to be an independent prognostic factor that predicts OS better than MGMT status.

Abbreviations used in this paper:KPS = Karnofsky Performance Scale; OS = overall survival; PCR = polymerase chain reaction; PFS = progression-free survival.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address correspondence to: Maurizio Salvati, M.D., Via Cardinal Agliardi 15, 00165 Rome, Italy. email: salvati.maurizio@libero.it.

Please include this information when citing this paper: published online June 1, 2012; DOI: 10.3171/2012.4.JNS101702.

  • 1

    Bhat KP, , Pelloski CE, , Zhang Y, , Kim SH, , deLaCruz C, & Rehli M, : Selective repression of YKL-40 by NF-kappaB in glioma cell lines involves recruitment of histone deacetylase-1 and -2. FEBS Lett 582:31933200, 2008

    • Search Google Scholar
    • Export Citation
  • 2

    Boisselier B, , Marie Y, , El Hallani S, , Kaloshi G, , Iershov A, & Kavsan V, : No association of (−131C→G) variant of CHI3L1 gene with risk of glioblastoma and prognosis. J Neurooncol 94:169172, 2009

    • Search Google Scholar
    • Export Citation
  • 3

    Cao VT, , Jung TY, , Jung S, , Jin SG, , Moon KS, & Kim IY, : The correlation and prognostic significance of MGMT promoter methylation and MGMT protein in glioblastomas. Neurosurgery 65:866875, 2009

    • Search Google Scholar
    • Export Citation
  • 4

    Dunn J, , Baborie A, , Alam F, , Joyce K, , Moxham M, & Sibson R, : Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124131, 2009

    • Search Google Scholar
    • Export Citation
  • 5

    Esteller M, , Garcia-Foncillas J, , Andion E, , Goodman SN, , Hidalgo OF, & Vanaclocha V, : Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:13501354, 2000

    • Search Google Scholar
    • Export Citation
  • 6

    Hegi ME, , Diserens AC, , Godard S, , Dietrich PY, , Regli L, & Ostermann S, : Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:18711874, 2004

    • Search Google Scholar
    • Export Citation
  • 7

    Hegi ME, , Diserens AC, , Gorlia T, , Hamou MF, , de Tribolet N, & Weller M, : MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:9971003, 2005

    • Search Google Scholar
    • Export Citation
  • 8

    Hentschel SJ, & Sawaya R: Optimizing outcomes with maximal surgical resection of malignant gliomas. Cancer Contr 10:109114, 2003

  • 9

    Junker N, , Johansen JS, , Hansen LT, , Lund EL, & Kristjansen PE: Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells. Cancer Sci 96:183190, 2005

    • Search Google Scholar
    • Export Citation
  • 10

    Karayan-Tapon L, , Quillien V, , Guilhot J, , Wager M, , Fromont G, & Saikali S, : Prognostic value of O6-methylguanine-DNA methyltransferase status in glioblastoma patients, assessed by five different methods. J Neurooncol 97:311322, 2010

    • Search Google Scholar
    • Export Citation
  • 11

    Keles GE, , Lamborn KR, , Chang SM, , Prados MD, & Berger MS: Volume of residual disease as a predictor of outcome in adult patients with recurrent supratentorial glioblastomas multiforme who are undergoing chemotherapy. J Neurosurg 100:4146, 2004

    • Search Google Scholar
    • Export Citation
  • 12

    Lacroix M, , Abi-Said D, , Fourney DR, , Gokaslan ZL, , Shi W, & DeMonte F, : A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190198, 2001

    • Search Google Scholar
    • Export Citation
  • 13

    Louis DN, , Ohgaki H, , Wiestler OD, & Cavenee WK: World Health Organization Classification of Tumours of the Central Nervous System ed 4 Lyon, IARC Press, 2007

    • Search Google Scholar
    • Export Citation
  • 14

    McKinney PA: Brain tumors: incidence, survival, and etiology. J Neurol Neurosurg Psychiatry 75 Suppl 2 75:1217, 2004

  • 15

    Metellus P, , Coulibaly B, , Nanni I, , Fina F, , Eudes N, & Giorgi R, : Prognostic impact of O6-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort. Cancer 115:47834794, 2009

    • Search Google Scholar
    • Export Citation
  • 16

    Nigro JM, , Misra A, , Zhang L, , Smirnov I, , Colman H, & Griffin C, : Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res 65:16781686, 2005

    • Search Google Scholar
    • Export Citation
  • 17

    Nutt CL, , Betensky RA, , Brower MA, , Batchelor TT, , Louis DN, & Stemmer-Rachamimov AO: YKL-40 is a differential diagnostic marker for histologic subtypes of high-grade gliomas. Clin Cancer Res 11:22582264, 2005

    • Search Google Scholar
    • Export Citation
  • 18

    Ohgaki H, , Dessen P, , Jourde B, , Horstmann S, , Nishikawa T, & Di Patre PL, : Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:68926899, 2004

    • Search Google Scholar
    • Export Citation
  • 19

    Ohgaki H, & Kleihues P: Epidemiology and etiology of gliomas. Acta Neuropathol 109:93108, 2005

  • 20

    Parkinson JF, , Wheeler HR, , Clarkson A, , McKenzie CA, , Biggs MT, & Little NS, : Variation of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in serial samples in glioblastoma. J Neurooncol 87:7178, 2008

    • Search Google Scholar
    • Export Citation
  • 21

    Pelloski CE, , Lin E, , Zhang L, , Yung WK, , Colman H, & Liu JL, : Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res 12:39353941, 2006

    • Search Google Scholar
    • Export Citation
  • 22

    Pelloski CE, , Mahajan A, , Maor M, , Chang EL, , Woo S, & Gilbert M, : YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res 11:33263334, 2005

    • Search Google Scholar
    • Export Citation
  • 23

    Salvati M, , Formichella AI, , D'Elia A, , Brogna C, , Frati A, & Giangaspero F, : Cerebral glioblastoma with oligodendrogliomal component: analysis of 36 cases. J Neurooncol 94:129134, 2009

    • Search Google Scholar
    • Export Citation
  • 24

    Schold SC Jr, , Kokkinakis DM, , Chang SM, , Berger MS, , Hess KR, & Schiff D, : O6-benzylguanine suppression of O6-alkylguanine-DNA alkyltransferase in anaplastic gliomas. Neuro Oncol 6:2832, 2004

    • Search Google Scholar
    • Export Citation
  • 25

    Sonoda Y, , Kumabe T, , Watanabe M, , Nakazato Y, , Inoue T, & Kanamori M, : Long-term survivors of glioblastoma: clinical features and molecular analysis. Acta Neurochir (Wien) 151:13491358, 2009

    • Search Google Scholar
    • Export Citation
  • 26

    Stupp R, , Mason WP, , van den Bent MJ, , Weller M, , Fisher B, & Taphoorn MJ, : Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987996, 2005

    • Search Google Scholar
    • Export Citation
  • 27

    Tanwar MK, , Gilbert MR, & Holland EC: Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma. Cancer Res 62:43644368, 2002

    • Search Google Scholar
    • Export Citation
  • 28

    Wrensch M, , Fisher JL, , Schwartzbaum JA, , Bondy M, , Berger M, & Aldape KD: The molecular epidemiology of gliomas in adults. Neurosurg Focus 19:5 E5, 2005

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 366 117 10
Full Text Views 187 11 0
PDF Downloads 75 5 0
EPUB Downloads 0 0 0