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

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

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

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.

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 [

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.

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.

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.

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.

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

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.

To evaluate feasibility, disease control, survival, and toxicity after adaptiveA 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 grade3 toxicity in ≥30% of patients. Three treatment plans based on 3 PET/CT scans were consecutively delivered in 6 weeks. The range of dose painting was 66.0-85.0 Gy 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 2‑year toxicity could only be assessed in 1 of the 2 surviving patients, in whom grade 4 mucosal wound healing problems were observed; no other grade3 toxicity was observed. In this respect, a 30% 2‑year survival free of grade3 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.

The purpose of this study was to report the long-term outcome ofSeventy-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. EitherMedian 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 doses91 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).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.

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.

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.

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.

To report the impact on target volume delineation and dose to normal tissue using anatomic versus biological imaging (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 (GTVSixty-three percent of the GTVPositron emitting tomography-information potentially changes the target volume for bone metastases. DPBN between 6 and 10 Gy significantly decreases dose to the normal tissue compared to conventional radiotherapy.

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

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.

The aim of this study was to investigate whether normoglycemic glucose concentrations interfere with cerebral F-18 FDG uptake. The 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. Mean plasma glucose level was 86 mg/dL (SD of 9 mg/dL) in group 1 and 97 mg/dL (SD of 10 mg/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 (p

Dissociation involves a disruption in the integrated functions of consciousness, memory, identity, or perception of the environment. Attempts at localizing dissociative responses have yielded contradictory results regarding brain activation, laterality, and regional involvement. Here, we used a single-day split-dose activation paradigm with single photon emission computed tomography and 99m-Tc ethylcysteinatedimer as a brain perfusion tracer in a patient with Tourette's syndrome undergoing bilateral high-frequency thalamic stimulation for the treatment of tics who developed an alternate personality state during right thalamic stimulation. We documented increased regional cerebral blood flow in bilateral prefrontal and left temporal brain areas during the alternate identity state. We conclude that our findings support the temporal lobe as well as the frontolimbic disconnection hypotheses of dissociation.

Primary mesothelioma of the pericardium is a very rare malignancy. The antemortem diagnosis is difficult and requires a multidisciplinary approach. The use of F-18 fluorodeoxyglucose-positron emission tomography/computed tomography whole body scan has been recently advocated to improve staging and to monitor treatment in pleural mesothelioma. This is the first case describing the use of F-18 fluorodeoxyglucose-positron emission tomography/computed tomography in the diagnostic work-up of a primary pericardial mesothelioma.

This study reports on the uptake of 99mTc-RP527 by human breast carcinoma and its relationship to gastrin-releasing peptide receptor (GRP-R) expression as measured by immunohistochemistry (IHC). Methods: Nine patients referred because of a clinical diagnosis suggestive of breast carcinoma and 5 patients with tamoxifen-resistant bone-mestastasized breast carcinoma underwent 99mTc-RP527 scintigraphy. The findings were compared with routine staging examinations in all patients and with routine histology and IHC GRP-R staining in the first 9 patients. All 9 patients with suspected breast lesions were tumor positive. Results: The uptake of 99mTc-RP527 was evident in the primary tumor in 8 of 9 patients and in involved lymph nodes and part of the distant metastasis limited to the bone when present. 99mTc-RP527 uptake was not found in any of the tamoxifen-resistant patients. Conclusion: Uptake by primary breast carcinoma was significantly correlated with the presence of GRP-Rs as assessed by means of IHC.

To verify the applicability of a recently described resolution-independent method for the semi-quantification of 123I-FP-CIT scans.Visual interpretation, 'conventional' and resolution-independent semi-quantification was performed on 60 123I-FP-CIT scans. Using ROC analysis, the results were compared to the final clinical diagnosis after a follow-up of at least 18 months. Sensitivity and specificity values were calculated and a cut-off value of the specific binding, which differentiated between normal and abnormal scans with high sensitivity and specificity, was given.Application of the resolution-independent method to a new set of 123I-FP-CIT SPECT data yielded a cut-off value of the specific striatal binding of 55 ml. Corresponding values of sensitivity and specificity were 95% and 72%, respectively. Further, based on the values of the area under the ROC curve and the 95% confidence interval of different semi-quantitative methods, the resolution-independent semi-quantification agreed best with the final clinical diagnosis.We found a similar value of the specific 123I-FP-CIT binding as the one previously described in the literature, which proved the validity of the resolution-independent method. Further, this method, among other 'conventional' semi-quantitative methods, agreed best with the final clinical diagnosis. For this reason we recommend its use to aid in the diagnostic process.

