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The current study analyzed the outcome after stereotactic brachytherapy (SBT) using iodine-125 seeds in anaplastic astrocytoma, oligoastrocytoma or oligodendroglioma not suitable for resection. Out of 223 patients harbouring a malignant glioma treated according to a prospective protocol, 172 patients were selected who received SBT to treat a WHO grade III de-novo/residual tumor (n = 99) or a tumor recurrence after multimodal treatment (n = 73). We assessed progression free survival (PFS), overall survival (OS), radiological and clinical outcome and determined prognostic factors using univariate and multivariate regression analyses. The median follow-up time was 38 months. Median OS and median PFS was 28.9 and 21.4 months in the de-novo group vs. 49.4 and 32.6 months in the recurrence group. Recurrent tumors had more frequently (p = 0.01) an oligodendroglial-component compared to de novo tumors. According to cohort-specific univariate analyses KPS at SBT had a significant (p = 0.008) impact on OS in the de-novo group. In the recurrence group, (Cox regression analysis) OS was significantly associated with histology subtype (oligoastro-/oligodendroglioma vs. astrocytoma, p = 0.043). Transient and permanent morbidity (~1 %) was low. For patients unable to undergo surgery due to eloquent tumour location or reduced general condition SBT is an effective treatment option, which does not foreclose additional therapeutic interventions.

Purpose: Resection is generally considered the gold standard for treatment of low-grade (WHO grades I and II) gliomas (LGGs) in childhood. However, approximately 30% to 50% of these tumors are inoperable because of their localization in highly eloquent brain areas. A few reports have suggested stereotactic brachytherapy (SBT) with implantation of iodine-125 ((125)I) seeds as a safe and effective local treatment alternative. This single-center study provides a summary of the long-term outcome after SBT in one of the largest reported patient series., Patients and Methods: All pediatric patients treated with SBT ((125)I seeds; cumulative therapeutic dose 50-65 Gy within 9 months) by our group for LGG with follow-up of more than 6 months were included. Clinical and radiologic outcome, time to progression, and overall survival were evaluated. Prognostic factors (age, sex, Karnofsky performance score, tumor volume, and histology) for survival and disease progression were investigated., Results: In all, 147 of 160 pediatric patients treated with SBT (from 1982 through 2009) were analyzed in detail. Procedure-related mortality was zero, and the 30-day morbidity was transient and low (5.4%). Survival rates at 5 and 10 years were 93%, and 82%, respectively, with no significant difference between WHO grades I and II tumors (median follow-up, 67.1 ± 57.7 months). Twenty-one (14.8%) of 147 patients presented with tumor relapse. The remaining 126 patients revealed complete response in 24.6%, partial response in 31.0%, and stable disease in 29.6%. Neurologic status improved (57.8%) or remained stable (23.0%). None of the evaluated factors had significant impact on the study's end points except tumor volume more than 15 mL, which caused significantly higher rates of tumor recurrence (P < .05)., Conclusion: We demonstrate that SBT represents a safe, minimally invasive, and highly effective local treatment option for pediatric patients with inoperable LGG WHO grades I and II.

