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Introduction Considering the need for rapid change of treatment in recurrent glioblastoma (GB), it is of utmost importance to characterize PET radiopharmaceuticals that allow early discrimination of tumor from therapy-related effects. In this study, we examined the value of 2-[18F]FELP as a LAT1 tumor-specific PET tracer in comparison with [18F]FDG and [18F]FET in a combined orthotopic rat radiation necrosis and glioblastoma model. A second experiment compared 2-[18F]FELP to [18F]FDG in a mouse glioblastoma - inflammation model. Methods Using the small animal radiation research platform (SARRP), radiation necrosis (RN) was induced in the left frontal lobe of the rat brain. When radiation-induced changes were visible on MRI, F98 rat glioblastoma cells were stereotactically inoculated in the contralateral right frontal lobe. When tumor growth was confirmed on MRI, 2-[18F]FELP, [18F]FET and [18F]FDG PET scans were acquired on three consecutive days. In an inflammation experiment, mice were inoculated in the left thigh with U87 human glioblastoma cells. After heterotopic tumor growth was confirmed macroscopically, inflammation was induced by injection of turpentine subcutaneously in the right thigh. Subsequently, 2-[18F]FELP and [18F]FDG scans were acquired on two consecutive days. Results The in vivo PET images demonstrated that 2-[18F]FELP could differentiate glioblastoma and radiation necrosis using SUVmean (p = 0.0016) and LNRmean (p = 0.009), while [18F]FET was only able to differentiate both lesions by means of the SUVmean. (p = 0.047) Delayed [18F]FDGlate PET (4 h postinjection) was also able to distinguish glioblastoma from radiation necrosis, but smaller lesion-to-normal brain ratios were observed (SUVmean: p = 0.009; LNRmean: p = 0.028). In the inflammation study, 2-[18F]FELP showed no significant uptake in the inflammation lesion when compared to the control group (SUVmean: p = 0.149; LNRmean: p = 0.083). In contrast, both conventional and delayed [18F]FDG displayed significant uptake in the turpentine-invoked lesion (SUVmean: p = 0.021; LNRmean: p = 0.021). Conclusion This study suggests that the 2-[18F]FELP PET is able to differentiate glioblastoma from radiation necrosis and that the 2-[18F]FELP uptake is less likely to be contaminated by the presence of inflammation than the [18F]FDG signal. Advances in knowledge These results are clinically relevant for the differential diagnosis between tumor and radiation necrosis because radiation necrosis always contains a certain amount of inflammatory cells. Hence, 2-[18F]FELP is preferred to discriminate tumor from radiation necrosis.

INTRODUCTION Current guidelines recommend the use of semiautomated assessment of F-18 FDG PET brain studies. Accuracy is influenced by the normal data, which requires knowledge of the included subjects and how they were acquired. Due to confidentiality, such information is often not completely disclosed. Our aim was to determine the variation in FDG uptake between several commercially available and our in-house normal database. METHODS Our database contains 83 healthy subjects. Outlier detection using SPM further ensured normality, resulting in exclusion of three subjects. The remaining 80 subjects were analyzed using three commercially available software packages. Z-score data per patient and per lobe were extracted and pooled in predefined age groups (18-40, 41-60 and 61-80 years old) with a calculation of mean Z-scores and SD. Correlation between Z-score output of different software was investigated. RESULTS In the 18-40 years age group, frontotemporal hypermetabolism was found with all software. Decreased cerebellar uptake was found with two software packages. Mean Z-scores are closer to zero in the 41-60 years age group compared to the younger group, and mostly within the normal range in the 61-80 years age group with all software. A moderate to high linear correlation between Z-score output was found, but individual Z-scores varied widely. CONCLUSIONS The three software packages yielded varying Z-score output, partially explained by an age mismatch between our subjects and subjects in their normal databases. A definitive explanation for the remaining differences is lacking. This emphasizes the importance of age-matched normal data and knowledge of the included databases to allow adequate preprocessing.

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.

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.