Objective: When taking into account the Society of Nuclear Medicine (SNM) and European Association of Nuclear Medicine (EANM) guidelines on diuretic renography in children, we see important divergences in the preparation, acquisition, processing, and interpretation of the results. In this study, we estimated the quality of renal drainage according to these two guidelines. Patients and methods: Ninety kidneys with hydronephrosis or severe vesicorenal reflux were processed and analyzed according to the SNM (estimation of the T1/2 of the washout curve and conclusions about the possible existence of obstruction) and EANM guidelines (estimation of normalized residual activity or NORA, and output efficiency or OE on the late postmicturition images, without any conclusion about the possible existence of obstruction). Among the 90 kidneys, 39, 20, and 31 were considered to have normal, equivocal, or poor drainage (obstruction), respectively, when the SNM guidelines were used. Results: All 39 kidneys with good drainage according to SNM were also considered as normal using the EANM guidelines. Among the 20 equivocal cases based on T1/2, concordance between the two guidelines was obtained in only 35 and 0% when using NORA and OE (OE was considered normal in all 20 cases), respectively. Among the 31 cases defined as obstructed by SNM, only five were classified as 'poor drainage' using NORA and no single case was classified thus using OE. Conclusion: This limited study demonstrates that the use of different guidelines can lead to different interpretations of the results. This is unacceptable, and an agreement between both pediatric task groups of the SNM and EANM is urgently required.

Background: Impulsive behaviours in patients with cluster B personality disorders are associated with low glucose metabolism and regional cerebral blood flow in the frontal cortex and subcortical structures. The aim of this study is to confirm the presence of a particular pattern of brain perfusion in a sample of borderline (BPD) and anti-social personality disorder (ASPD) patients using brain perfusion single photon emission computed tomography (SPECT). Methods: A brain perfusion SPECT study was performed in 37 patients with BPD or ASPD (and no Axis I diagnosis) and 34 healthy control participants. Data were acquired on a triple head Toshiba gamma camera. Scatter and attenuation correction was done. Reconstructed SPECT images were analyzed by Statistical Parametrical Mapping (SPM99). Results: There were no significant differences in age and gender distributions between the patients and the healthy controls. With regard to the functional imaging results, patients were characterized by a reduced regional cerebral blood flow (rCBF) in right temporal and prefrontal brain areas, including the right lateral temporal cortex (BA 21), the right frontopolar cortex (BA 10) and the right ventrolateral prefontal cortex (BA 47). Conclusions: Patients with BPD and ASPD who showed impulsive behaviour have diminished rCBF in areas of the right prefrontal and temporal cortex.

Background Human planning is a complex mental process that may be evaluated by the 'Tower of London' (TOL) task, which includes setting up and maintaining multiple subgoals at the same time. Although positron emission tomography and functional magnetic resonance imaging have provided reliable data on the recruitment of a neural network engaged in planning tasks, the experimental settings of these studies cannot be applied in clinical conditions. Hence, this study reports on the TOL task under classical neuropsychological test conditions using single photon emission computed tomography (SPECT) activation in 10 healthy subjects. Methods Participants first performed a control task and then an activation task, i.e., the TOL planning task In the planning task, subjects were required to change, in the minimum number of moves possible, an initial arrangement of beads to match a goal arrangement. Subjects solved a set of eight TOL problems of increasing difficulty. A control task was designed such that it eliminates planning abilities, which is the process of interest. Planning times and accuracy were measured as performance parameters and functional imaging data were analysed with statistical parametric mapping (SPM99) to determine significant voxel-wise activations between the planning task and the control task. Results Both overall and for each difficulty level, measures of accuracy were within the normal range. Similar results were found for the overall thinking time and thinking times of each difficulty level. That is, performance of the healthy subjects during the TOL task replicated the typical pattern of results found with appropriate control samples in the literature. Also, activation of the right prefrontal cortex was consistent with other functional imaging results, thereby validating the use of the TOL task in a SPECT activation paradigm. Conclusions Based on the present study it may be concluded that the close resemblance of the test conditions of the SPECT activation procedure with those of the TOL task in the investigation room constitutes a major advantage for future application of the SPECT activation procedure in clinical conditions.

