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Background: In clinical practice, several radiopharmaceuticals are used for PSMA-PET imaging, each with distinct biodistribution patterns. This may impact treatment decisions and outcomes, as eligibility for PSMA-directed radioligand therapy is usually assessed by comparing tumoral uptake to normal liver uptake as a reference. In this study, we aimed to compare tracer uptake intraindividually in various reference regions including liver, parotid gland and spleen as well as the respective tumor-to-background ratios (TBR) of different 18F-labeled PSMA ligands to today's standard radiopharmaceutical 68Ga-PSMA-11 in a series of patients with biochemical recurrence of prostate cancer who underwent a dual PSMA-PET examination as part of an individualized diagnostic approach. Results: Differences in background activity among different PSMA-PET tracers lead to variations in tumor-to-background ratios (TBR). In [18F]F-DCFPyL-PET, TBR with the liver as the reference organ (TBRliver) was comparable to [68Ga]Ga-PSMA-11-PET, while [18F]F-PSMA-1007-PET and [18F]F-JK-PSMA-7-PET showed significantly lower values. Using the parotid gland as the reference (TBRparotidgland), [18F]F-DCFPyL-PET exhibited significantly higher values, whereas [18F]F-PSMA-1007-PET and [18F]F-JK-PSMA-7-PET were comparable. For the spleen (TBRspleen), [18F]F-JK-PSMA-7-PET was comparable, but [18F]F-DCFPyL-PET and [18F]F-PSMA-1007-PET showed significantly higher and lower values, respectively. An additional Bland-Altman analyses revealed low bias for [18F]F-DCFPyL-PET in TBRparotidgland, whereas significant differences in TBRliver and TBRspleen for the other tracers resulted in higher bias. Conclusion: Different PSMA-PET tracers exhibit distinct biodistribution patterns, leading to variations in tumor-to-background ratios (TBR) in reference organs such as the liver, parotid gland, and spleen. Patient selection for PSMA-directed radioligand therapy is currently based on a semiquantitative approach using the liver as a reference region in [68Ga]Ga-PSMA-11-PET. Thus, the use of alternative [18F]-labeled tracers may result in under- or overestimation of a patient's suitability for therapy. This highlights the importance of a comprehensive understanding of the differences in tracer-specific uptake behavior for accurate decisions regarding PSMA-expression levels. However, as the patient cohort in this study is at earlier disease stages, the generalizability of these findings to later-stage patients remains unclear and requires further investigation. [ABSTRACT FROM AUTHOR]

Nuclear reaction cross sections for the formation of 72As and 71As in proton-induced reactions on enriched 72Ge targets were measured up to 45 MeV utilizing three different cyclotrons at the Forschungszentrum Jülich. The stacked-thin sample activation technique in combination with high-resolution γ-ray spectrometry was used. The major γ-ray peaks of 72As and 71As formed via the 72Ge(p,n)72As and 72Ge(p,2n)71As reactions, respectively, were analyzed. The incident proton energy and flux on a foil were determined using several monitor reactions. Based on integrated counts, irradiation data and the nuclear decay data, the reaction cross sections were measured. All data describe the first measurements. Theoretical nuclear model calculations were then carried out by using the codes TALYS 1.96, EMPIRE 3.2 and ALICE-IPPE. A very good agreement between the measured data and calculated values was found. The new data enabled us to calculate the thick target yields and estimate the radionuclidic impurities for a given energy range. Over the optimum energy range Ep = 14 → 7 MeV, the calculated thick target yield of 72As amounts to 272 MBq/μAh with no 71As impurity at all. The 72Ge(p,n)72As reaction on the enriched 72Ge is thus very suitable for clinical scale production of 72As at a medical cyclotron. [ABSTRACT FROM AUTHOR]