Brain tumour segmentation in medical images is a very challenging task due to the large variety in tumour shape, position, appearance, scanning modalities and scanning parameters. Most existing segmentation algorithms use information from four different MRI-sequences, but since this is often not available, there is need for a method able to delineate the different tumour tissues based on a minimal amount of data. We present a novel approach using a Random Forests model combining voxelwise texture and abnormality features on a contrast-enhanced T1 and FLAIR MRI. We transform the two scans into 275 feature maps. A random forest model next calculates the probability to belong to 4 tumour classes or 5 normal classes. Afterwards, a dedicated voxel clustering algorithm provides the final tumour segmentation. We trained our method on the BraTS 2013 database and validated it on the larger BraTS 2017 dataset. We achieve median Dice scores of 40.9% (low-grade glioma) and 75.0% (high-grade glioma) to delineate the active tumour, and 68.4%/80.1% for the total abnormal region including edema. Our fully automated brain tumour segmentation algorithm is able to delineate contrast enhancing tissue and oedema with high accuracy based only on post-contrast T1-weighted and FLAIR MRI, whereas for non-enhancing tumour tissue and necrosis only moderate results are obtained. This makes the method especially suitable for high-grade glioma.

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

Background The purpose of this study was to report the long-term outcome of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)-guided dose painting for head and neck cancer in comparison to conventional intensity-modulated radiotherapy (IMRT) in a matched case-control study. Methods Seventy-two patients with nonmetastatic head and neck cancer treated with dose painting were compared with 72 control patients matched on tumor site and T classification. Either 18F-FDG-PET-guided dose painting by contour (DPBC) or voxel intensity-based dose painting by number (DPBN) was performed; control patients underwent standard IMRT. A total median dose to the dose-painted target was 70.2-85.9 Gy/30-32 fractions versus 69.1 Gy/32 fractions with conventional IMRT. In 31 patients, dose painting was adapted to per-treatment changes in the tumor and organs-at-risk (OAR). Results Median follow-up in living dose-painting and control patients was 87.7 months (range 56.1-119.3) and 64.8 months (range 46.3-83.4), respectively. Five-year local control rates in the dose-painting patients were 82.3% against 73.6% in the control (P = .36); in patients treated to normalized isoeffective doses >91 Gy (NID2Gy) local control reached 85.7% at 5 years against 73.6% in the control group (P =.39). There was no difference in regional (P = .82) and distant control (P = .78). Five-year overall and disease-specific survival rates were 36.3% versus 38.1% (P = .50) and 56.5% versus 51.7% (P = .72), respectively. A half of the dose-painting patients developed acute grade ≥3 dysphagia (P = .004). Late grade 4 mucosal ulcers at the site of dose escalation in 9 of 72 patients was the most common severe toxicity with dose painting versus 3 of 72 patients with conventional IMRT (P = .11). Patients in the dose-painting group had increased rates of acute and late dysphagia (P = .004 and P = .005). Conclusion Dose-painting strategies can be used to increase dose to specific tumor subvolumes. Five-year local, regional, and distant control rates are comparable with patients treated with conventional IMRT. Volume and intensity of dose escalation should be further tailored, given the possible increase in severe acute and chronic toxicity. Adapting treatment and decreasing dose to the swallowing structures might contribute to lower toxicity rates when applied in smaller tumor volumes. Whether adaptive DPBN can significantly improve outcomes is currently being investigated in a novel clinical trial.

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 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.

Introduction To report the impact on target volume delineation and dose to normal tissue using anatomic versus biological imaging (18F-FDG-PET) for bone metastases. Methods Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8 Gy in a single fraction with conventionally planned radiotherapy (ConvRT-8 Gy) or 8 Gy in a single fraction with dose-painting-by-numbers (DPBN) dose range between 6 and 10 Gy) (DPBN-8 Gy) or 16 Gy in a single fraction with DPBN (dose range between 14 and 18 Gy) (DPBN-16 Gy). The primary endpoint was overall pain response at 1 month. Volumes of the gross tumour volume (GTV) – both biological (GTVPET) and anatomical (GTVCT) -, planning target volume (PTV), dose to the normal tissue and maximum standardized-uptake values (SUVMAX) were analysed (secondary endpoint). Results Sixty-three percent of the GTVCT volume did not show 18F-FDG-uptake. On average, 20% of the GTVPET volume was outside GTVCT. The volume of normal tissue receiving 4 Gy, 6 Gy and 8 Gy was at least 3×, 6× and 13× smaller in DPBN-8 Gy compared to ConvRT-8 Gy and DPBN-16 Gy (P

