Dominique Slaets

PET with 18F-labelled choline-based tracers for tumour imaging: a review of the literature

PurposeTo give an up-to-date overview of the potential clinical utility of 18F-labelled choline derivatives for tumour imaging with positron emission tomography.MethodsA PubMed search for 18F-labelled choline analogues was performed. Review articles and reference lists were used to supplement the search findings.Results18F-labelled choline analogues have been investigated as oncological PET probes for many types of cancer on the basis of enhanced cell proliferation. To date, studies have focused on the evaluation of prostate cancer. Available studies have provided preliminary results for detecting local and metastatic disease. Experience with 18F-fluorocholine PET in other tumour types, including brain and liver tumours, is still limited. In the brain, excellent discrimination between tumour and normal tissue can be achieved due to the low physiological uptake of 18F-fluorocholine. In the liver, in which there is a moderate to high degree of physiological uptake in normal tissue, malignancy discrimination may be more challenging.ConclusionPET/CT with 18F-fluorocholine can be used to detect (recurrent) local prostate cancer, but seems to have limited value for T (tumour) and N (nodal) staging. In patients presenting with recurrent biochemical prostate cancer, it is a suitable single-step examination with the ability to exclude distant metastases when local salvage treatment is intended. In the brain, high-grade gliomas, metastases and benign lesions can be distinguished on the basis of 18F-fluorocholine uptake. Moreover, PET imaging is able to differentiate between radiation-induced injury and tumour recurrence. In the liver, 18F-fluorocholine PET/CT seems promising for the detection of hepatocellular carcinoma.

Distribution patterns of 18F-labelled fluoromethylcholine in normal structures and tumors of the head: a PET/MRI evaluation.

Purpose To evaluate the distribution of 18F-labelled fluoromethylcholine (FCho) in normal structures and tumors of the head region using positron emission tomography (PET) and magnetic resonance imaging. Materials and Methods We retrospectively reviewed the positron emission tomography, magnetic resonance imaging, and the coregistered images obtained in 17 patients with suspected high-grade gliomas. The accumulation of 18F-FCho in the normal structures and in brain lesions was visually and semiquantitatively assessed. A 4-point grading system was used for the visual analysis. A standardized uptake value (SUV) was used to quantify uptake. Results In the normal brain parenchyma, 18F-FCho uptake was faint (SUVmean, 0.15 ± 0.03 (SD)). Uptake was generally moderate in the choroid plexus (SUVmean, 0.82 ± 0.16), cavernous sinus (SUVmean, 0.87 ± 0.19), extraocular eye muscles (SUVmean, 1.10 ± 0.27), masticatory muscles (SUVmean, 0.99 ± 0.22), and bone marrow (SUVmean, 1.06 ± 0.26), whereas uptake was usually moderately intense in the pituitary gland (SUVmean, 1.90 ± 0.21). Uptake was variable in the lacrimal glands and the mucosa of the nasal cavity (for SUVmean of subgroups see text). Intense uptake was observed in the parotid glands (SUVmean, 3.27 ± 0.73). (Moderately) intense 18F-FCho uptake was observed in glioblastomas (range SUVmax, 2.26–6.37) and typical meningiomas (range SUVmax, 3.75–5.81). Uptake was globally faint in grade II and III gliomas (range SUVmax, 0.33–0.78). 18F-FCho uptake was also demonstrated in benign lesions, such as a tumefactive demyelinating brain lesion. Conclusions 18F-FCho uptake was faint in the normal brain parenchyma and usually moderate in the choroid plexus, cavernous sinus, extraocular eye muscles, masticatory muscles, and bone marrow. Uptake in the pituitary gland was generally moderately intense, whereas uptake in the lacrimal glands and the mucosa of the nasal cavity was variable. Parotid glands had intense uptake. Also, uptake in glioblastomas and meningiomas was usually (moderately) intense, whereas uptake in grade II and III gliomas was globally faint. However, 18F-FCho uptake was not tumor specific.

Antiepileptic drugs modulate P-glycoproteins in the brain: a mice study with 11C-desmethylloperamide

P-glycoprotein transporters (P-gp) located at the blood-brain barrier (BBB) are likely to play a role in refractory epilepsy. In vitro studies already pointed out that several antiepileptic drugs (AEDs) are substrate of P-gp. This study proposes a new in vivo approach to investigate the interaction between some AEDs and P-gp located at the BBB. (11)C-desmethylloperamide ((11)C-dLop), a radiolabelled substrate of P-gp, was intravenously administrated after pretreatment with saline or AEDs (sodium valproate, levetiracetam, topiramate and phenytoin) at their human therapeutic and four times their therapeutic dose. The effect of the different pretreatment on the intracerebral concentration of (11)C-dLop was determined to indirectly investigate possible in vivo interactions between AEDs and P-gp. Pretreatment with levetiracetam, topiramate and phenytoin at therapeutic doses significantly decreased intracerebral concentration of (11)C-dLop. Pretreatment with a therapeutic dose of sodium valproate did not influence brain uptake of (11)C-dLop. In case of pretreatment with supratherapeutic doses of AED, (11)C-dLop brain uptake was not different compared to pretreatment with saline. The metabolisation rate of (11)C-dLop in plasma was unaltered, indicating that observed differences in brain uptake of the tracer were not due to pharmacokinetic changes. The following conclusion can be made: levetiracetam, topiramate and phenytoin demonstrate biphasic modulation of the BBB P-gp. At therapeutic doses they act as inducers of efflux, at supratherapeutic doses they have no effect on the efflux rate. Sodium valproate does not interact with P-gp at therapeutic nor at higher doses.