Purpose: Morphological imaging using MRI is essential for brain tumour diagnostics. Dynamic susceptibility contrast (DSC) perfusion-weighted MRI (PWI), as well as amino acid PET, may provide additional information in ambiguous cases. Since PWI is often unavailable in patients referred for amino acid PET, we explored whether maps of relative cerebral blood volume (rCBV) in brain tumours can be extracted from the early phase of PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). Procedure: Using a hybrid brain PET/MRI scanner, PWI and dynamic 18F-FET PET were performed in 33 patients with cerebral glioma and four patients with highly vascularized meningioma. The time interval from 0 to 2 min p.i. was selected to best reflect the blood pool phase in 18F-FET PET. For each patient, maps of MR-rCBV, early 18F-FET PET (0–2 min p.i.) and late 18F-FET PET (20–40 min p.i.) were generated and coregistered. Volumes of interest were placed on the tumour (VOI-TU) and normal-appearing brain (VOI-REF). The correlation between tumour-to-brain ratios (TBR) of the different parameters was analysed. In addition, three independent observers evaluated MR-rCBV and early 18F-FET maps (18F-FET-rCBV) for concordance in signal intensity, tumour extent and intratumoural distribution. Results: TBRs calculated from MR-rCBV and 18F-FET-rCBV showed a significant correlation (r = 0.89, p < 0.001), while there was no correlation between late 18F-FET PET and MR-rCBV (r = 0.24, p = 0.16) and 18F-FET-rCBV (r = 0.27, p = 0.11). Visual rating yielded widely agreeing findings or only minor differences between MR-rCBV maps and 18F-FET-rCBV maps in 93 % of the tumours (range of three independent raters 91–94%, kappa among raters 0.78–1.0). Conclusion: Early 18F-FET maps (0–2 min p.i.) in gliomas provide similar information to MR-rCBV maps and may be helpful when PWI is not possible or available. Further studies in gliomas are needed to evaluate whether 18F-FET-rCBV provides the same clinical information as MR-rCBV. [ABSTRACT FROM AUTHOR]

Cerebral glucose hypometabolism is a typical hallmark of Alzheimer's disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [18F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [18F]PI-2620 for tau deposition, [18F]DPA-714 for TSPO expression associated with neuroinflammation, and [18F]UCB-H for synaptic density in a transgenic tauopathy mouse model. Seven-month-old rTg4510 mice (n = 8) and non-transgenic littermates (n = 8) were examined in a small animal PET scanner with the tracers listed above. Hypometabolism was observed throughout the forebrain of rTg4510 mice. Tau pathology, increased TSPO expression, and synaptic loss were co-localized in the cortex and hippocampus and correlated with hypometabolism. In the thalamus, however, hypometabolism occurred in the absence of tau-related pathology. Thus, cerebral hypometabolism was associated with two regionally distinct forms of molecular pathology: (1) characteristic neuropathology of the Alzheimer-type including synaptic degeneration and neuroinflammation co-localized with tau deposition in the cerebral cortex, and (2) pathological changes in the thalamus in the absence of other markers of AD pathophysiology, possibly reflecting downstream or remote adaptive processes which may affect functional connectivity. Our study demonstrates the feasibility of a multitracer approach to explore complex interactions of distinct AD-pathomechanisms in vivo in a small animal model. The observations demonstrate that multiple, spatially heterogeneous pathomechanisms can contribute to hypometabolism observed in AD mouse models and they motivate future longitudinal studies as well as the investigation of possibly comparable pathomechanisms in human patients. [ABSTRACT FROM AUTHOR]