To develop a clinically applicable method to estimate patient-specific organ and blood doses and lifetime attributable risks (LAR) from paediatric torso CT examinations. Individualized voxel models were created from full-body CT data of 10 paediatric patients (2–18 years). Patient-specific dose distributions of chest and abdominopelvic CT scans were simulated using Monte Carlo methods. Blood dose was calculated as a weighted sum of simulated organ doses. LAR of cancer incidence and mortality were estimated, according to BEIR-VII. A second simulation and blood dose calculation was performed using only the thoracic and abdominopelvic region of the original voxel models. For each simulation, the size-specific dose estimate (SSDE) was calculated. SSDE showed a significant strong linear correlation with organ dose (r > 0.8) and blood dose (r > 0.9) and LAR (r > 0.9). No significant differences were found between blood dose calculations with the full-body voxel models and the thoracic or abdominopelvic models. Even though clinical CT images mostly do not cover the whole body of the patient, they can be used as a voxel model for blood dose calculation. In addition, SSDE can estimate patient-specific organ and blood doses and LAR in paediatric torso CT examinations. • Blood dose can be simulated using the patient’s clinical CT images. • SSDE estimates patient-specific organ/blood dose and LAR in paediatric CAP CT-examinations. • SSDE makes on-the-spot dose and LAR estimations possible in routine clinical practice.

Preclinical research has been indispensable in the exploration of the neurological basis of major depressive disorder (MDD). The present study aimed to examine effects on regional brain activity of two frequently used depression models, the chronic unpredictable mild stress (CUMS)- and the chronic corticosterone (CORT) depression model. The CUMS and CORT depression model were induced by exposing male Long-Evans rats to a 4-week procedure of unpredictable mild stressors or a 3-week procedure of chronic corticosterone, respectively. Positron emission tomography with [18F]FDG was performed to determine alterations in regional brain activity. In addition, depressive- and anxiety-like behaviour was assessed via the forced swim test and the open field test, respectively. The chronic CORT administration, but not the CUMS model, significantly induced depressive-like behaviour and elevated plasma corticosterone levels. Compared to control, induction of the CORT depression model resulted in a significantly reduced glucose consumption in the insular cortex and the striatum, and a significantly elevated consumption in the cerebellum and the midbrain. Induction of the CUMS model replicated the findings with respect to the activity in the striatum region, and cerebellum, but missed significance in the insular cortex and the midbrain. Based on the alterations in behaviour and regional [18F]FDG uptake, a superior face validity and construct validity can be observed after induction of depression via chronic CORT injections, compared to the used CUMS paradigm.

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.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, and Nasu Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy are both underrecognized progressive degenerative white matter diseases that can present with young dementia, leukoencephalopathy and brain calcifications. We report and compare three cases in terms of clinical phenotype, imaging and neuropathological findings. Both cases have led to the identification of two novel causal mutations.

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.

To evaluate feasibility, disease control, survival, and toxicity after adaptive F-18-fluorodeoxyglucose (FDG) positron emisson tomography (PET) guided radiotherapy in patients with recurrent and second primary head and neck squamous cell carcinoma. A prospective trial investigated the feasibility of adaptive intensity modulated radiotherapy (IMRT)+/- concomitant cetuximab in 10 patients. The primary endpoint was achieving a 2-year survival free of grade > 3 toxicity in a 30% of patients. Three treatment plans based on 3 PET/CT scans were consecutively delivered in 6 weeks. The range of dose painting was 66.0-85.0Gy in the dose-painted tumoral volumes in 30 fractions. Two-year locoregional and distant control rates were 38 and 76%, respectively. Overall and disease-free survival at 2 years was 20%. No grade 4 or 5 acute toxicity was observed in any of the patients, except for arterial mucosal hemorrhage in 1 patient. Three months after radiotherapy, grade 4 dysphagia and mucosal wound healing problems were observed in 1/7 and 1/6 of patients, respectively. Grade 5 toxicity (fatal bleeding) was seen in 2 patients, at 3.8 and 4.1 months of follow-up. Data on 2aEuroyear toxicity could only be assessed in 1 of the 2 surviving patients, in whom grade 4 mucosal wound healing problems were observed; no other grade > 3 toxicity was observed. In this respect, a 30% 2aEuroyear survival free of grade > 3 toxicity will not be achieved. Adaptive PET-guided reirradiation is feasible. However, due to slow accrual and treatment results that seemed inconsistent with achieving the primary endpoint, the trial was stopped early.

