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The use of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro Ki determination, the most promising compound, 2-[18F]-2-fluoroethyl-l-phenylalanine (2-[18F]FELP), was selected for further evaluation and in vitro comparison with [18F]FET. Subsequently, 2-[18F]FELP was assessed in vivo and compared with [18F]FET and [18F]FDG in a F98 glioblastoma rat model. 2-[18F]FELP showed improved in vitro characteristics over [18F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[18F]FELP is a promising new PET tracer for brain tumor imaging.

Objective We investigated the potential of [18F]fluorodeoxyglucose ([18F]FDG) and [18F]Fluoromethylcholine ([18F]FCho) PET, compared to contrast-enhanced MRI, for the early detection of treatment response in F98 glioblastoma (GB) rats. Methods When GB was confirmed on T2- and contrast-enhanced T1-weighted MRI, animals were randomized into a treatment group (n = 5) receiving MRI-guided 3D conformal arc micro-irradiation (20 Gy) with concomitant temozolomide, and a sham group (n = 5). Effect of treatment was evaluated by MRI and [18F]FDG PET on day 2, 5, 9 and 12 post-treatment and [18F]FCho PET on day 1, 6, 8 and 13 post-treatment. The metabolic tumor volume (MTV) was calculated using a semi-automatic thresholding method and the average tracer uptake within the MTV was converted to a standard uptake value (SUV). Results To detect treatment response, we found that for [18F]FDG PET (SUVmean x MTV) is superior to MTV only. Using (SUVmean x MTV), [18F]FDG PET detects treatment effect starting as soon as day 5 post-therapy, comparable to contrast-enhanced MRI. Importantly, [18F]FDG PET at delayed time intervals (240 min p.i.) was able to detect the treatment effect earlier, starting at day 2 post-irradiation. No significant differences were found at any time point for both the MTV and (SUVmean x MTV) of [18F]FCho PET. Conclusions Both MRI and particularly delayed [18F]FDG PET were able to detect early treatment responses in GB rats, whereas, in this study this was not possible using [18F]FCho PET. Further comparative studies should corroborate these results and should also include (different) amino acid PET tracers.

Despite numerous clinical trials and pre-clinical developments, the treatment of glioblastoma (GB) remains a challenge. The current survival rate of GB averages one year, even with an optimal standard of care. However, the future promises efficient patient-tailored treatments, including targeted radionuclide therapy (TRT). Advances in radiopharmaceutical development have unlocked the possibility to assess disease at the molecular level allowing individual diagnosis. This leads to the possibility of choosing a tailored, targeted approach for therapeutic modalities. Therapeutic modalities based on radiopharmaceuticals are an exciting development with great potential to promote a personalised approach to medicine. However, an effective targeted radionuclide therapy (TRT) for the treatment of GB entails caveats and requisites. This review provides an overview of existing nuclear imaging and TRT strategies for GB. A critical discussion of the optimal characteristics for new GB targeting therapeutic radiopharmaceuticals and clinical indications are provided. Considerations for target selection are discussed, i.e. specific presence of the target, expression level and pharmacological access to the target, with particular attention to blood-brain barrier crossing. An overview of the most promising radionuclides is given along with a validation of the relevant radiopharmaceuticals and theranostic agents (based on small molecules, peptides and monoclonal antibodies). Moreover, toxicity issues and safety pharmacology aspects will be presented, both in general and for the brain in particular.

Simple Summary The current routine treatment for glioblastoma (GB), the most lethal high-grade brain tumor in adults, aims to induce DNA damage in the tumor. However, the tumor cells might be able to repair that damage, which leads to therapy resistance. Fortunately, DNA repair defects are common in GB cells, and their survival is often based on a sole backup repair pathway. Hence, targeted drugs inhibiting essential proteins of the DNA damage response have gained momentum and are being introduced in the clinic. This review gives a perspective on the use of radiopharmaceuticals targeting DDR kinases for imaging in order to determine the DNA repair phenotype of GB, as well as for effective radionuclide therapy. Finally, four new promising radiopharmaceuticals are suggested with the potential to lead to a more personalized GB therapy. Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

Seizures are common in patients with high-grade gliomas (30&ndash, 60%) and approximately 15&ndash, 30% of glioblastoma (GB) patients develop drug-resistant epilepsy. Reliable animal models are needed to develop adequate treatments for glioma-related epilepsy. Therefore, fifteen rats were inoculated with F98 GB cells (GB group) and four rats with vehicle only (control group) in the right entorhinal cortex. MRI was performed to visualize tumor presence. A subset of seven GB and two control rats were implanted with recording electrodes to determine the occurrence of epileptic seizures with video-EEG recording over multiple days. In a subset of rats, tumor size and expression of tumor markers were investigated with histology or mRNA in situ hybridization. Tumors were visible on MRI six days post-inoculation. Time-dependent changes in tumor morphology and size were visible on MRI. Epileptic seizures were detected in all GB rats monitored with video-EEG. Twenty-one days after inoculation, rats were euthanized based on signs of discomfort and pain. This study describes, for the first time, reproducible tumor growth and spontaneous seizures upon inoculation of F98 cells in the rat entorhinal cortex. The development of this new model of GB-related epilepsy may be valuable to design new therapies against tumor growth and associated epileptic seizures.

