A study of embryonic stem cell-related proteins in human astrocytomas: identification of Nanog as a predictor of survival.

Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO Grade II) and 98 high-grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n = 42) with high levels of Nanog protein (p = 0.0067) and of Klf4 protein (p = 0.0368), in high-grade astrocytomas (n = 85) with high levels of Nanog (p = 0.0042), Klf4 (p = 0.0447), and c-Myc (p = 0.0078) and in glioblastomas only (n = 71) with high levels of Nanog (p = 0.0422) and of c-Myc (p = 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p = 0.0039), high-grade astrocytomas (p = 0.0124) and glioblastomas only (p = 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.

Baseline 11C-methionine PET reflects the natural course of grade 2 oligodendrogliomas.

OBJECTIVES: The aim of the present study was to assess the usefulness of positron emission tomography (PET) with the amino acid tracer 11C-methionine (MET) as a predictor of time to progression (TTP) in patients with supratentorial grade 2 gliomas. METHODS: Twenty-seven patients with glioma grade 2 subjected to a baseline PET scan received no anti-tumour treatment except for a diagnostic operation, and were followed until tumour progression. The prognostic impact of the MET uptake and of other prognostic factors was studied. RESULTS: Twenty-five of the patients (93%) experienced tumour progression after a median of 103 weeks. Low uptake of MET was a predictor for long TTP in patients with oligodendrogliomas (p = 0.04) but not in astrocytomas/oligoastrocytomas. Other predictors for long TTP were oligodendroglioma histology (p = 0.009) and seizures as presenting symptom (p = 0.03). Favourable prognostic factors for overall survival were oligodendroglioma histology (p = 0.002) and good performance status (p = 0.03). CONCLUSIONS: PET MET has a definite role in the therapeutic management of grade 2 gliomas. However, for the optimal use of PET MET in the clinical management of these patients, histological subclassification of the tumour is required.

On the issue of early and aggressive treatment in grade 2 gliomas.

PURPOSE: To study the effects of surgery and timing of radiotherapy on patient survival in grade 2 gliomas. METHODS: One hundred and eighty-nine patients with diffuse astrocytomas, oligoastrocytomas, and oligodendrogliomas, World Health Organization grade 2, treated between 1982 and 2000 were identified. The impact of treatment given and clinical parameters were studied in univariate- and multivariate survival analyses. RESULTS: Median survival for the whole patient sample was 6.4 years and the 5-year survival rate was 60%. Macroscopic total resection was beneficial in the univariate analysis (P=0.03) but not when adjusting for confounders. Early subtotal resection did not prolong survival. Early radiotherapy was associated with a shorter survival time compared to delayed or no irradiation (P=0.004). However, this difference was mainly due to an unequal distribution of prognostic factors and was not significant in the multivariate analysis. The most important predictors for long survival time were young age ( P<0.001), oligodendroglioma histology ( P<0.001), and small tumour size ( P=0.02). CONCLUSIONS: Early conventional treatment with surgery and radiotherapy had no positive effect on patient survival. This opens up the possibility of trying and evaluating other first-line treatment regimens in this disease.

Evaluation of 11C-methionine PET as a surrogate endpoint after treatment of grade 2 gliomas.

The aim of the present study was to assess the usefulness of positron emission tomography (PET) as a surrogate endpoint by analysing the uptake variability of 11C-methionine (MET) in follow-up scans.A total of 96 PET MET scans were re-evaluated in 32 patients with histologically confirmed supratentorial grade 2 gliomas. In untreated patients, all follow-up PET scans showed an increased tumour volume after median 68 weeks, but only 46% of cases had an increased hot spot uptake. An improved outcome was observed in patients with stable hot spot uptake per se (P = 0.07) and in combinations with minor increase in tumour volume (P = 0.02). After conventional therapy, 52% of PET scans showed a reduced hot spot uptake the first year and 43% were reduced after more than a year. Successful MET decline after therapy did not correlate with outcome. PET MET may be a promising surrogate endpoint after treatment of grade 2 gliomas. Evaluation of both hot spot activity and uptake volume on PET may strengthen the association with clinical outcome.

Potential significance of (11)C-methionine PET as a marker for the radiosensitivity of low-grade gliomas.

The role for radiotherapy in patients with low-grade gliomas remains controversial. Two large prospective studies have failed to demonstrate a radiotherapeutic dose-response effect, and EORTC trial 22845 found no difference in survival between patients receiving adjuvant radiotherapy and those who received radiotherapy at tumour progression. The aim of this retrospective study was to analyse the patterns of carbon-11 methionine (MET) uptake on positron emission tomography (PET) in tumours treated with immediate radiotherapy and in those treated with delayed radiotherapy at the time of tumour progression. The 21 adult patients studied had histologically confirmed low-grade gliomas and had undergone a pre-treatment PET scan and a follow-up PET scan at the time of progression. Eleven of the patients had undergone initial radiotherapy a median of 5 weeks after the surgical procedure. The median time to progression was 3.5 years for this group, compared with 1.6 years for the group with delayed radiotherapy ( P=0.06). At the time of progression, non-irradiated tumours had a significantly higher MET uptake ( P=0.02) and a larger uptake volume ( P=0.008) compared with baseline, whereas irradiated tumours showed no statistically significant change. We observed a correlation between high pre-treatment uptake of MET and reduction in MET uptake in response to radiotherapy ( P=0.008). All irradiated tumours recurred within the radiation field. In conclusion, our results demonstrate signs of a residual radiation effect at the time of tumour progression in low-grade gliomas with high pre-treatment uptake of MET. Pre-treatment methionine uptake may be a marker for the radiosensitivity of low-grade gliomas.

Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas.

Little is known about the expression of mitogens and other tumour-related substances in the cerebrospinal fluid (CSF) of glioma patients. The aim of the current study was to determine the presence of aberrant proteins in the CSF of patients with low-grade gliomas. Lumbar puncture was performed in 8 adult patients with supratentorial low-grade gliomas at the time of diagnosis and in 7 controls. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry were used to detect and quantify deviant proteins in the CSF. Two isoforms of alpha(2)-Heremans-Schmid glycoprotein (AHSG) were identified and demonstrated in higher levels in patients with low-grade gliomas compared with the control group consisting of patients with mixed neurological diagnoses (p = 0.001 and p = 0.04, respectively). In 1 patient, the level of AHSG was significantly reduced after gross total resection of the tumour. AHSG appears in the present proteome screening as a novel substance in glioma research. This glycoprotein is expressed in the fetal human brain and is believed to be involved in the embryonic development of the neocortex. Further analyses are planned to determine the significance of the increased levels of AHSG in the CSF of patients with low-grade gliomas.