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 Antalgic radiotherapy for bone metastases might be improved by implementing biological information in the radiotherapy planning using 18 F-FDG-PET-CT based dose painting by numbers (DPBN). Materials and methods Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8Gy in a single fraction with conventionally planned radiotherapy (arm A) or 8Gy in a single fraction with DPBN (dose range between 610Gy and 10Gy) (arm B) or 16Gy in a single fraction with DPBN (dose range between 1410Gy and 18Gy) (arm C). The primary endpoint was overall pain response at 1month. The phase II trial was designed to select the experimental arm with sufficient promise of efficacy to continue to a phase III trial. Results Forty-five patients were randomized. Eight (53%), 12 (80%) and 9 patients (60%) had an overall response to treatment in arm A, B and C, respectively. The estimated odds ratio of overall response for arm B vs. A is 3.5 (95% CI: 0.44–17.71, p =0.12). The estimated odds ratio of arm C vs. A is 1.31 (95% CI: 0.31–5.58, p =0.71). Conclusion A single fraction of 8Gy with DPBN will be further evaluated in a phase III-trial.

Introduction Discrimination between (high-grade) brain tumor recurrence and radiation necrosis (RN) remains a diagnostic challenge because both entities have similar imaging characteristics on conventional magnetic resonance imaging (MRI). Metabolic imaging, such as positron emission tomography (PET) could overcome this diagnostic dilemma. In this study, we investigated the potential of 2-[ 18 F]-fluoro-2-deoxy-D-glucose ( 18 F-FDG), O-(2-[ 18 F]-fluoroethyl)-L-tyrosine ( 18 F-FET), and [ 18 F]-Fluoromethyl-dimethyl-2-hydroxyethylammonium ( 18 F-fluoromethylcholine, 18 F-FCho) PET in discriminating high-grade tumor from RN. Methods We developed a glioblastoma (GB) rat model by inoculating F98 GB cells into the right frontal region. Induction of RN was achieved by irradiating the right frontal region with 60Gy using three arcs with a beam aperture of 3×3mm (n=3). Dynamic PET imaging with 18 F-FDG, 18 F-FET, and 18 F-FCho, as well as 18 F-FDG PET at a delayed time interval (240min postinjection), was acquired. Results MRI revealed contrast-enhancing tumors at 15days after inoculation (n=4) and contrast-enhancing RN lesions 5–6months postirradiation (n=3). On 18 F-FDG PET, the mean lesion-to-normal ratio (LNR mean ) was significantly higher in GB than in RN (p=0.034). The difference in the LNR mean between tumors and RN was higher on the late 18 F-FDG PET images than on the PET images reconstructed from the last time frame of the dynamic acquisition (this is at a conventional time interval). LNRs obtained from 18 F-FCho PET were not significantly different between GB and RN (p=1.000). On 18 F-FET PET, the LNR mean was significantly higher in GB compared to RN (p=0.034). Conclusions Unlike 18 F-FCho, 18 F-FDG and 18 F-FET PET were effective in discriminating GB from RN. Interestingly, in the case of 18 F-FDG, delayed PET seems particularly useful. Advances in knowledge and implications for patient care Our results suggest that (delayed) 18 F-FDG and 18 F-FET PET can be used to discriminate GB (recurrence) from RN. Confirmation of these results in clinical studies is needed.

The accurate diagnosis of brain tumors is of primary importance for optimal therapy planning. In clinical practice, this is determined on a biopsy, exposing the patient to the risk of complications. Moreover, sampling bias and performer variability may influence the result. Several studies have investigated the histological grading of brain tumors in a non-invasive way by extracting features from medical images. A multicenter study where both tumor grade and cell type are simultaneously predicted is however lacking. In this study we collected structural MRI-scans from 294 patients with glioma acquired in different centers (the local hospital and two online databases). The goal was to predict tumor grade and cell type of individual patients using a radiomics study with Random Forests. In a multiclass design, we obtain a global accuracy of 59.9% to predict tumor grade and 53.4% to predict cell type. Converting the problem to binary classification, we obtain an accuracy of 98.3% to distinguish between meningioma and glioma, and 84.5% to distinguish between low-grade glioma and glioblastoma. A high degree of diagnosis variability and overlap between different low-grade classes might cause the reduced prediction accuracy. Our results however show that radiomics on structural MRI is a suitable approach for non-invasively assessing brain tumor diagnosis and might be used for individual treatment planning.

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.