Current glioblastoma (GB) small animal mod- els for cranial radiation therapy (RT) use simple single beam technologies, which differ from the advanced con- formal image-guided radiation techniques used in clinical practice. This technological disparity presents a major disadvantage for the development of new therapeutic approaches. Hence, we established a F98 GB rat model using magnetic resonance imaging (MRI)-guided three- dimensional (3D)-conformal arc RT with the Small Animal Radiation Research Platform (SARRP). Ten Fischer rats were inoculated with F98 tumor cells. When the tumor reached a volume of approximately 27 mm 3 on T2- weighted MR images, the animals were randomized into a treatment group (n = 5) receiving RT and concomitant temozolomide, and a sham group (n = 5) receiving control injections. For the treated animals, contrast-enhanced T1- weighted MR images were acquired followed by a cone- beam computed tomography (CBCT) on the SARRP system. Both scans were co-registered; MRI was used to define the target whereas CBCT was used for calculating a dose plan (20 Gy, three non-coplanar arc beams, 3 9 3 mm collimator). Tumor volumes were evaluated on follow-up contrast-enhanced T1-weighted MR images. Verification of treatment accuracy with cH2AX immuno- histochemical staining was performed. Tumors in the control animals showed rapid proliferation during follow- up, encompassing almost the entire right cerebral hemi- sphere at day 12-15. Treated animals showed no significant tumor growth from 2 to 9 days post RT. cH2AX results confirmed the accuracy of dose delivery. This model, which is quite similar to the approach in the clinic, is valid for combined RT and chemotherapy of GB in rats.

Introduction. Vagus nerve stimulation is a novel treatment for patients with medically refractory epilepsy, who are not candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. To date only studies with relatively short follow-up are available. In these studies efficacy increased with time and reached a maximum after a period of 6 to 12 months. Implantation of a vagus nerve stimulator requires an important financial investment but a cost-benefit analysis has not been published. Patients and Methods. Our own experience with VNS in Gent comprises 15 patients with mean age of 29 years (range: 17–44 years) and mean duration of epilepsy of 18 years (range: 4–32 years). All patients underwent a comprehensive presurgical evaluation and were found not to be suitable candidates for resective epilepsy surgery. Mean post-implantation follow-up is 24 months (range: 7–43 months). In patients with follow-up of at least one year, efficacy of treatment in terms of seizure control and seizure severity was assessed one year before and after the implantation of a vagus nerve stimulator. Epilepsy-related direct medical costs (ERDMC) before and after the implantation were also compared. Results. A mean reduction of seizure frequency from 14 seizures/month (range: 2–40/month) to 8 seizures/month (range: 0–30/month) was achieved (Wilcoxon signed rank test n=14; p=0.0016). Five patients showed a marked seizure reduction of ≥50%; 6 became free of complex partial seizures, 3 of whom became entirely seizure free for more than 12 months; 2 patients had a worthwhile reduction of seizure frequency between 30–50%; in 2 patients seizure frequency reduction has remained practically unchanged. Seizure freedom or ≥50% seizure reduction was achieved within the first 4 months after implantation in 6/11 patients. Before the implantation, the mean yearly epilepsy-related direct medical costs per patient were estimated to be 8830US$ (n=13; range: 1879–31129US$; sd=7667); the average number of hospital admission days per year was 21 (range: 4–100; sd=25.7). In the 12 months after implantation, ERDMC had decreased to 4215US$ (range: 615–11794US$; sd=3558) (Wilcoxon signed rank test n=13; p=0.018) and the average number of admission days to 8 (range: 0–35) (Wilcoxon signed rank test n=13; p=0.023). Conclusion. VNS is an effective treatment of refractory epilepsy and remains effective during long-term follow-up. Cost-benefit analysis suggests that the cost of VNS is saved within two years following implantation.

