Koen Mertens

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.

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.

Single-Photon Emission Computed Tomographic Imaging of the Early Time Course of Therapy-Induced Cell Death Using Technetium 99m Tricarbonyl His-Annexin A5 in a Colorectal Cancer Xenograft Model

As apoptosis occurs over an interval of time after administration of apoptosis-inducing therapy in tumors, the changes in technetium 99m (99mTc)-tricarbonyl (CO)3 His-annexin A5 (His-ann A5) accumulation over time were examined. Colo205-bearing mice were divided into six treatment groups: (1) control, (2) 5-fluorouracil (5-FU; 250 mg/kg), (3) irinotecan (100 mg/kg), (4) oxaliplatin (30 mg/kg), (5) bevacizumab (5 mg/kg), and (6) panitumumab (6 mg/kg). 99mTc-(CO)3 His-ann A5 was injected 4, 8, 12, 24, and 48 hours posttreatment, and micro–single-photon emission computed tomography was performed. Immunostaining of caspase-3 (apoptosis), survivin (antiapoptosis), and LC3-II (autophagy marker) was also performed. Different dynamics of 99mTc-(CO)3 His-ann A5 uptake were observed in this colorectal cancer xenograft model, in response to a single dose of three different chemotherapeutics (5-FU, irinotecan, and oxaliplatin). Bevacizumab-treated mice showed no increased uptake of the radiotracer, and a peak of 99mTc-(CO)3 His-ann A5 uptake in panitumumab-treated mice was observed 24 hours posttreatment, as confirmed by caspase-3 immunostaining. For irinotecan-, oxaliplatin-, and bevacizumab-treated tumors, a significant correlation was established between the radiotracer uptake and caspase-3 immunostaining (r = .8, p < .05; r = .9, p < .001; r = .9, p < .001, respectively). For 5-FU- and panitumumabtreated mice, the correlation coefficients were r = .7 (p = .18) and r = .7 (p = .19), respectively. Optimal timing of annexin A5 imaging after the start of different treatments in the Colo205 model was determined.

Structural and metabolic features of two different variants of multiple sclerosis: a PET/MRI study.

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).

The optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine: a dynamic positron emission tomography study.

PurposeTo determine the optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine (18F-FCho) PET. Materials and methodsDynamic PET imaging with 18F-FCho (acquisition time of 28 min) was performed in 24 patients with space-occupying lesions in the brain. On the coregistered PET and MRI, lesion-to-normal tissue uptake ratios (LNRs) were calculated. Time–activity curves (TACs) were generated on the basis of the LNRs. Changes in LNR over time were calculated on the basis of the linear part of the TAC (last 22 min of the acquisition). ResultsTACs for 18F-FCho in gliomas of different grading showed that, after a rapid uptake phase, the mean increase in LNR was 1.07±0.93 for glioblastomas, −0.52±1.56 for anaplastic astrocytomas, 0.04±0.13 for grade 2 oligoastrocytomas and 0.37 in a case of a pilocytic astrocytoma. The average increase in LNR was 0.46 for a brain metastasis, 0.41±0.69 for radiation-induced mass lesions and 1.07 for a tumefactive demyelinating lesion. In contrast, TACs for 18F-FCho in meningiomas showed that, after a rapid uptake phase, the average change in LNR was −5.25±4.19 for typical meningiomas and −3.04 in a case of a mixed angiomatous and clear cell meningioma. ConclusionOn the basis of the TACs, PET imaging with 18F-FCho starting within minutes after the administration of the tracer is preferred for the detection of brain tumours and other brain lesions. If discrimination between meningioma and other brain tumours is of concern, both ‘early’ and ‘late’ PET imaging could be helpful.

Validation of 18F-FDG PET at conventional and delayed intervals for the discrimination of high-grade from low-grade gliomas: a stereotactic PET and MRI study.

Aim The aim of this study was to validate 18F-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 18F-FDG uptake both determined at the stereotactic biopsy site indicate that PET, particularly at delayed intervals, is valid for discriminating LGG from HGG.