In this study, the potential of semiquantitative and quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) was investigated to differentiate glioblastoma (GB) from radiation necrosis (RN) in rats. F98 GB growth was seen on 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)). Dynamic contrast-enhanced time series, obtained from the DCE-MRI data, were fitted to determine four 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 semiquantitative and quantitative parameters (extended Tofts model) were created using Olea Sphere (O). Semiquantitative 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) (K trans), the rate constant EES to plasma (K ep), plasma volume (V p), and EES volume (V e). All (semi)quantitative parameters were compared between GB and RN using the Mann-Whitney U test. ROC analysis was performed. Wash-in rate (k) and wash-out rate (D) were significantly higher in GB compared to RN using curve fitting (p = 0.016 and p = 0.014). TTPF and TTPO were significantly lower in GB compared to RN (p = 0.001 and p = 0.005, respectively). The highest sensitivity (87 %) and specificity (80 %) were obtained for TTPF by applying a threshold of 581 s. K trans, K ep, and V e were not significantly different between GB and RN. A trend towards higher V p values was found in GB compared to RN, indicating angiogenesis in GB (p = 0.075). Based on our results, in a rat model of GB and RN, wash-in rate, wash-out rate, and the time to peak extracted from DCE-MRI time series data may be useful to discriminate GB from RN.

Purpose In this study, we investigated fluorine-18 fluoromethylcholine (F-FCho) PET and contrast-enhanced MRI for predicting therapy response in glioblastoma (GB) patients according to the Response Assessment in Neuro-Oncology criteria. Our second aim was to investigate which imaging modality enabled prediction of treatment response first. Materials and methods Eleven GB patients who underwent no surgery or debulking only and received concomitant radiation therapy (RT) and temozolomide were included. The gold standard Response Assessment in Neuro-Oncology criteria were applied 6 months after RT to define responders and nonresponders. F-FCho PET and MRI were performed before RT, during RT (week 2, 4, and 6), and 1 month after RT. The contrast-enhancing tumor volume on T1-weighted MRI (GdTV) and the metabolic tumor volume (MTV) were calculated. GdTV, standardized uptake value (SUV)mean, SUVmax, MTV, MTV×SUVmean, and percentage change of these variables between all time-points were assessed to differentiate responders from nonresponders. Results Absolute SUV values did not predict response. MTV must be taken into account. F-FCho PET could predict response with a 100% sensitivity and specificity using MTV×SUVmean 1 month after RT. A decrease in GdTV between week 2 and 6, week 4 and 6 during RT and week 2 during RT, and 1 month after RT of at least 31%, at least 18%, and at least 53% predicted response with a sensitivity and specificity of 100%. As such, the parameter that predicts therapy response first is MR derived, namely, GdTV. Conclusion Our data indicate that both F-FCho PET and contrast-enhanced T1-weighted MRI can predict response early in GB patients treated with RT and temozolomide.

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.

Aim: The aim of this study was to validate F-18-FDG PET imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). Methods: Twenty-one patients with gliomas undergoing a stereotactic biopsy underwent PET scanning at conventional and delayed intervals, diagnostic and stereotactic MR examinations. To calculate the uptake at the biopsy site, a 2-mm voxel was selected. Uptake in this voxel was expressed as a percentage of the average uptake per voxel in the normal brain. The difference in uptake between HGG and LGG at conventional and late intervals and the difference in uptake difference between HGG and LGG at both intervals were analyzed using t tests as well as a mixed-model analysis of variance. Results: At conventional intervals, uptake in LGG was 67% of that in the normal brain. Between early and late intervals, a significant decrease in uptake of 11% (+/- 2.5%) was noted (P = 0.001). Uptake in HGG at conventional intervals was 138% of that in the normal brain. Between early and late intervals, a significant increase in uptake of 43% (+/- 11%) was noted (P = 0.005). The difference in uptake between HGG and LGG was significant both at conventional and delayed intervals (P < 0.001). Moreover, the difference in uptake between both groups was significantly greater (31%) at delayed than at conventional intervals (2%) (P < 0.001). Conclusions: The results of this correlative study between tumor grade and F-18-FDG uptake both determined at the stereotactic biopsy site indicate that PET, particularly at delayed intervals, is valid for discriminating LGG from HGG.