Imaging results of F-18 fluorodeoxyglucose (FDG) PET/CT scanning and Tc-99m pertechnetate scintigraphy of the thyroid gland are described and compared with pathology in a patient who was followed after left nephrectomy for renal cell carcinoma diagnosed 10 years earlier. On F-18 FDG PET/CT scanning, a multinodular struma with increased localized F-18 FDG uptake in 4 nodules was seen. Two nodules with increased glucose metabolism appeared normal on Tc-99m pertechnetate scintigraphy. Pathology indicated hyperplastic nodules. High focal F-18 FDG uptake was also seen in a lesion that corresponded with a "cold" nodule on Tc-99m pertechnetate scintigraphy, suggesting malignant disease. However, pathology revealed hyperplastic nodules with a background of aspecific lymphocytic thyroiditis. A fourth nodule with increased F-18 FDG uptake appeared mixed ("cold"/"hot") on Tc-99m pertechnetate scintigraphy. On pathology, a well-differentiated follicular carcinoma was found. These findings, in a single patient, illustrate the wide spectrum of matched and mismatched F-18 FDG and Tc-99m pertechnetate thyroid uptake along with their variable pathologic correlates.

OBJECTIVE: Bulimia nervosa has been associated with alterations in central serotonergic (5-HT) function. This study investigated iodine-labeled 4-amino-N-[1-[3-(4-fluorophenoxy) propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150) binding to the 5-HT2A receptor in the brain by using single photon emission computed tomography in acutely ill bulimia nervosa patients. METHOD: Cortical 123I-5-I-R91150 binding in 10 normal-weight patients with bulimia nervosa, purging type, was compared with that of 11 healthy volunteers. RESULTS: The 5-HT2A binding index of the bulimia nervosa patients, with and without correction for age, was not significantly different from that of the comparison group. CONCLUSIONS: As a group, acutely ill bulimia nervosa patients cannot be discriminated from healthy subjects on the basis of cortical 123I-5-I-R91150 binding to the 5-HT2A receptor.

To determine the optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine (18F-FCho) PET.Dynamic 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).TACs 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.On 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.

Purpose: To evaluate the distribution of F-18-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 F-18-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, F-18-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 F-18-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). F-18-FCho uptake was also demonstrated in benign lesions, such as a tumefactive demyelinating brain lesion. Conclusions: F-18-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, F-18-FCho uptake was not tumor specific.

To investigate the time-dependent changes in (18)F-FDG uptake by the thymus and marrow following combination chemotherapy for lymphoma in a paediatric study population.Included in the study were 27 paediatric patients who were in complete metabolic remission after chemotherapy and who underwent off-therapy follow-up with serial whole-body PET-CT scans. A total of 142 PET-CT scans were recorded. (18)F-FDG uptake by the thymus and marrow was assessed both visually and semiquantitatively. Visual uptake was scored on the three-dimensional maximum intensity projection of the whole-body PET image according to a three-point scale. For the semiquantitative assessment, standard uptake values were measured. To find a pattern in the (18)F-FDG uptake by the thymus and marrow a moving average technique was applied.Our time series analysis indicated that the marrow activity was highest at cessation of chemotherapy and declined thereafter. During an off-chemotherapy period of on average 6 months, marrow activity decreased quickly. From 6 months onward, the activity declined more slowly. The posttherapy changes in (18)F-FDG uptake by the thymus were quite different from the changes in uptake by the marrow. The lowest thymic FDG uptake was found at cessation of chemotherapy. Thereafter, thymic activity steadily increased, reached a peak on average 10 months after therapy, and then slowly decreased.Knowledge of the time-dependent changes in metabolic activity in the thymus and marrow is important to avoid misinterpretation of increased (18)F-FDG uptake as disease in the off-therapy setting.