BACKGROUND Previously, a rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was established. Similarly to the clinic, CT and MRI were combined during the treatment planning process. PET imaging was subsequently added which allowed us to implement sub-volume boosting using a micro-irradiation system. However, combining three imaging modalities (CT, MRI and PET) using a micro-irradiation system, proved to be labour intensive because multimodal imaging, treatment planning and dose delivery have to be completed sequentially in the preclinical setting. MATERIAL AND METHODS Two different methodologies were compared in silico for performing preclinical [18F]FET PET based radiation therapy (20 Gy based on MRI, 8 Gy boost based on PET) based on three different cases. Method 1 is based on the previously published methods1,2. However, the process is automated using an in-house developed MATLAB code. Method 2 consists of a more sophisticated method where a series of isocenters and jaw dimensions for the motorised variable collimator were determined based on the [18F]FET PET uptake. Both methods were evaluated by means of the dose volume histograms (DVH) and Q-volume histograms. RESULTS The setup parameters for both methods were calculated. The DVHs for method 2 are systematically closer to the ideal dose distribution compared to method 1. These findings are confirmed by the D90 and D50 values which are considerably lower for method 1. When observing the Q-factor, method 2 always results in dose distributions that are closer to the dose objectives (method 1: 0.141±0.046; method 2: 0.064±0.011). CONCLUSION The described novel method to optimize the preclinical treatment planning process has many advantages in terms of dose delivery, time efficiency and variability, when compared to the previously used methods1,2. These improvements are important to narrow the gap between clinical and preclinical radiation research and for the development of new therapeutics and/or radiation therapy procedures for glioblastoma. 1. Bolcaen, J., Descamps, B., Boterberg, T., Vanhove, C. & Goethals, I. PET and MRI Guided Irradiation of a Glioblastoma Rat Model Using a Micro-irradiator. J. Vis. Exp. 1–10 (2017) doi:10.3791/56601. 2. Verhoeven, J. et al. Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model. Radiat. Oncol. 14, (2019).

To identify predictive factors for the development of late grade 4 mucosal ulcers in adaptive dose-escalated treatments for head-and-neck cancer.Patient data of four dose-escalated three-phase adaptive dose-painting by numbers (DPBN) clinical trials were analyzed in this study. Correlations between the development of late grade 4 ulcers and factors related with the treatment, disease characteristics and the patient were investigated. Dosimetrical thresholds were searched among the highest doses received by 1.75 cmFrom 39 studied patients, nine developed late grade 4 mucosal ulcers. The continuation to either smoke or drink alcohol after therapy was the factor that showed a strong (eight out of nine patients) association with the occurrence of grade 4 ulcers. Six of the patients who continued to smoke or/and drink had DThe search for patterns provided strong reasons to apply a dosimetrical threshold for the peak-dose volume of 1.75 cm

INTRODUCTION: Glucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [(18)F]fluorophenylglutamine and [(18)F]fluorobiphenylglutamine MATERIALS AND METHODS: Both tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [(3)H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [(18)F]fluorophenylglutamine and [(18)F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model. RESULTS: The radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18 % (n=10) ([(18)F]fluorophenylglutamine) and 8.05 ± 3.25 % (n=5) ([(18)F]fluorobiphenylglutamine). In vitro inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [(18)F]FBPG in the mice PC-3 xenograft and a moderate uptake of [(18)F]FPG in the PC-3 tumors. CONCLUSION: We investigated the imaging potential of two novel PET radiotracers [(18)F]FPG and [(18)F]FBPG. [(18)F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [(18)F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: We hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[(18)F]fluoroglutamine). [(18)F]FPG shows clear tumor uptake in vivo, has no in vivo defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport.

Purpose Even with an optimal treatment protocol, the median survival of glioblastoma (GB) patients is only 12–15 months. Hence, there is need for novel effective therapies that improve survival outcomes. Recent evidence suggests an important role for connexin (Cx) proteins (especially Cx43) in the microenvironment of malignant glioma. Cx43-mediated gap junctional communication has been observed between tumor cells, between astrocytes and between tumor cells and astrocytes. Therefore, gap junction directed therapy using a pharmacological suppressor or modulator, such as tonabersat, could be a promising target in the treatment of GB. In this preclinical study, we evaluated the possible therapeutic potential of tonabersat in the F98 model. Procedures Female Fischer rats were inoculated with ± 25.000 F98 tumor cells in the right frontal lobe. Eight days post-inoculation contrast-enhanced T1-weighted (CE-T1w) magnetic resonance (MR) images were acquired to confirm tumor growth in the brain. After tumor confirmation, rats were randomized into a Control Group, a Connexin Modulation Group (CM), a Standard Medical Treatment Group (ST), and a Standard Medical Treatment with adjuvant Connexin Modulation Group (STCM). To evaluate therapy response, T2-weighted (T2w) and CE-T1w sequences were acquired at several time points. Tumor volume analysis was performed on CE-T1w images and statistical analysis was performed using a linear mixed model. Results Significant differences in estimated geometric mean tumor volumes were found between the ST Group and the Control Group and also between the STCM Group and the Control Group. In addition, significant differences in estimated geometric mean tumor volumes between the ST Group and the STCM Group were demonstrated. No significant differences in estimated geometric mean tumor volumes were found between the Control Group and the CM Group. Conclusion Our results demonstrate a therapeutic potential of tonabersat for the treatment of GB when used in combination with radiotherapy and temozolomide chemotherapy.