Standardized added metabolic activity (SAM) is a PET parameter for assessing the total metabolic load of malignant processes, avoiding partial volume effects and lesion segmentation. The potential role of this parameter in the assessment of response to chemotherapy and bevacizumab was tested in patients with metastatic colorectal cancer with potentially resectable liver metastases (mCRC). F-18-FDG PET/CT was performed in 18 mCRC patients with liver metastases before treatment and after five cycles of FOLFOX/FOLFIRI and bevacizumab. Of the 18 patients, 16 subsequently underwent resection of liver metastases. Baseline and follow-up SUVmax, and SAM as well as reduction in SUVmax (a dagger SUVmax) and SAM (a dagger SAM) of all liver metastases were correlated with morphological response, and progression-free and overall survival (PFS and OS). A significant reduction in metabolic activity of the liver metastases was seen after chemotherapy with a median a dagger SUVmax of 25.3 % and a dagger SAM of 94.5 % (p = 0.033 and 0.003). Median baseline SUVmax and SAM values were significantly different between morphological responders and nonresponders (3.8 vs. 7.2, p = 0.021; and 34 vs. 211, p = 0.002, respectively), but neither baseline PET parameters nor morphological response was correlated with PFS or OS. Follow-up SUVmax and SAM as well as a dagger SAM were found to be prognostic factors. The median PFS and OS in the patient group with a high follow-up SUVmax were 10.4 months and 32 months, compared to a median PFS of 14.7 months and a median OS which had not been reached in the group with a low follow-up SUVmax (p = 0.01 and 0.003, respectively). The patient group with a high follow-up SAM and a low a dagger SAM had a median PFS and OS of 9.4 months and 32 months, whereas the other group had a median PFS of 14.7 months and a median OS which had not been reached (p = 0.002 for both PFS and OS). F-18-FDG PET imaging is a useful tool to assess treatment response and predict clinical outcome in patients with mCRC who undergo chemotherapy before liver metastasectomy. Follow-up SUVmax, follow-up SAM and a dagger SAM were found to be significant prognostic factors for PFS and OS.

BACKGROUND Multimodality imaging such as proton magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) have provided information specific to the underlying mechanisms of many brain diseases, including multiple sclerosis (MS). PURPOSE To determine the structural and metabolic characterization of two particular variants of MS, namely tumefactive MS and Balo's concentric sclerosis (BCS). METHODS Conventional MR imaging, diffusion and perfusion MR, MR spectroscopy and PET imaging with F-18 fluorodeoxyglucose (FDG) and F-18 fluoromethylcholine (FCho) were performed. RESULTS In a case with pathologically proven tumefactive MS, magnetic resonance imaging (MRI) showed a pseudotumoral lesion with incomplete ring enhancement, peripheral diffusion restriction, and high choline and lactate peaks on MRS. On follow-up, the lesion showed significant growth. In a case of BCS, MRI showed an onion-like lesion without contrast enhancement or diffusion restriction, and only a moderate increase in choline on MRS. The lesion remained stable on follow-up. On PET, there was no uptake of F-18 FDG in either type of MS lesion. Conversely, uptake of F-18 FCho was moderate in tumefactive MS, whereas no F-18 FCho uptake was noted in the lesion with, on MRI, typical features of BCS. CONCLUSIONS Our findings illustrate that metabolic features may differ between variants of MS possibly signifying different disease activity.

Context and purpose: The mechanisms of ageing of the healthy brain are not entirely clarified to date. In recent years several authors have tried to elucidate this topic by using F-18-FDG positron emission tomography. However, when correcting for partial volume effects (PVE), divergent results were reported. Therefore, it is necessary to evaluate these methods in the presence of atrophy due to ageing. In this paper we first evaluate the performance of two PVE correction techniques with a phantom study: the Rousset method and iterative deconvolution. We show that the ability of the latter method to recover the true activity in a small region decreases with increasing age due to brain atrophy. Next, we have calculated age-dependent recovery factors to correct for this incomplete recovery. These factors were applied to PVE-corrected F-18-FDG PET scans of healthy subjects for mapping the age-dependent metabolism in the brain. Results: Many regions in the brain show a reduced metabolism with ageing, especially in grey matter in the frontal and temporal lobe. An increased metabolism is found in grey matter of the cerebellum and thalamus. Conclusion: Our study resulted in age-dependent recovery factors which can be applied following standard PVE correction methods. Cancelling the effect of atrophy, we found regional changes in F-18-FDG metabolism with ageing. A decreasing trend is found in the frontal and temporal lobe, whereas an increasing metabolism with ageing is observed in the thalamus and cerebellum.