This study was undertaken to evaluate changes in relative (99m)Tc-hydrazinonicotinamide (HYNIC)-annexin V tumor uptake over time in patients undergoing chemotherapeutic treatment at baseline and at 5-7 h and 40-44 h after treatment initiation. Imaging results are related to clinical outcomes, as assessed with response evaluation criteria in solid tumors (RECIST).We prospectively included 20 patients (11 men and 9 women; mean age, 59.8 y; range, 22-75 y) scheduled for chemotherapy (n = 19) or bisphosphonate treatment (n = 1). Curable disease was present in 5 patients. The other patients had metastatic disease and were treated in a palliative setting. Three of the 20 enrolled patients were excluded from analysis: 1 patient ultimately refused the proposed chemotherapy treatment; because of difficulties with the labeling procedure, 1 patient did not receive a pretreatment scan; and 1 patient presented with an allergic reaction (rash and nausea) to the (99m)Tc-HYNIC-annexin V formulation. The remaining 17 patients underwent 3 scintigraphic scans with (99m)Tc-HYNIC-annexin V: before treatment and 5-7 h and 40-44 h after treatment initiation. The tumor response was evaluated with RECIST and related to observed changes in the ratios of tumor activity to background activity for the largest known lesion; values exceeding 25% the baseline value on either the 5- to 7-h scan or the 40- to 44-h scan were considered significant.With the proposed sequential imaging protocol and a 25% change threshold, responders to treatment could be separated from nonresponders with a 94% accuracy (16/17 patients).Sequential (99m)Tc-HYNIC-annexin V imaging may allow for assessment of the response to chemotherapy within 3 d after treatment initiation.

Objective Using single photon emission computed tomography (SPECT), we sought brain perfusion correlates of eating disorder symptoms in anorexia and bulimia nervosa patients. Method We investigated 67 female eating disordered (ED) patients. Eating disorder symptoms were measured by the Eating Disorders Inventory (EDI). Determination of brain areas in which regional perfusion co-varied with drive for thinness, bulimia, body dissatisfaction, ineffectiveness, perfectionism, interpersonal distrust, interoceptive awareness and maturity fears was done by open explorative correlation analysis using Statistical Parametrical Mapping (SPM). Results A significant positive correlation between scores on body dissatisfaction and ineffectiveness, and brain perfusion in the prefrontal and parietal cortex was demonstrated. There were no correlations between other eating disorder symptoms and brain perfusion. Conclusion Based on the finding of an association between regional brain flow and body dissatisfaction and ineffectiveness, we argue that neurobiological findings in ED patients may not only reflect emotional and behavioural factors but cognitive–evaluative features as well.

Objective Using single photon emission computed tomography and the 5-HT2A receptor antagonist, 123I-5-I-R91150, we explored differences in 5-HT2A binding index in anorexia nervosa patients with and without bulimic features. We also searched for associations between temperament dimensions and cortical 5-HT2A binding. Method About 9 restrictive and 7 bulimic anorexia nervosa patients were examined and cortical 123I-5-I-R91150 binding index values were compared between the two subgroups. Open explorative correlation analysis was used to examine any relationships between binding index values and temperament scores, as assessed with the Temperament and Character Inventory. Results 5-HT2A binding index was significantly reduced in the parietal cortex in bulimic anorexia nervosa patients in comparison with restrictive anorectics. Further, a positive correlation was documented between reward dependence and parietal 5-HT2A binding index across patients in the two subgroups. Discussion Restrictive anorexia nervosa patients differ from binging/purging anorexia nervosa patients on the basis of a reduced parietal 5-HT2A binding index in the latter. We speculate that the finding of a positive correlation between parietal 5-HT2A binding and reward dependence might reflect an association between these two variables, at least in anorexia nervosa patients.

Psychomotor slowing in patients with diffuse brain injury frequently underlies impaired cognitive performance on neuropsychological tests, for example, the Stroop Colored Word test. The aim of the present study was to determine the neural basis associated with performance on the Stroop interference subtask in patients with diffuse brain injury. We hypothesized that patients would be slower than healthy controls, and that this would be associated with brain activations other than those seen in healthy subjects. Brain perfusion, using a split-dose activation paradigm with single photon emission tomography (SPECT) and the Stroop test, was assessed in 9 patients with diffuse brain injury. The Stroop interference score was calculated as a behavioral parameter, and functional imaging data were analyzed with statistical parametrical mapping (SPM99) to determine significant voxel-wise differences of activation between the control and the activation condition. Patients were impaired on the interference subtask of the Stroop test. Comparison of the SPECT data obtained during the activation condition with those obtained during the control condition by means of SPM showed significant activations in the left inferior parietal lobe, the right anterior cingulate extending into the right middle frontal gyrus and the right caudate, and the left posterior cingulate cortex. Patients with diffuse brain injury were slower than healthy controls on the interference subtask of the Stroop test, suggesting difficulty with resistance to distractions. This finding was associated with activation effects in posterior (mainly parietal) brain areas in addition with activation of previously observed anterior (mainly anterior cingulate) brain regions.