Background and Purpose: Glioblastomas are the most aggressive of all gliomas. The prognosis of these gliomas, which are classified as grade IV tumors by the World Health Organization (WHO), is poor. Combination therapy, including surgery, radiotherapy, and chemotherapy has variable outcomes and is expensive. In light of rising healthcare costs, there are societal demands for the justification of medical expenses. Therefore, we calculated the cost-effectiveness of follow-up [18F] fluoroethyl-L-tyrosine ([18F] FET) positron emission tomography (PET) scans performed on patients with glioblastoma after surgery and before commencing temozolomide maintenance treatment. Materials and Methods: To determine the cost-effectiveness of follow-up [18F] FET PET procedures, we examined published clinical data and calculated the associated costs in the context of Belgian healthcare. We subsequently performed one-way deterministic sensitivity analysis and Monte Carlo analysis on the calculated ratios. Results: The decision tree based on overall survival rates showed that the number of non-responders identified using PET was 57.14% higher than the number of non-responders identified using conventional MRI. Further, the decision tree based on progression-free survival rates revealed a comparable increase of 57.50% non-responders identified. The calculated cost of two required PET scans per patient during the follow-up treatment phase was 780.50 euros. Two cost-effectiveness ratios were determined for overall survival and progression-free survival rates. Both of these calculations yielded very similar results: incremental cost-effectiveness ratios of 1,365.86 and 1,357.38 euros, respectively, for each identified non-responder. The findings of the sensitivity analysis supported the calculated results, confirming that the obtained data were robust. Conclusion: Our comparative study of conventional MRI and [18F] FET PET revealed that the latter is a valuable tool for predicting the treatment responses of patients with glioblastomas to follow-up temozolomide maintenance treatment while considering its cost-effectiveness. Thus, [18F] FET PET scans enable clinical outcomes to be predicted accurately and at a low cost. Moreover, given the robustness of the data in the sensitivity analyses, the level of certainty of this outcome is acceptable.

Background Glioblastoma (GB) is the most common primary malignant brain tumor. Standard medical treatment consists of a maximal safe surgical resection, subsequently radiation therapy (RT) and chemotherapy with temozolomide (TMZ). An accurate definition of the tumor volume is of utmost importance for guiding RT. In this project we investigated the feasibility and treatment response of subvolume boosting to a PET-defined tumor part. Method F98 GB cells inoculated in the rat brain were imaged using T2- and contrast-enhanced T1-weighted (T1w) MRI. A dose of 20 Gy (5 × 5 mm2) was delivered to the target volume delineated based on T1w MRI for three treatment groups. Two of those treatment groups received an additional radiation boost of 5 Gy (1 × 1 mm2) delivered to the region either with maximum [18F]FET or [18F]FAZA PET tracer uptake, respectively. All therapy groups received intraperitoneal (IP) injections of TMZ. Finally, a control group received no RT and only control IP injections. The average, minimum and maximum dose, as well as the D90-, D50- and D2- values were calculated for nine rats using both RT plans. To evaluate response to therapy, follow-up tumor volumes were delineated based on T1w MRI. Results When comparing the dose volume histograms, a significant difference was found exclusively between the D2-values. A significant difference in tumor growth was only found between active therapy and sham therapy respectively, while no significant differences were found when comparing the three treatment groups. Conclusion In this study we showed the feasibility of PET guided subvolume boosting of F98 glioblastoma in rats. No evidence was found for a beneficial effect regarding tumor response. However, improvements for dose targeting in rodents and studies investigating new targeted drugs for GB treatment are mandatory. Electronic supplementary material The online version of this article (10.1186/s13014-019-1290-4) contains supplementary material, which is available to authorized users.

Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the current state-of-the-art treatment, which consists of maximal surgical resection followed by radiation therapy, concomitant, and adjuvant chemotherapy, progression remains rapid due to aggressive tumor characteristics. Several new therapeutic targets have been investigated using chemotherapeutics and targeted molecular drugs, however, the intrinsic resistance to induced cell death of brain cells impede the effectiveness of systemic therapies. Also, the unique immune environment of the central nervous system imposes challenges for immune-based therapeutics. Therefore, it is important to consider other approaches to treat these tumors. There is a well-known dose-response relationship for glioblastoma with increased survival with increasing doses, but this effect seems to cap around 60 Gy, due to increased toxicity to the normal brain. Currently, radiation treatment planning of glioblastoma patients relies on CT and MRI that does not visualize the heterogeneous nature of the tumor, and consequently, a homogenous dose is delivered to the entire tumor. Metabolic imaging, such as positron-emission tomography, allows to visualize the heterogeneous tumor environment. Using these metabolic imaging techniques, an approach called dose painting can be used to deliver a higher dose to the tumor regions with high malignancy and/or radiation resistance. Preclinical studies are required for evaluating the benefits of novel radiation treatment strategies, such as PET-based dose painting. The aim of this review is to give a brief overview of promising PET tracers that can be evaluated in laboratory animals to bridge the gap between PET-based dose painting in glioblastoma patients.

Background and Purpose: Glioblastomas are the most aggressive of all gliomas. The prognosis of these gliomas, which are classified as grade IV tumors by the World Health Organization (WHO), is poor. Combination therapy, including surgery, radiotherapy, and chemotherapy has variable outcomes and is expensive. In light of rising healthcare costs, there are societal demands for the justification of medical expenses. Therefore, we calculated the cost-effectiveness of follow-up [F-18] fluoroethyl-L-tyrosine ([F-18] FET) positron emission tomography (PET) scans performed on patients with glioblastoma after surgery and before commencing temozolomide maintenance treatment. Materials and Methods: To determine the cost-effectiveness of follow-up [F-18] FET PET procedures, we examined published clinical data and calculated the associated costs in the context of Belgian healthcare. We subsequently performed one-way deterministic sensitivity analysis and Monte Carlo analysis on the calculated ratios. Results: The decision tree based on overall survival rates showed that the number of non-responders identified using PET was 57.14% higher than the number of non-responders identified using conventional MRI. Further, the decision tree based on progression-free survival rates revealed a comparable increase of 57.50% non-responders identified. The calculated cost of two required PET scans per patient during the follow-up treatment phase was 780.50 euros. Two cost-effectiveness ratios were determined for overall survival and progression-free survival rates. Both of these calculations yielded very similar results: incremental cost-effectiveness ratios of 1,365.86 and 1,357.38 euros, respectively, for each identified non-responder. The findings of the sensitivity analysis supported the calculated results, confirming that the obtained data were robust. Conclusion: Our comparative study of conventional MRI and [F-18] FET PET revealed that the latter is a valuable tool for predicting the treatment responses of patients with glioblastomas to follow-up temozolomide maintenance treatment while considering its cost-effectiveness. Thus, [F-18] FET PET scans enable clinical outcomes to be predicted accurately and at a low cost. Moreover, given the robustness of the data in the sensitivity analyses, the level of certainty of this outcome is acceptable.