The purpose of this study was to assess the impact of stereotactic brachytherapy (SBT) on survival time and outcome when applied after resection of low-grade glioma (LGG) of World Health Organization grade II. From January 1982 through December 2006 we treated 1024 patients who had glioma with stereotactic implantation of iodine-125 seeds and SBT in accordance with a prospective protocol. For the present analysis, we selected 95 of 277 patients with LGG, in whom SBT was applied to treat progressive (43 patients) or recurrent (52 patients) tumor after resection. At 24 months after seed implantation, the tumor response rate was 35.9%, and the tumor control rate was 97.3%. The median progression-free-survival (PFS) duration after SBT was 52.7 ± 7.1 months. Five-year and 10-year PFS probabilities were 43.4% and 10.7%, respectively. Malignant tumor transformation, the diagnosis "astrocytoma," and tumor volume >20 mL were significantly associated with reduced PFS. Tumor progression or relapse after SBT (53 of 95 patients) was treated with tumor resection, a second SBT, chemotherapy, and/or radiotherapy. The median overall survival duration (from the first diagnosis of LGG until the patient's last contact) was 245.0 ± 4.9 months. Patients still under observation after seed implantation had a median follow-up time of 156.4 ± 55.7 months. Perioperative transient morbidity was 1.1%, and the frequency of permanent morbidity caused by SBT was 3.3%. In conclusion, SBT of recurrent or progressive LGG after resection located in functionally critical brain areas has high local efficacy and comparably low morbidity. Referred to individually adopted glioma treatment concepts SBT provides a reasonably long PFS, thus improving overall survival. In selected patients, SBT can lead to delays in the application of chemotherapy and/or radiotherapy.

Over 10 years ago, the first successful gene therapy paradigms for experimental brain tumors models have been conducted, and they were thought to revolutionize the treatment of patients with gliomas. Application of gene therapy has been quickly forced into clinical trials, the first patients being enrolled in 1994, with overall results being disappointing. However, single patients seemed to benefit from gene therapy showing long-term treatment response, and most of these patients bearing small glioblastomas. Whereas the gene therapy itself has been performed with high sophistication, limited attention has been paid on technologies, which (i) allow an identification of viable target tissue in heterogenous glioma tissue and which (ii) enable an assessment of successful vector administration and vector-mediated gene expression in vivo. However, these measures are a prerequisite for the development of successful gene therapy in the clinical application. As biological treatment strategies such as gene and cell-based therapies hold promise to selectively correct disease pathogenesis, successful clinical implementation of these treatment strategies rely on the establishment of molecular imaging technology allowing the non-invasive assessment of endogenous and exogenous gene expression in vivo. Imaging endogenous gene expression will allow the characterization and identification of target tissue for gene therapy. Imaging exogenously introduced cells and genes will allow the determination of the 'tissue dose' of transduced cell function and vector-mediated gene expression, which in turn can be correlated to the induced therapeutic effect. Only these combined strategies of non-invasive imaging of gene expression in vivo will enable the establishment of safe and efficient vector administration and gene therapy protocols for clinical application. Here, we review some aspects of imaging in gene therapy trials for glioblastoma, and we present a 'proof-of-principle' 2nd-generation gene therapy protocol integrating molecular imaging technology for the establishment of efficient gene therapy in clinical application.

Gliomas are the most common types of brain tumors, which invariably lead to death over months or years. Before new and potentially more effective treatment strategies, such as gene therapy, can be effectively introduced into clinical application the following goals must be reached: (1) the determination of localization, extent and metabolic activity of the glioma; (2) the assessment of functional changes within the surrounding brain tissue; (3) the identification of genetic changes on the molecular level leading to disease; and in addition (4) a detailed non-invasive analysis of both endogenous and exogenous gene expression in animal models and in the clinical setting. Non-invasive imaging of endogenous gene expression by means of positron emission tomography (PET) may reveal insight into the molecular basis of pathogenesis and metabolic activity of the glioma and the extent of treatment response. When exogenous genes are introduced to serve for a therapeutic function, PET imaging techniques may reveal the assessment of the location, magnitude and duration of therapeutic gene expression and its relation to the therapeutic effect. Here, we review the main principles of PET imaging and its key roles in neurooncology research.