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.

To study age-related metabolic changes in N-acetylaspartate (NAA), total creatine (tCr), choline (Cho) and myo-inositol (Ins).Proton magnetic resonance spectroscopy (1H-MRS) was performed in the posterior cingulate cortex (PCC) and the left hippocampus (HC) of 90 healthy subjects (42 women and 48 men aged 18-76 years, mean±SD, 48.4±16.8 years). Both metabolite ratios and absolute metabolite concentrations were evaluated. Analysis of covariance (ANCOVA) and linear regression were used for statistical analysis.Metabolite ratios Ins/tCr and Ins/H2O were found significantly increased with age in the PCC (P0.05 and P≤0.001, respectively), and in the HC (P0.01 for both). An increased tCr/H2O was only observed in the PCC (P0.01). Following absolute quantification based on the internal water signal, significantly increased concentrations of Ins and tCr in the PCC confirmed the relative findings (P0.01 for both).Age-related increases of tCr and Ins are found in the PCC, whereas this holds only true for Ins in the HC, indicating possible gliosis in the ageing brain. No age-dependent NAA decreases were observed in the PCC nor the HC. The 1H-MRS results in these specific brain regions can be important to differentiate normal ageing from age-related pathologies such as mild cognitive impairment (MCI) and Alzheimer's disease.

SummaryPurpose: Evaluate the predictive and prognostic value of semi-quantitative FDG-PET variables derived from pretreatment FDG-PET images in patients suffering from locally advanced squamous cell carcinoma of the head and neck (SCCHN), treated by means of concomitant radiochemotherapy. Patients, methods: 40 patients with newly diagnosed SCCHN that were treated with concomitant radiochemotherapy underwent FDG-PET/CT for treatment planning; 18 patients had neck dissection prior to their baseline scan and to receiving radiochemotherapy. FDG-PET images were used to calculate metabolic tumour volumes using region growing and a threshold of 50% (MTV50) of primary lesions and involved lymph nodes as well as the mean and maximum standard uptake value (SUVmean and SUVmax) of the primary tumours. Results: Neither SUVmean nor SUVmax values of the primary tumour were significantly different between responders and non-responders whereas MTV50 values of the primary tumour proved significantly higher in non-responders. SUVmean, SUVmax and MTV50 of the primary tumour were not predictive for overall or disease free survival. Contrariwise, dichotomized summed MTV50 values (cut-off ≥ 31 cm3) of the primary tumour and involved lymph nodes in patients that didn’t have neck dissection prior to radiochemotherapy were predictive for disease free and overall survival in both univariate and multivariate analysis (p ≤ 0.05). Conclusion: Summed MTV50 values of both the primary tumour and involved lymph nodes provided independent prognostic information on disease free and overall survival.

Summary Aim: This study aimed at assessing the relationship between over-expression of glucose transporters and hexokinases, tumour proliferation and apoptosis corrected for cellularity and partial volume corrected (pvc) FDG SUV values in primary squamous cell carcinoma of the head and neck (pSCCHN). Patients, methods: In 27 consecutive patients suffering from pSCCHN, FDG SUVmax and mean pvc values of the primary tumour were derived from a pre-surgical routine staging FDG PET/CT examination. GLUT-1, GLUT-3, HK-1, HK-3 expression, tumour proliferation (Ki-67 staining) and the number of apoptotic cells (cleaved caspase-3 staining), corrected for tumour cellularity, were subsequently assessed on the corresponding post-surgically obtained biopsies and tumour specimens. FDG SUVmax and mean pvc values of pSCCHN were correlated with the corresponding histological findings. Results: FDG SUV max and mean pvc values correlated significantly: with GLUT-1 scores r = 0.408 (p = 0.04) and r = 0.439 (p = 0.03) as well as with the number of apoptotic cells r = 0.529 (p = 0.008) and r = 0.484 (p = 0.017). The number of apoptotic cells also correlated to GLUT-3 scores: r = 0.62 (p = 0.001) and GLUT-1 scores r = 0.528 (p = 0.008). Conclusion: FDG SUV pvc proved significantly related to GLUT-1 expression by tumour cells and to the absolute number of apoptotic cells. The latter finding warrants further exploration and confirmation by additional studies.

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.