Dan Ribom

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

Abstract. 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.

Epileptic seizures and survival in early disease of grade 2 gliomas

Background and purpose:  The aims of this study were (i) to determine the correlation between seizure activity and the metabolic rate of the tumour measured by 11C‐methionine PET (MET PET) in patients with grade 2 gliomas, and (ii) to assess the prognostic impact of early seizure manifestations on patient survival.

Adding 11C-methionine PET to the EORTC prognostic factors in grade 2 gliomas

PurposeThe management of adult patients with grade 2 gliomas remains a challenge for the clinical neuro-oncologist. Several clinical prognostic factors appear to be as important as treatment factors in determining outcome. From the European Organisation for Research and Treatment of Cancer (EORTC) trials 22844 and 22845, a prognostic scoring system has been proposed based on the presence of unfavourable prognostic factors. The aim of the present study was to assess the additional prognostic value of 11C-methionine (MET) measured by positron emission tomography (PET) in the setting of the EORTC prognostic scoring system.MethodsIn this retrospective review, 129 patients with supratentorial grade 2 gliomas were subjected to a PET study as part of the pre-treatment tumour investigation. One hundred and three cases were classified as low-risk patients (0–2 unfavourable factors) and 26 cases as high-risk patients (3–5 unfavourable factors) according to the EORTC criteria. MET PET was evaluated as an extra prognostic factor in both groups.ResultsIn the high-risk group, patients with high MET uptake had a worse outcome than patients with low MET uptake. A similar trend was found for the low-risk group in patients with oligodendrocytic tumours.ConclusionsOur findings further strengthen the role of MET PET as an important prognostic tool in the management of this group of patients.

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.

PROX1 is a predictor of survival for gliomas WHO grade II

Background:The clinical course of World Health Organisation grade II gliomas remains variable and their time point of transformation into a more malignant phenotype is unpredictable. Identification of biological markers that can predict prognosis in individual patients is of great clinical value. PROX1 is a transcription factor that has a critical role in the development of various organs. PROX1 has been ascribed both oncogenic and tumour suppressive functions in human cancers. We have recently shown that PROX1 may act as a diagnostic marker for high-grade gliomas. The aim of this study was to address the prognostic value of PROX1 in grade II gliomas.Methods:A total of 116 samples were evaluated for the presence of PROX1 protein. The number of immunopositive cells was used as a variable in survival analysis, together with established prognostic factors for this patient group.Results:Higher PROX1 protein was associated with poor outcome. In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours.Conclusion:PROX1 is a novel predictor of survival for grade II gliomas.

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.

Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas

Objective: To determine whether the expression of platelet derived growth factor α receptor (PDGFRα) in low grade astrocytomas and oligoastrocytomas is associated with survival. Methods: Formalin fixed and paraffin embedded tumour samples of 40 consecutive patients with supratentorial diffuse astrocytomas and oligoastrocytomas of WHO grade 2, resected between 1986 and 1993, were used for immunohistochemical staining. The fraction of tumour cells expressing PDGFRα protein was quantified and entered into univariate and multivariate survival analyses. Changes in PDGFα expression over time were analysed in seven patients in whom reoperations had been performed. Results: Patients with a relatively high fraction of PDGFRα expressing cells had a more favourable outcome in both univariate (p = 0.04) and multivariate analyses (p = 0.02). Expression of PDGFRα was greater in oligoastrocytomas than in astrocytomas (p = 0.05). In four reoperated patients with histologically confirmed malignant transformation, there was a marked decrease in the number of cells expressing the receptor. Conclusions: There is an association between high PDGFRα expression and long survival time in patients with grade 2 astrocytomas and oligoastrocytomas. The findings suggest that expression of the receptor may be a useful prognostic marker in such patients.

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 α2-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.

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

Abstract Objectives: The aim of the present study was to assess the usefulness of positron emission to ography (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.

Growth factor analysis of low-grade glioma CSF: PDGF and VEGF are not detectable.

Abstract. Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) are involved in the development of grade 2 gliomas. The aim of the present study was to determine the presence of these growth factors in the cerebrospinal fluid (CSF) and to assess their usefulness as biological markers. CSF was collected from 7 adult patients with newly diagnosed supratentorial low-grade gliomas by lumbar puncture and was analysed together with matched serum samples using radioreceptor and enzyme-linked immunosorbant assays. Neither PDGF nor VEGF were detected in the CSF, and FGF-2 was measurable at extremely low concentrations in only 2 of 7 patients. Serum levels were within normal limits. We conclude that these growth factors are not released into the CSF in any significant amounts and are therefore not suitable as biological markers in grade 2 gliomas.