In Vitro 2-Deoxy-2-[18F]Fluoro-D-Glucose Uptake: Practical Considerations

In oncology 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]-FDG), a glucose analogue, is the most used positron emission tomography (PET) tracer. There are however some limitations due to low metabolic activity or high surrounding physiological uptake in several tumors or regions. Investigating new tracers or methods is expensive and elaborative when animal experiments or phase I clinical trials are used. In vitro experiments can overcome these limitations. We analyzed the influence of incubation time, cell medium conditions, administered activity, and cell density on [(18)F]-FDG uptake in six different cell cultures. Glucose transporter 1 (GLUT1)- and hexokinase 2 (HK2)-expression at high and low cell density was analyzed using immunocytochemistry. FDG-uptake increases over time and absence of glucose in the incubation medium increases uptake. By increasing the administered activity, uptake per protein also increases and tracer uptake per protein is lower at higher cell densities. Immunocytochemical analysis reveals a lower expression of both GLUT1 and HK2 at higher cell concentrations. All investigated parameters influenced FDG uptake and therefore we can conclude it is of utmost importance to keep administered activity, incubation medium, and time constant and to correct uptake when cell density changes due to environmental conditions, such as therapy.

Normoglycemic plasma glucose levels affect F-18 FDG uptake in the brain

ObjectiveThe aim of this study was to investigate whether normoglycemic glucose concentrations interfere with cerebral F-18 FDG uptake.MethodsThe analysis was based on 2 sets of paired PET scans in 94 patients who were in complete metabolic remission after the successful completion of treatment for lymphoma. For these 188 PET scans, 2 subgroups were defined according to the plasma glucose level at the time of scanning. Group 1 contained the PET images that were associated with the lower of both normoglycemic plasma glucose levels, whereas group 2 contained the PET images that were associated with the higher of both plasma glucose levels. SUVs (standard uptake values) in the cerebellum between both groups were compared using paired sample T test. Subsequently, SUVs were normalized to a standard glucose concentration and normalized SUVs were again compared. Further, we calculated the coefficient of variation of SUVs in group 1 and 2 both before and after the normalization step.ResultsMean plasma glucose level was 86xa0mg/dL (SD of 9xa0mg/dL) in group 1 and 97xa0mg/dL (SD of 10xa0mg/dL) in group 2. Mean SUV was 3.8 (SD of 1.1) for group 1 and 3.5 (SD of 1.1) for group 2. Mean SUV in group 1 was slightly but statistically significantly higher than the mean SUV in group 2 (pxa0<xa00.01). Mean normalized SUV was 3.6 (SD of 1.1) in group 1 and 3.7 (SD of 1.3) in group 2. A paired comparison between normalized SUVs in both groups indicated that there was no statistically significant difference (pxa0<xa00.31). The coefficient of variation for the SUVs in group 1 and 2 before normalization was 29 and 30%, respectively. The coefficient of variation for the normalized SUVs in group 1 and 2 was 30 and 34%, respectively.ConclusionsOur results indicated that plasma glucose levels that are within the normoglycemic range have a small but systematic effect on F-18 FDG uptake in the brain (following an inverse relationship). Normalizing plasma glucose levels to a standard glucose concentration successfully reduced the intra-subject variability of SUV measures. Inter-subject variability, however, remained high suggesting that other factors have an influence as well.

Metabolisches Tumorvolumen – Prognostische Bedeutung bei lokal fortgeschrittenen Plattenepithelkarzinomen im Kopf-Hals-Bereich

PURPOSEnEvaluate 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.nnnPATIENTS, METHODSn40 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.nnnRESULTSnNeither 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 didnt have neck dissection prior to radiochemotherapy were predictive for disease free and overall survival in both univariate and multivariate analysis (p≤0.05).nnnCONCLUSIONnSummed MTV50 values of both the primary tumour and involved lymph nodes provided independent prognostic information on disease free and overall survival.