Numerous studies have shown that the serotonin(1A) (5-HT1A) receptor is implicated in the pathophysiology and treatment of several psychiatric and neurological disorders. Furthermore, functional imaging studies in a variety of species have demonstrated that 4-(2'-Methoxyphenyl)-1-[2'-(N-2 ''-pyridinyl)-p-[F-18]fluorobenzamidoethylpiperazine ([F-18]MPPF) is a valid and useful PET tracer to visualize the 5HT(1A) receptor. However, to our knowledge, [F-18] MPPF has never been demonstrated in the canine brain. The ability to image the 5HT(1A) receptor with PET in dogs could improve diagnosis and therapy in both canine and human behavioural and neuropsychiatric disorders. To examine the potential use of [F-18]MPPF in dogs, five healthy adult laboratory beagles underwent a 60-minutes dynamic PET scan with [F-18]MPPF while arterial blood samples were taken. For each region of interest, total distribution volume (V-T) and corresponding binding potential (BPND) were calculated using the 1-tissue compartment model (1-TC), 2-Tissue compartment model (2-TC) and Logan plot. The preferred model was chosen based on the goodness-of-fit, calculated with the Akaike information criterium (AIC). Subsequently, the BPND values of the preferred compartment model were compared with the estimated BPND values using three reference tissue models (RTMs): the 2-step simplified reference tissue model (SRTM2), the 2-parameter multilinear reference tissue model (MRTM2) and the Logan reference tissue model. According to the lower AIC values of the 2-TC model compared to the 1-TC in all ROIs, the 2-TC model showed a better fit. Calculating BPND using reference tissue modelling demonstrated high correlation with the BPND obtained by metabolite corrected plasma input 2-TC. This first-indog study indicates the results of a bolus injection with [F-18] MPPF in dogs are consistent with the observations presented in the literature for other animal species and humans. Furthermore, for future experiments, compartmental modelling using invasive blood sampling could be replaced by RTMs, using the cerebellum as reference region.

BACKGROUND: Gliomas are the most frequent malignant primary brain tumours in adults, accounting for about 70% of adult malignant primary brain tumours. They can be categorised into low-grade gliomas (LGG, WHO grade I-II) or high-grade gliomas (HGG, WHO grade III-IV). Accurate and early diagnosis of these tumours, for which histopathological analysis is the gold standard, is key to determine the optimal treatment procedure. Because biopsy and tumour resection are invasive procedures, there has been a growing interest in automated classification of brain tumours based on medical imaging. This retrospective study intends to evaluate automatic tumour segmentation and radiomics features from [(18)F]FET PET and contrast-enhanced T1-weighted (T1ce) MRI images for discrimination between LGG and HGG. MATERIAL AND METHODS: A pretreatment [(18)F]FET PET scan and anatomical MRI were performed in 30 patients. Histopathological analysis led to the diagnosis of 14 LGG and 16 HGG patients. An in-house developed and previously validated segmentation algorithm was used to automatically delineate the tumour simultaneously on T1ce and FLAIR MRI. This resulted in the identification of four tumour-related tissues: necrosis, oedema, non-enhancing tumour and contrast-enhancing tumour. These different tumour masks were used to extract 2913 quantitative radiomics features per patient from the T1ce and PET images. For each feature, a two sample t-test was performed between LGG and HGG patients as an initial feature selection. The 150 features with the lowest p-values were retained. Next, forward sequential selection and five-fold cross-validation was implemented to identify up to 15 features that are able to make the optimal distinction between LGG and HGG using a Random Forests classification model. The accuracy was assessed using leave-one-out validation. This procedure was performed three times: using only T1ce features, only PET features, and both T1ce and [(18)F]FET features. RESULTS: We achieve accuracies of 86.6%, 83.3% and 96.7% for the classification tasks using MRI-based, PET-based and combined features, respectively. The best result is obtained when combining one texture feature calculated on T1ce in the oedema and non-enhancing tumour region with two histogram and five texture features calculated on [(18)F]FET PET, both in the oedematous and total abnormal regions. This model achieves an excellent discrimination between LGG and HGG (accuracy 96.7%, AUC=0.951), using a minimal amount of features. We further observe that many predictive features are based on infiltrating rather than tumour core regions. CONCLUSION: This study illustrates that automatic tumour segmentation and extraction of radiomics features from combined [(18)F]FET PET and T1ce MRI scans are able to discriminate between LGG and HGG. Further evaluation on larger datasets is however necessary to validate this result.