Management of low-grade gliomas continues to be a challenging task, because CT and MRI do not always differentiate from nontumoral lesions. Furthermore, tumor extent and aggressiveness often remain unclear because of a lack of contrast enhancement. Previous studies indicated that large neutral amino acid tracers accumulate in most brain tumors, including low-grade gliomas, probably because of changes of endothelial and blood-brain barrier function. We describe 11C-methionine uptake measured with PET in a series of 196 consecutive patients, most of whom were studied because of suspected low-grade gliomas. Uptake in the most active lesion area, relative to contralateral side, was significantly different among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions, and this difference was independent from contrast enhancement in CT or MRI. Corticosteroids had no significant effect on methionine uptake in low-grade gliomas but reduced uptake moderately in high-grade gliomas. Differentiation between gliomas and nontumoral lesions by a simple threshold was correct in 79%. Recurrent or residual tumors had a higher uptake than primary gliomas. In conclusion, the high sensitivity of 11C-methionine uptake for functional endothelial or blood-brain barrier changes suggests that this tracer is particularly useful for evaluation and follow-up of low-grade gliomas.

Forty-six patients with suspected brain tumors were investigated by positron emission tomography (PET). Using 11C-methionine PET, the spatial extent of increased uptake in gliomas was larger than that of contrast enhancement on CT/MR images in 67% or the same in 33%. Ten of 46 patients treated with brachytherapy for low-grade gliomas were also investigated with 18F-2-fluorodeoxyglucose (FDG)-PET. One year after seed implantation, the glucose metabolism had not changed, but the decline of methionine uptake was significant. In conclusion, 11C-methionine PET may improve tumor delineation and, following brachytherapy, provides more information on the therapeutic effects than FDG.

Ninety-seven consecutive patients with primarily inoperable or only partially resectable gliomas have been analysed retrospectively. Mean tumour surface doses of 70 Gy (low grade gliomas) and 56 Gy (high grade gliomas) have been applied with stereotactically implanted Iodine-125 seeds at low dose rates. Patients with a glioma grade III or grade IV and permanent seed implantation additionally received a fractionated external beam irradiation. With mean follow-up times of 55.8 months (glioma grade I), 51 months (glioma grade II) and 59.6 months (glioma grade III) the estimated mean survival probabilities are 105 months, 102 months and 65.7 months respectively. In the glioma grade IV group the estimated mean survival time has been 15.6 months after continuous interstitial irradiation (response rate: 36%). Temporary interstitial irradiation in cases with a glioma grade IV (dose rate: 2.1 Gy/day) caused initial tumour shrinkage in 77%. Neurological deficits following radiation induced vasogenic oedema were reversible in 2 patients and irreversible in another 2 patients. 6 years after the Iodine-125 implantation and continuous interstitial irradiation 1 patient developed a severe localised radiation necrosis.

Twenty patients with histologically confirmed gliomas were studied with positron emission tomography (PET) and proton magnetic resonance spectroscopy (1H-MRS). PET with 18F-2-fluoro-2-deoxy-D-glucose (FDG) provided tomograms of the metabolic rate of glucose. MRS images were obtained by combining volume-selective excitation with phase-encoded acquisition. With 32 x 32 gradient phase-encoding steps, an in-plane resolution of 7 x 7 mm was achieved. From this set of spectra, lactate maps were created and compared with PET maps of glucose metabolism. Maximum glucose metabolic rates within tumors (relative to metabolic rates of glucose in contralateral regions of the brain) were correlated significantly with maximum lactate concentrations (relative to N-acetyl aspartate peaks in the contralateral part of the brain). In 8 tumors, no lactate was detected, and in 7 of these the maximum glucose metabolic rate was below the median value. The tumor with the highest lactate concentration also had the highest glucose metabolic rate. The topographic relation between glucose metabolic rate and lactate concentration could be analyzed in 9 patients by three-dimensional alignment of the PET and MRS images. In that analysis, maximum lactate concentrations were often not found in the same location as maximum glucose metabolism, but lactate tended to accumulate in tumor cysts, necrotic areas, and the vicinity of the lateral ventricles. The combination of FDG PET and 1H-MRS imaging demonstrates details of the spatial relation between the two poles of nonoxidative glycolysis, glucose uptake and lactate deposition.(ABSTRACT TRUNCATED AT 250 WORDS)