Disease Control and Late Toxicity in Adaptive Dose Painting by Numbers Versus Nonadaptive Radiation Therapy for Head and Neck Cancer: A Randomized Controlled Phase 2 Trial.

PURPOSE: Local recurrence remains the main cause of death in stage III-IV nonmetastatic head and neck cancer (HNC), with relapse-prone regions within high 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)-signal gross tumor volume. We investigated if dose escalation within this subvolume combined with a 3-phase treatment adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18F-FDG-PET voxel intensity-based dose painting by numbers (A-DPBN) with nonadaptive standard intensity modulated radiation therapy (S-IMRT). METHODS AND MATERIALS: This 2-center randomized controlled phase 2 trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: nonmetastatic HNC of oral cavity, oro-/hypopharynx, or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS ≥ 70; ≥18 years; and informed consent. PRIMARY OUTCOMES: 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in 2 steps to an absolute dose-volume limit (≤1.75 cm3 can receive >84 Gy and normalized isoeffective dose >96 Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. RESULTS: Ninety-five patients were randomized (A-DPBN, 47; S-IMRT, 48). Median follow-up was 31 months (IQR, 14-48 months); 29 patients died (17 of cancer progression). A-DPBN resulted in superior LC compared with S-IMRT, with 1- and 2-year LC of 91% and 88% versus 78% and 75%, respectively (hazard ratio, 3.13; 95% CI, 1.13-8.71; P = .021). RC and overall survival were comparable between arms, as was overall grade (G) ≥3 late toxicity (36% vs 20%; P = .1). More ≥G3 late mucosal ulcers were observed in active smokers (29% vs 3%; P = .005) and alcohol users (33% vs 13%; P = .02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients who smoked at diagnosis developed ≥G3 (46% vs 12%; P = .005) and ≥G4 (29% vs 8%; P = .048) mucosal ulcers. One arterial blowout occurred after a G5 mucosal toxicity. CONCLUSIONS: A-DPBN resulted in superior 1- and 2-year LC for HNC compared with S-IMRT. This supports further exploration in multicenter phase 3 trials. It will, however, be challenging to recruit a substantial patient sample for such trials, as concerns have arisen regarding the association of late mucosal ulcers when escalating the dose in continuing smokers.

Introducing HDAC-Targeting Radiopharmaceuticals for Glioblastoma Imaging and Therapy.

Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy.

Retrospective real-life study on preoperative imaging for minimally invasive parathyroidectomy in primary hyperparathyroidism.

The objective of this study was to retrospectively evaluate preoperative imaging modalities for localization of parathyroid adenomas with a view to enable minimally invasive parathyroidectomy and in particular, to consider the contribution of 18F-fluorocholine-PET/CT. 104 patients with primary hyperparathyroidism, who underwent parathyroid surgery in a single centre during a 6-year period were included. Of these, 103 underwent ultrasound, 97 99mTc-Pertechnetate/SestaMIBI-SPECT, 20 MRI and 30 18F-fluorocholine-PET/CT. Based on surgical findings, sensitivities and specificities for correct lateralisation in orthotopic locations were: for ultrasound 0.75 (0.65-0.83) and 0.89 (0.81-0.94), for 99mTc-MIBI-SPECT 0.57 (0.46-0.67) and 0.97 (0.91-0.99), for MRI 0.60 (0.36-0.81) and 0.83 (0.59-0.96) and for 18F-fluorocholine-PET/CT 0.90 (0.73-0.98) and 0.90 (0.73-0.98). Correctly lateralized adenomas were significantly larger than those not found with ultrasound (p = 0.03) and SPECT (p = 0.002). Pre-operative PTH-levels were higher in single adenomas detected by scintigraphy than in those not (p = 0.02). 64 patients could be treated with a minimally invasive procedure. Cure after parathyroidectomy was obtained in 94% of patients. 18F-Fluorocholine-PET/CT could be shown to be a highly accurate modality to localize parathyroid adenomas preoperatively, obviating the need for total exploration in the majority of patients in whom ultrasound and scintigraphic results are discordant or both negative.

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma.

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.

Positron Emission Tomography-based Dose Painting Radiation Therapy in a Glioblastoma Rat Model using the Small Animal Radiation Research Platform.

A rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was previously established. Similar to the clinical treatment, computed tomography (CT) and magnetic resonance imaging (MRI) were combined during the treatment-planning process. Positron emission tomography (PET) imaging was subsequently added 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 labor-intensive because multimodal imaging, treatment planning, and dose delivery have to be completed sequentially in the preclinical setting. This also results in a workflow that is more prone to human error. Therefore, a user-friendly algorithm to further optimize preclinical multimodal imaging-based radiation treatment planning was implemented. This software tool was used to evaluate the accuracy and efficiency of dose painting radiation therapy with micro-irradiation by using an in silico study design. The new methodology for dose painting radiation therapy is superior to the previously described method in terms of accuracy, time efficiency, and intra- and inter-user variability. It is also an important step towards the implementation of inverse treatment planning on micro-irradiators, where forward planning is still commonly used, in contrast to clinical systems.

A perspective on the radiopharmaceutical requirements for imaging and therapy of glioblastoma.

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.

Comparison of an in-house acquired brain F-18 FDG PET normal database with commercially available normal data.

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.

Assessment of the effect of therapy in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI.

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.

Development of a Rat Model for Glioma-Related Epilepsy.

Seizures are common in patients with high-grade gliomas (30-60%) and approximately 15-30% 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.

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine.

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 [18F]fluorophenylglutamine and [18F]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 [3H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [18F]fluorophenylglutamine and [18F]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) ([18F]fluorophenylglutamine) and 8.05 ± 3.25% (n = 5) ([18F]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 [18F]FBPG in the mice PC-3 xenograft and a moderate uptake of [18F]FPG in the PC-3 tumors. CONCLUSION: We investigated the imaging potential of two novel PET radiotracers [18F]FPG and [18F]FBPG. [18F]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 [18F]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-[18F]fluoroglutamine). [18F]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.

2-[18F]FELP, a novel LAT1-specific PET tracer, for the discrimination between glioblastoma, radiation necrosis and inflammation.

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.

Striatal dopamine D2 binding correlates with locus of control: Preliminary evidence from [11C]raclopride Positron Emission Tomography.

The ability to exert control has been widely investigated as a hallmark of adaptive behaviour. Dopamine is recognized as the key neuromodulator mediating various control-related processes. The neural mechanisms underlying the subjective perception of being in control, or Locus of Control (LOC) are however less clear. LOC indicates the subjective tendency to attribute environmental outcomes to one's actions (internal LOC) or instead to external incontrollable factors (external LOC). Here we hypothesized that dopamine levels also relate to LOC. Previous work shows that dopamine signaling mediates learning of action-outcome relationships, outcome predictability, and opportunity cost. Prominent theories propose dopamine dysregulation as the key pathogenetic mechanism in schizophrenia and depression. Critically, external LOC is a risk factor for schizophrenia and depression, and predicts increased vulnerability to stress. However, a direct link between LOC and dopamine levels in healthy control had not been demonstrated. The purpose of our study was to investigate this link. Using [11C]raclopride Positron Emission Tomography we tested the relationship between D2 receptor binding in the striatum and LOC (measured with the Rotter Locus of Control scale) in 15 healthy volunteers. Our results show a large and positive correlation: increased striatal D2 binding was associated with External LOC. This finding opens promising avenues for the study of several psychological impairments that have been associated with both dopamine and LOC, such as addiction, schizophrenia, and depression.

Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma: A preclinical F98 glioblastoma rat model study.

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.

Cost-Effectiveness of [18F] Fluoroethyl-L-Tyrosine for Temozolomide Therapy Assessment in Patients With Glioblastoma.

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.

PET quantification of [18F]MPPF in the canine brain using blood input and reference tissue modelling.

Numerous studies have shown that the serotonin1A (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- [18F]fluorobenzamidoethylpiperazine ([18F]MPPF) is a valid and useful PET tracer to visualize the 5HT1A receptor. However, to our knowledge, [18F]MPPF has never been demonstrated in the canine brain. The ability to image the 5HT1A 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 [18F]MPPF in dogs, five healthy adult laboratory beagles underwent a 60-minutes dynamic PET scan with [18F]MPPF while arterial blood samples were taken. For each region of interest, total distribution volume (VT) 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-in-dog study indicates the results of a bolus injection with [18F]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.

Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model.

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.

New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma.

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.

The Path Toward PET-Guided Radiation Therapy for Glioblastoma in Laboratory Animals: A Mini Review.

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.

Magnetic resonance imaging-guided radiation therapy using animal models of glioblastoma.

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.