INTRODUCTION: Gliomas are the most frequent malignant primary brain tumours in adults and can be classified into low-grade gliomas (LGG, WHO grade I-II) and high-grade gliomas (HGG, WHO grade III-IV). Overall survival rate of HGG is poor (months) when compared to LGG (years). Accurate and early diagnosis, for which histopathology is the gold standard, is essential to decide the optimal treatment. Because biopsy and resection bear certain risks, interest is shown in non-invasive diagnostic methods to guide treatment decisions. In this study, different [(18)F]Fluoro-Ethyl-Tyrosine ([(18)F]FET) positron emission tomography (PET) parameters were examined for discriminating HGG from LGG. MATERIAL AND METHODS: A pre-treatment [(18)F]FET PET scan and an anatomical MRI were performed in 30 patients. Twenty-four PET-derived parameters, e.g. metabolic tumour volume (MTV), total lesion uptake (TLU) and tumour-to-background ratio (TBR), were calculated using various standardised uptake value (SUV) thresholds. Subsequently, an in-house developed and segmentation algorithm was used to label different tissue categories on both contrast-enhanced T(1)-weighted and FLAIR MR images: necrosis (N), oedema (OE), non-enhancing tumour (NET) and contrast-enhancing tumour (CET). MR-derived tumour masks were applied on the PET images to calculate 55 PET parameters. PET- and MR-derived FET PET parameters were compared between HGG and LGG. Significantly different parameters were analysed by receiver-operating characteristics (ROC) analysis, yielding area under the curve (AUC) values. Pathological diagnosis served as the reference. RESULTS: Significant differences between HGG and LGG were observed for 13 and 17 for the PET- and MR-derived PET parameters, respectively. The AUC values for significant PET-derived FET PET parameters ranged between 0.78 and 0.85. The lowest AUC value corresponded with TBR(1.5) that is defined as the tumour-to-background ratio for the voxels exceeding 1.5 times the mean background SUV. The highest AUC value corresponded with MTV(1.5) that is defined as the total volume of voxels with a SUV exceeding 1.5 times the mean background SUV. The AUC values for significant MR-derived FET PET parameters ranged between 0.71 and 0.84. The lowest AUC value corresponded with TLU(N+OE+CET+NET) that is defined as the total lesion uptake in a volume covering N, OE, CET and NET. The highest AUC value corresponded with TBR(max) for all tumour tissue categories (N, OE, CET, NET). TBR(max) is defined as the maximal tumour-to-background ratio for N, OE, CET and NET. CONCLUSION: This study illustrates that various PET- and MR-derived [(18)F]FET PET parameters differ significantly between HGG and LGG. Hence, PET and MRI of brain tumours may aid the pre-treatment diagnostic classification of gliomas. Further studies in large populations are needed to investigate which parameters may serve as a surrogate for biopsy.

BACKGROUND: Temozolomide has been approved for the treatment of glioblastoma by the FDA in 2005 and became the standard of care very fast. However, more than 50% of the patients treated with temozolomide do not show any clinical response. MRI forms the main imaging modality to assess the therapy effectiveness. Galldiks et al. reported in 2012 that PET with ([(18)F] FET) was a better imaging tool to predict the clinical outcome of the therapy than standard MRI. Techniques such as MRI and PET deliver tremendous information albeit at a high cost. With increasing healthcare costs being a huge burden on society, cost-effectiveness becomes an important parameter in medical interventions. Therefore, the cost-effectiveness of [(18)F] FET for therapy assessment of temozolomide after surgery is calculated here. MATERIAL AND METHODS: Clinical data derived from the paper reported by Galldiks et al. was used to set up a decision tree to assess the effectiveness of PET and MRI. In this paper the authors describe the comparison of [(18)F] FET and gadolinium enhanced T2 for the prediction of clinical outcome after surgery and radiotherapy/temozolomide in glioblastoma patients. They report the TBRmax for PET and volume of gadolinium uptake directly after surgery and after the first session of radiotherapy and temozolomide. After the second scan the patients received another 4 weeks of temozolomide. For the two imaging modalities responders and non-responders were identified based on TBRmax and gadolinium volume difference between scan one and two. Clinical response was assessed on overall survival and progression free survival. Costs were calculated from a Belgian healthcare perspective including all costs done by the government and by social security. Cost-effectiveness was calculated as incremental cost-effectiveness ratio for one extra correct prognosis (ICER 1) and for one non-responder identified (ICER 2). Sensitivity analysis was done by means of one-way deterministic analysis and Monte Carlo analysis. RESULTS: Chances on right prediction of clinical outcome rose with 20.70% for PET in comparison with MRI based on overall survival of the patient and with 22.76% based on progression free survival. Chances on recognition of a non-responder rose with 57.14% based on overall survival and with 58.35% based on progression free survival. Total costs of [(18)F] FET-scan is 390.25 euro and a total of 780.50 euro for the two scans combined. These results give an ICER 1 value of 3769.77 euro and 3427.07 euro based on respectively overall survival and progression free survival. The results for ICER 2 are 1365.86 euro and 1357.38 euro. Sensitivity analysis show very robust values with low variability. CONCLUSION: [(18)F] FET reports a cost-effectiveness of around 1360 euro per non-responder recognized. Sensitivity analysis show these are robust calculations with low variability.

Background Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. Methods In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (

PurposeMetastatic brain tumors pose a severe problem in the treatment of patients with breast carcinoma. Preclinical models have been shown to play an important role in unraveling the underlying mechanisms behind the metastatic process and evaluation of new therapeutic approaches. As the size of the rat brain allows improved in vivo imaging, we attempted to establish a rat model for breast cancer brain metastasis that allows follow-up by 7 tesla (7T) preclinical Magnetic Resonance Imaging (MRI).ProceduresGreen fluorescent protein-transduced (eGFP) MDA-MB-231br breast cancer cells were labeled with micron-sized particles of iron oxide (MPIOs) and intracardially injected in the left ventricle of female nude rats and mice. 7T preclinical MRI was performed to show the initial distribution of MPIO-labeled cancer cells and to visualize metastasis in the brain. Occurrence of potential metastasis outside the brain was evaluated by 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/computed tomography (CT) and potential bone lesions were assessed using [18F]sodium fluoride ([18F]NaF) PET/CT.ResultsThe first signs of brain metastasis development were visible as hyperintensities on T2-weighted (T2w) MR images acquired 3 weeks after intracardiac injection in rats and mice. Early formation of unexpected bone metastasis in rats was clinically observed and assessed using PET/CT. Almost no bone metastasis development was observed in mice after PET/CT evaluation.ConclusionsOur results suggest that the metastatic propensity of the MDA-MB-231br/eGFP cancer cell line outside the brain is species-dependent. Because of early and abundant formation of bone metastasis with the MDA-MB-231br/eGFP cancer cell line, this rat model is currently not suitable for investigating brain metastasis as a single disease model nor for evaluation of novel brain metastasis treatment strategies.