Kinetics of angiogenic changes in a new mouse model for hepatocellular carcinoma

BackgroundThe increasing incidence of hepatocellular carcinoma in Western countries has led to an expanding interest of scientific research in this field. Therefore, a vast need of experimental models that mimic the natural pathogenesis of hepatocellular carcinoma (HCC) in a short time period is present. The goal of our study was (1) to develop an efficient mouse model for HCC research, in which tumours develop in a natural background of fibrosis and (2) to assess the time-dependent angiogenic changes in the pathogenesis of HCC.MethodsWeekly intraperitoneal injections with the hepatocarcinogenic compound N-nitrosodiethylamine was applied as induction method and samples were taken at several time points to assess the angiogenic changes during the progression of HCC.ResultsThe N-nitrosodiethylamine-induced mouse model provides well vascularised orthotopic tumours after 25 weeks. It is a representative model for human HCC and can serve as an excellent platform for the development of new therapeutic targets.

Comparison between kinetic modelling and graphical analysis for the quantification of [18F]fluoromethylcholine uptake in mice

BackgroundUntil now, no kinetic model was described for the oncologic tracer [18F]fluoromethylcholine ([18F]FCho), so it was aimed to validate a proper model, which is easy to implement and allows tracer quantification in tissues.MethodsBased on the metabolic profile, two types of compartmental models were evaluated. One is a 3C2i model, which contains three tissue compartments and two input functions and corrects for possible [18F]fluorobetaine ([18F]FBet) uptake by the tissues. On the other hand, a two-tissue-compartment model (2C1i) was evaluated. Moreover, a comparison, based on intra-observer variability, was made between kinetic modelling and graphical analysis.ResultsDetermination of the [18F]FCho-to-[18F]FBet uptake ratios in tissues and evaluation of the fitting of both kinetic models indicated that corrections for [18F]FBet uptake are not mandatory. In addition, [18F]FCho uptake is well described by the 2C1i model and by graphical analysis by means of the Patlak plot.ConclusionsThe Patlak plot is a reliable, precise, and robust method to quantify [18F]FCho uptake independent of scan time or plasma clearance. In addition, it is easily implemented, even under non-equilibrium conditions and without creating additional errors.

873 ANGIOGENIC CHANGES IN A NEW MOUSE MODEL FOR HEPATOCELLULAR CARCINOMA ASSESSED WITH STATE-OF-THE-ART IMAGING TECHNOLOGY

Background: The increasing incidence of hepatocellular carcinoma in Western countries has led to an expanding interest in this field. A vast need of experimental models that mimic the natural pathogenesis of hepatocellular carcinoma in a short time period is present. The goal of our study was (1) to develop an efficient mouse model for hepatocellular carcinoma research, (2) to assess time-dependent angiogenic changes and (3) to investigate tumour growth and neo-vascularisation using state-of-the-art imaging techniques. Methods: 5-week-old male mice received weekly intraperitoneal injections with N-nitrosodiethylamine (DEN) (35 mg/kg bodyweight) and samples were taken at several time points. Histology, ELISA and immunohistochemical stainings were used to identify the HCC-lesions and to quantify angiogenic factors VEGF and PlGF. HCC livers (25W) were perfused with Batson’s n°17 solution to produce vascular casts (arterial and venous). A state-of-the-art multimodal microPET/CT was used for in vivo detection of HCC-lesions with [18F]-fluoromethylcholine ([18F]FMCH) and for 3D-reconstruction of the vascular casts. Results: After 16W of DEN-injections a mild fibrosis (F1-F2) and dysplastic lesions appear, resulting in a pre-malignant environment. An increase of angiogenic factors VEGF and PlGF takes place, but not explicit enough to induce an increase in endothelial cells, which were upregulated after 20W. After 25W of DEN-injections, the dysplastic lesions have progressed to vascularised exophytic tumours which are macroscopically visible and give rise to a further increase in angiogenic factors, leading to the formation of new blood vessels. HCC-lesions were characterised by an increased uptake of [18F]FMCH, allowing visualisation of these hotspots (>3mm) with microPET/CT (figure 1). The vascular casts of HCC-livers clearly revealed the chaotic pattern and hierarchically disorganisation of tumour induced blood vessels (figure 2). Arteries formed a circumferential mantle around the hepatic tumours, while the central tumour regions showed a lower arterial density (figure 3). Electron microscopy revealed several angiogenic spots, with mostly sprouting angiogenesis, yet intussusceptive angiogenesis was also seen (figure 3). Conclusion: While most DEN-induced models take at least one year to develop tumours, weekly injections with DEN give rise to tumour occurrence after 25W. The well vascularised orthotopic tumours are a representative model for HCC and can serve as an excellent platform for the development of new therapeutic targets. The CT-reconstructions of vascular casts can be used as an interesting tool to study angiogenesis in animal models, especially for testing angiogenesis-inhibiting therapies. Furthermore, [18F]FMCH PET imaging may be clinically relevant for the visualization of HCC-lesions.