Indirect estimations of brain neurotransmitters in patients with anorexia nervosa (AN) and low weight have demonstrated a reduction in brain serotonin (5-HT) turnover in general and led to hypotheses about dysfunction in the 5-HT(2a) receptor system. It was our aim to investigate the central 5-HT(2a) receptor binding index using SPECT brain imaging.The 5-HT(2a) receptors of low-weight patients with AN were studied by means of the highly specific radioiodinated 5-HT(2a) receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide or (123)I-5-I-R91150. Fifteen patients with clinical diagnoses of AN and 11 age-matched healthy volunteers received intravenous injections of 185 MBq (123)I-5-I-R91150 and were scanned with high-resolution brain SPECT.Compared with healthy volunteers, patients with AN had a significantly reduced 5-HT(2a) binding index in the left frontal cortex, the left and right parietal cortex, and the left and right occipital cortex. A significant left-right asymmetry was noted in the frontal cortex (leftright).These results are in accordance with diminished metabolic and perfusion of frontal and parietal cortices reported in recent neuroimaging studies and imply localized disturbed serotonergic function. The data are discussed in the light of possible confounding factors related to the low-weight AN status. A regional cortical reduction in 5-HT(2a) binding index is not likely to be caused by a general reduction in serotonergic function due to the possible confounding factors. Suggestions for further research are given.

Serotonin (5-HT) and more specifically the 5-HT2A receptor is involved in cognitive and non-cognitive behavior and plays an important role in Alzheimer's disease (AD). The objective was to assess the 5-HT2A binding potential (BP) in healthy volunteers and AD with SPECT and I-123-5-I-R91150, a selective radio-iodinated 5-HT2A receptor antagonist. Twenty-six controls and nine AD patients were included. A semiquantitive analysis with normalization on cerebellar uptake provided estimates of BP for 26 cortical regions of interest. An age-related decline of neocortical BP was found (11.6% per decade). Compared to age-matched controls, a generally decreased neocortical BP in AD was found with a significant regional reduction in the orbitofrontal, prefrontal, lateral frontal, cingulate, sensorimotor, parietal inferior, and occipital region. These results are in line with previous postmortem, in vitro, and PET findings. The age-related decline highlights the necessity for matched advanced age study samples. The fact that the 5-HT2A receptor is differentially affected in AD patients has implications for both the etiological basis and therapeutic management of AD. (C) 2002 Elsevier Science Inc. All rights reserved.

The concept of working memory is central to theories of human cognition, because it is essential to human skills such as decision making and deductive reasoning. Although PET and functional MRI have provided robust data on the recruitment of specific pathways in working memory tasks, the experimental settings of these studies may not be transferable to a clinical situation. Hence, to develop neuropsychological SPECT activation probes that are suitable for daily clinical practice, this study reports on a neuropsychological activation task of spatial working memory under classical neuropsychological test conditions in healthy subjects.Reaction times and accuracy were measured as behavioral parameters and functional imaging data were analyzed with statistical parametric mapping to determine significant voxel-wise changes between the perception task and the memory task.Subjects reacted more slowly and performed less accurately during the memory task compared with the perception task, findings that are in keeping with other neuropsychological studies. Also, the overall pattern of brain activations revealed in our experiment is consistent with the data of the literature, thereby validating our test probe.From a practical viewpoint, the close resemblance of the test conditions of the SPECT procedure with those of the investigation room and the relative simplicity of the task under study probably constitute major advantages for future clinical application of the SPECT procedure in patients with cognitive impairments.