For decades, small animal radiation research was mostly performed using fairly crude experimental setups applying simple single-beam techniques without the ability to target a specific or well-delineated tumor volume. The delivery of radiation was achieved using fixed radiation sources or linear accelerators producing megavoltage (MV) X-rays. These devices are unable to achieve sub-millimeter precision required for small animals. Furthermore, the high doses delivered to healthy surrounding tissue hamper response assessment. To increase the translation between small animal studies and humans, our goal was to mimic the treatment of human glioblastoma in a rat model. To enable a more accurate irradiation in a preclinical setting, recently, precision image-guided small animal radiation research platforms were developed. Similar to human planning systems, treatment planning on these micro-irradiators is based on computed tomography (CT). However, low soft-tissue contrast on CT makes it very challenging to localize targets in certain tissues, such as the brain. Therefore, incorporating magnetic resonance imaging (MRI), which has excellent soft-tissue contrast compared to CT, would enable a more precise delineation of the target for irradiation. In the last decade also biological imaging techniques, such as positron emission tomography (PET) gained interest for radiation therapy treatment guidance. PET enables the visualization of e.g., glucose consumption, amino-acid transport, or hypoxia, present in the tumor. Targeting those highly proliferative or radio-resistant parts of the tumor with a higher dose could give a survival benefit. This hypothesis led to the introduction of the biological tumor volume (BTV), besides the conventional gross target volume (GTV), clinical target volume (CTV), and planned target volume (PTV). At the preclinical imaging lab of Ghent University, a micro-irradiator, a small animal PET, and a 7 T small animal MRI are available. The goal was to incorporate MRI-guided irradiation and PET-guided sub-volume boosting in a glioblastoma rat model.

Background: Although one of the most frequent diagnosed mental illnesses worldwide, it appears to be challenging to successfully treat major depressive disorder (MDD). Although the phenomenon of treatment-resistant depression (TRD) still remains unclear, the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible neurobiological marker to evaluate clinical effects of a variety of antidepressant treatments, including repetitive transcranial magnetic stimulation (rTMS). Accelerated high-frequency (HF)-rTMS may have the potential to rapidly result in beneficial clinical outcomes in TRD. No studies yet examined the clinical effects of such accelerated stimulation treatment paradigms on sgACC regional glucose metabolism (CMRglc), nor the predictive value of the latter for clinical outcome. Objective: First, we investigated the predictive value of baseline sgACC metabolic activity for clinical outcome. Second, we hypothesized that in clinical responders only accelerated HF-rTMS treatment would result in significant metabolic decreases. Methods: We recruited right-handed antidepressant-free unipolar melancholic TRD patients to participate in a two-week randomized sham-controlled crossover HF-rTMS treatment study. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). Fifteen patients underwent 18FDG PET (CMRglc) at baseline (T0), after the first week (T1) of accelerated HF-rTMS and at the end of the treatment after the second week (T2). Results: Higher baseline sgACC metabolic activity may indicate beneficial clinical outcome to this kind of accelerated HF-rTMS treatment. Moreover, clinical response resulted in a significant decrease in sgACC CMRglc. Non-response did not affect sgACC CMRglc. Conclusions: Our results add to the sgACC as a specific neurobiological marker for anti-depressive response in accelerated HF-rTMS treatment paradigms. Such protocols may not only have the ability to result in fast clinical responses but they may also have potential to acutely modulate a dysfunctional sgACC.

Glioblastoma (GB) is the most malignant and the most common type of glioma in adults, accounting for 60–70% of all malignant gliomas. Despite the current therapy, the clinical course of GB is usually rapid, with a mean survival time of approximately 1 year. For therapy response assessment in GB, magnetic resonance imaging (MRI) is the method of choice. In 2010, the Response Assessment in Neuro-Oncology (RANO) was introduced, including the tumor size (in 2D) as measured on T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR)-weighted images, in addition to the contrast-enhancing tumor part. Although the RANO criteria addressed some of the limitations of the previous MacDonald criteria for therapy evaluation in high-grade glioma, treatment-related side effects hamper correct response assessment. To address the above-mentioned drawbacks in the follow-up of GB, incorporating changes in tumor biology measured by advanced MRI and positron emission tomography (PET) imaging, which may precede anatomical changes of the tumor volume, is promising. Imaging biomarkers capable of predicting response at an early time point after treatment initiation are the premise of personalized treatment enabling change or discontinuation of therapy to prevent ineffective treatment or adverse events of treatment. In this chapter, an overview of applicable PET tracers for the therapy response assessment in GB and the determination of tumor recurrence versus treatment-related effects is given.

