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The epidermal growth factor receptor (EGFR) gene is frequently amplified and mutated in high-grade glioma (HGG). Immunohistochemical staining for the EGFRvIII mutant is a negative prognostic factor for patients with anaplastic glioma (Buckner et al., J. Clin. Oncol. 22 (14S), 1508, 2004). We investigated the prognostic and predictive value of EGFR-gene amplification determined with fl uorescence in situ hybridization (FISH) in HGG treated with temozolomide (Temodal, TMZ) at recurrence following surgery and radiotherapy. Clinical data and tumor material were collected from a retrospective cohort of patients treated at 4 Belgian hospitals. All patients were treated with TMZ at recurrence. In addition to conventional diagnostic histopathology, HGG were characterized by FISH for the amplification status of the EGFR-gene (Vysis, LSI EGFR/CEP 7 Dual Color Probe). Our patient population consisted of 36 men and 22 women (N 58) with a median age of 58 years (range, 16-80 years). At the initiation of TMZ treatment, tumors consisted of 14 AA/AOA and 44 GBM. Eighteen tumors were found to have an amplification of the EGFR gene (4/14 AA/AOA, 14/44 GBM). No signifi cant association was found between EGFR-gene amplifi cation and sex, age (at diagnosis or at initiation of TMZ), glioma localization, type of surgery (resection versus biopsy), histology (at diagnosis or at initiation of TMZ), the interval between diagnosis of HGG and the initiation of TMZ, or response to TMZ (objective response or disease control). We found no signifi cant correlation between EGFR-gene amplification and time to progression or overall survival following the initiation of TMZ treatment (Kaplan-Meier survival statistics, log-rank test, P

Gliomas are the most frequent primary brain tumors. They are derived from glial cells of astrocytic, oligodendroglial and ependymal origin. According to the WHO classification of brain tumors gliomas are divided in low-grade (grades I and II) and high-grade (grades III and IV) tumors. Low-grade tumors are well-differentiated, slow-growing lesions. Grade I tumors are well-circumscribed and often surgically curable, whereas grade II tumors are diffuse, infiltrating lesions with a marked potential over time for progression towards a high-grade malignant tumor. The optimal management of low-grade gliomas is still debated. Important prognostic factors such as histology, grade and location of the tumor, age and functional status of the patient, must be taken into consideration to select the most appropriate treatment. Major advances in the molecular genetic assessment of brain tumors and of gliomas in particular have lead to the identification of several molecular markers playing a crucial role in the development of gliomas and in their malignant transformation. Some of those markers were found very useful to assist in the histological diagnosis and to predict survival and response to therapy. A combined deletion of chromosomes arms 1p and 19q can be found in more than 50% of Grade II and III oligodendrogliomas and has been associated with chemosensitivity and a better prognosis. Once limited to the field of research, molecular biology has now entered the daily neuropathological practice and will undoubtedly play an increasing role in future classification and treatment of brain tumors.

Background: Tumor specific molecular-genetic features determine the prognosis and sensitivity to alkylating agents of central nervous system gliomas. The O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter is often hypermethylated in high-grade gliomas (HGG) and is a major determinant of the sensitivity to alkylating agents. The tumor suppressor gene p53 is a frequent target for mutation but its importance as a prognostic or predictive marker has not been established. We investigated the correlation between MGMT methylation status and p53 immunohistochemical staining and the benefit from treatment with temozolomide in patients with recurrent HGG. Patients and Methods: A real-time, quantitative methylation-specific PCR (QMSP) assay for the determination of the MGMT promoter methylation status and immunohistochemical staining for p53 TSG were performed on archival tissue blocks from 38 glioma patients (22 with glioblastoma, 12 with anaplastic astrocytoma [AA], and 4 with anaplastic oligoastrocytoma [AOA], treated with temozolomide at first recurrence. In addition we performed fluorescence in situ hybridization for the characterization of chromosomal loss of 1p, 19q and the 17p13.1 locus (p53) and for gains of the EGFR locus. Results: WHO differentiation grade, MGMT methylation status were significantly correlated with time to progression following temozolomide at first recurrence (Cox logistic regression analysis). Within the subgroups of grade III and IV glioma, significance for these two baseline variables was only observed for patients with anaplastic (oligo)astrocytoma. In this subgroup, as opposed to glioblastoma patients, TP53 IHC positivity more strongly predicted a favourable TTP. None of these 16 anaplastic gliomas had loss of 1p or 19q or amplification of EGFR. MGMT promoter methylation correlated with superior overall survival following temozolomide in patients with AA/AOA but not glioblastoma. Conclusions: The synchronous presence of both MGMT promoter methylation and p53 IHC status appear to be useful molecular markers to predict favourable survival following temozolomide at recurrence only in patients with anaplastic oligoastrocytoma without 1p/19q loss or EGFR amplification.