Purpose: Discrimination between glioblastoma (GB) and radiation necrosis (RN) remains challenging using conventional MRI. However, a correct diagnosis is important for patient management. We hypothesised that based on differences in vascular properties, such as vascular density, vascular permeability, blood flow, composition of the extracellular and extravascular space and interstitial pressure, dynamic contrast-enhanced (DCE) MRI would allow to distinguish GB from RN. As such, in this study, the potential of semi-quantitative and quantitative analysis of DCE-MRI was investigated to differentiate GB from RN in rats. Procedures: F98 GB cells were inoculated in the rat brain. GB growth was seen on follow-up MRI 8–23 days post-inoculation (n=15). RN lesions developed 6–8 months post-irradiation (n=10). DCE-MRI was acquired using a fast low angle shot (FLASH) sequence. Regions of interest (ROIs) encompassed peripheral contrast-enhancement in GB (n=15) and RN (n=10) as well as central necrosis within these lesions (GB (n=4), RN (n=3)). DCE-MRI data were fitted to determine 4 function variables (amplitude A, offset from zero C, wash-in rate k and wash-out rate D) as well as maximal intensity (ImaxF) and time-to-peak (TTPF). Secondly, maps of semi-quantitative and quantitative parameters (extended Tofts model) were created using Olea sphere (O). Semi-quantitative DCE-MRI parameters included wash-inO, wash-outO, area under the curve (AUCO), maximal intensity (ImaxO) and time-to-peak (TTPO). Quantitative parameters included the rate constant plasma to extravascular-extracellular space (EES) (Ktrans), the rate constant EES to plasma (Kep), plasma volume (Vp) and EES volume (Ve). All (semi-)quantitative parameters were compared between GB and RN using the Mann-Whitney U test and ROC analysis was performed. Results: Wash-in rates (k and wash-inO) were significantly higher in GB compared to RN (p=0.016 and p=0.041, respectively). Wash-out rate (D) was only significantly higher in GB using curve fitting (p=0.014). TTPF and TTPO were significantly lower in GB compared to RN (p=0.001 and p < 0.001, respectively). The highest sensitivity (93%) and specificity (90%) was obtained for TTPO by applying a threshold of 415 s. Ktrans, Kep, Vp and Ve were not significantly different between GB and RN. Conclusions: Based on our results in a rat model, DCE-MRI may be useful to discriminate GB from RN. Wash-in rates (k and wash-inO), TTPF and TTPO, which can be derived from a 5-min DCE-MRI acquisition, are able to distinguish GB from RN while other quantitative and semi-quantitative parameters are not. Whether DCE-MRI will also be able to differentiate GB from RN in humans must be further explored.

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i. v. injection 0.83 mg/ kg. Blood samples were taken up to 12 hours after i. v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Glioblastoma is the most aggressive and most common malignant primary brain tumour in adults and has a high mortality and morbidity. Because local tumour control in glioblastoma patients is still elusive in the majority of patients, there is an urgent need for alternative treatment strategies. However, to implement changes to the existing clinical standard of care, research must be conducted to develop alternative treatment strategies. A novel approach in radiotherapy is the introduction of pre-clinical precision image-guided radiation research platforms. The aim of this review is to give a brief overview of the efforts that have been made in the field of radiation research using animal models of glioblastoma. Because MRI has become the reference imaging technique for treatment planning and assessment of therapeutic responses in glioblastoma patients, we will focus in this review on small animal radiotherapy combined with MRI.

This first-in-dog study evaluates the use of the PET-radioligand [C-11] DASB to image the density and availability of the serotonin transporter (SERT) in the canine brain. Imaging the serotonergic system could improve diagnosis and therapy of multiple canine behavioural disorders. Furthermore, as many similarities are reported between several human neuropsychiatric conditions and naturally occurring canine behavioural disorders, making this tracer available for use in dogs also provide researchers an interesting non-primate animal model to investigate human disorders. Five adult beagles underwent a 90 minutes dynamic PET scan and arterial whole blood was sampled throughout the scan. For each ROI, the distribution volume (V-T), obtained via the one-and two-tissue compartment model (1-TC, 2-TC) and the Logan Plot, was calculated and the goodness-of-fit was evaluated by the Akaike Information Criterion (AIC). For the preferred compartmental model BPND values were estimated and compared with those derived by four reference tissue models: 4-parameter RTM, SRTM2, MRTM2 and the Logan reference tissue model. The 2-TC model indicated in 61% of the ROIs a better fit compared to the 1-TC model. The Logan plot produced almost identical VT values and can be used as an alternative. Compared with the 2-TC model, all investigated reference tissue models showed high correlations but small underestimations of the BPND-parameter. The highest correlation was achieved with the Logan reference tissue model (Y = 0.9266 x + 0.0257; R-2 = 0.9722). Therefore, this model can be put forward as a non-invasive standard model for future PET-experiments with [C-11] DASB in dogs.

Background Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains challenging but has a large impact on further treatment and prognosis. In this study, the uptake mechanisms of 18F-fluorodeoxyglucose (18F-FDG), 18F-fluoroethyltyrosine (18F-FET) and 18F-fluoromethylcholine (18F-FCho) positron emission tomography (PET) tracers were investigated in a F98 GB and RN rat model applying kinetic modeling (KM) and graphical analysis (GA) to clarify our previous results. Methods Dynamic 18F-FDG (GB n = 6 and RN n = 5), 18F-FET (GB n = 5 and RN n = 5) and 18F-FCho PET (GB n = 5 and RN n = 5) were acquired with continuous arterial blood sampling. Arterial input function (AIF) corrections, KM and GA were performed. Results The influx rate (Ki) of 18F-FDG uptake described by a 2-compartmental model (CM) or using Patlak GA, showed more trapping (k3) in GB (0.07 min-1) compared to RN (0.04 min-1) (p = 0.017). K1 of 18F-FET was significantly higher in GB (0.06 ml/ccm/min) compared to RN (0.02 ml/ccm/min), quantified using a 1-CM and Logan GA (p = 0.036). 18F-FCho was rapidly oxidized complicating data interpretation. Using a 1-CM and Logan GA no clear differences were found to discriminate GB from RN. Conclusions Based on our results we concluded that using KM and GA both 18F-FDG and 18F-FET were able to discriminate GB from RN. Using a 2-CM model more trapping of 18F-FDG was found in GB compared to RN. Secondly, the influx of 18F-FET was higher in GB compared to RN using a 1-CM model. Important correlations were found between SUV and kinetic or graphical measures for 18F-FDG and 18F-FET. 18F-FCho PET did not allow discrimination between GB and RN.

Background Currently, the underlying neurobiological mechanism as to how repetitive transcranial magnetic stimulation (rTMS) can alter depressive states remains unclear. Animal data suggest that its influence could occur at the neurotransmitter level, such as modulation of the serotonin system. Methods Twenty-one antidepressant-free medication-resistant unipolar depressed patients, and 21 age- and gender-matched healthy subjects were studied. We examined the neurobiologic impact of 10 high-frequent (HF)-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC) on postsynaptic 5-HT 2A receptor binding indices (BI) measured with 123 I-5-I-R91150 single photon emission computed tomography (SPECT) only in patients. Results Compared with the control group, patients displayed significantly less bilateral dorsolateral prefrontal cortical and significantly higher left hippocampal baseline 5-HT 2A receptor BI. Successful HF-rTMS treatment correlated positively with 5-HT 2A receptor BI in the DLPFC bilaterally and correlated negatively with right hippocampal 5-HT 2A receptor uptake values. Conclusions Our results indicate that HF-rTMS treatment affect the serotonergic system. Our data also suggest that this kind of treatment affects 5-HT 2A receptor BI in the DLPFC and in the hippocampus in different ways.

ObjectiveTo report the clinical, radiologic, biochemical, and molecular characteristics in a 46-year-old participant with adult-onset Leigh syndrome (LS), followed by parkinsonism.MethodsCase description with diagnostic workup included blood and CSF analysis, skeletal muscle investigations, blue native polyacrylamide gel electrophoresis, whole exome sequencing targeting nuclear genes involved in mitochondrial transcription and translation, cerebral MRI, 123I-FP-CIT brain single-photon emission computed tomography (SPECT), and C-11 raclopride positron emission tomography (PET).ResultsThe participant was found to have a defect in the oxidative phosphorylation caused by a c.626C>T mutation in the gene coding for mitochondrial methionyl-tRNA formyltransferase (MTFMT), which is a pathogenic mutation affecting intramitochondrial protein translation. The proband had a normal concentration of lactate in blood and no abnormal microscopic findings in skeletal muscle. Cerebral MRI showed bilateral lesions in the striatum, mesencephalon, pons, and medial thalamus. Lactate concentration in CSF was increased. FP-CIT SPECT and C-11 raclopride PET demonstrated a defect in the dopaminergic system.ConclusionsWe report on a case with adult-onset LS related to a MTFMT mutation. Two years after the onset of symptoms of LS, the proband developed a parkinson-like disease. The c.626C>T mutation is the most common pathogenic mutation found in 22 patients reported earlier in the literature with a defect in MTFMT. The age of the previously reported cases varied between 14 months and 24 years. Our report expands the phenotypical spectrum of MTFMT-related neurologic disease and provides clinical evidence for involvement of MTFMT in extrapyramidal syndromes.

INTRODUCTION: Glioblastoma (GB) is the most common primary malignant brain tumor in adults. The standard of care consists of maximal possible surgical resection with concomitant radiation therapy (RT) and temozolomide (TMZ). Currently the target volume delineation for RT is based on CT and MRI. In this study we investigated the feasibility of incorporating PET for guiding RT and the impact on treatment outcome by applying subvolume boosting to a [(18)F]-FAZA or [(18)F]-FET defined tumor part. METHODS: F98 GB cells inoculated in the rat brain were imaged using T2- and contrast-enhanced T1-weighted (CE-T1w) MRI. After tumor growth, a 30 min [(18)F]-FAZA (2h p.i.) or [(18)F]-FET (30min p.i.) PET was acquired. Subsequently, a treatment planning CT was obtained on the small animal radiation research platform (SARRP). After manual coregistration of CE-T1w-MRI, CT and PET images, a dose of 20 Gy was delivered to the target volume based on the CE-T1w-MRI (group 1–3). In group 2 and 3 an additional radiation boost of 5 Gy (1x1 mm) was delivered to the region with maximal PET probe uptake. On five consecutive days, TMZ (5 mg i.p.) was administered in groups 1–3. Group 4 was used as a sham group, receiving injections with saline. Tumor volumes on follow-up MRI were determined by drawing volumes of interest around the tumor on CE-T1w-MRI (PMOD). RESULTS: CE-T1w-MRI showed a heterogeneous tumor, enabling to select the MRI target volume. Both [(18)F]-FAZA and [(18)F]-FET exhibited an increased tumor uptake. Using three non-coplanar arcs, the dose delivered to the normal surrounding brain tissue was minimized. Significant differences in tumor volumes were found between the therapy and control groups (from day 2 onwards). No significant differences were observed between the different therapy groups (p-value range 0.082 - 1 for [(18)F]-FET; 0.327–1 for [(18)F]-FAZA PET). CONCLUSIONS: Despite being very labor-intensive, MRI guided irradiation with PET subvolume boosting is feasible. Based on tumor growth, a significant difference was found between therapy and no therapy. Unfortunately, no significant difference could be observed between the treatment groups. Additional information from molecular imaging techniques enables the visualization of metabolically highly active regions. GB are highly heterogeneous solid tumors, hence the concept of biological target volume and multidimensional conformal RT seems promising.