Purpose: We present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands. Procedures: The precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [177Lu]Lu-PSMA-617. The ligand [89Zr]Zr-PSMA-DFO was compared with [68Ga]Ga-PSMA-11 and [18F]F-JK-PSMA-7 in vitro by determination of the Kd value, cellular uptake, internalization in LNCaP cells, biodistribution studies with LNCaP prostate tumor xenografts in mice, and in vivo by small-animal PET imaging in LNCaP tumor mouse models. A first-in-human PET was performed with [89Zr]Zr-PSMA-DFO on a patient presenting with a biochemical recurrence after brachytherapy and an ambiguous intraprostatic finding with [18F]F-JK-PSMA-7 but histologically benign cells in a prostate biopsy 7 months previously. Results: [89Zr]Zr-PSMA-DFO was prepared with a radiochemical purity ≥ 99.9% and a very high in vitro stability for up to 7 days at 37 °C. All radiotracers showed similar specific cellular binding and internalization, in vitro and comparable tumor uptake in biodistribution experiments during the first 5 h. The [89Zr]Zr-PSMA-DFO achieved significantly higher tumor/background ratios in LNCaP tumor xenografts (tumor/blood: 309 ± 89, tumor/muscle: 450 ± 38) after 24 h than [68Ga]Ga-PSMA-11 (tumor/blood: 112 ± 57, tumor/muscle: 58 ± 36) or [18F]F-JK-PSMA-7 (tumor/blood: 175 ± 30, tumor/muscle: 114 ± 14) after 4 h (p < 0.01). Small-animal PET imaging demonstrated in vivo that tumor visualization with [89Zr]Zr-PSMA-DFO is comparable to [68Ga]Ga-PSMA-11 or [18F]F-JK-PSMA-7 at early time points (1 h p.i.) and that PET scans up to 48 h p.i. clearly visualized the tumor at late time points. A late [89Zr]Zr-PSMA-DFO PET scan on a patient with biochemical recurrence (BCR) had demonstrated intensive tracer accumulation in the right (SUVmax 13.25, 48 h p.i.) and in the left prostate lobe (SUV max 9.47), a repeat biopsy revealed cancer cells on both sides. Conclusion: [89Zr]Zr-PSMA-DFO is a promising PSMA PET tracer for detection of tumor areas with lower PSMA expression and thus warrants further clinical evaluation. [ABSTRACT FROM AUTHOR]

Purpose: PSMA imaging is frequently used for monitoring of androgen deprivation therapy (ADT) in prostate cancer. In a previous study, [18F]-JK-PSMA-7 exhibited favorable properties for tumor localization after biochemical recurrence. In this retrospective study, we evaluated the performance of [18F]-JK-PSMA-7 under ADT. Procedures: We examined the performance of [18F]-JK-PSMA-7 in 70 patients (first cohort) with increasing or detectable PSA values under ADT (PSA < 2 ng/ml for 21/70 patients). We further analyzed 58 independent patients with PSA levels < 2 ng/ml under ADT, who were imaged with [68Ga]PSMA-11 or [18F]DCFPyL (second cohort). Finally, we compared detection rates between [18F]-JK-PSMA-7, [68Ga]PSMA-11, and [18F]DCFPyL. Results: In the first cohort, we detected [18F]-JK-PSMA-7-positive lesions in 63/70 patients. In patients with PSA levels ≥ 2 ng/ml, the detection rate was 100 % (49/49). In patients with PSA < 2 ng/ml, the detection rate was significantly lower (66.7 %, 14/21, p = 9.7 × 10−5) and dropped from 85.7 % (12/14, PSA levels between 0.3 and 2.0 ng/ml) to 28.6 % (2/7) for PSA levels < 0.3 ng/ml (p = 1.73 × 10−2). In the second cohort (PSA < 2 ng/ml), the detection rate was 79.3 % (46/58) for [68Ga]PSMA-11 or [18F]DCFPyL. Again, the detection rate was significantly higher (p = 1.1 × 10−2) for patients with PSA levels between 0.3 and 2.0 ng/ml (87.0 %, 40/46) relative to those with PSA levels < 0.3 ng/ml (50 %, 6/12). No significant difference was found between [18F]-JK-PSMA-7 and [68Ga]PSMA-11 or [18F]DCFPyL in patients with PSA levels < 2 ng/ml (p = 0.4295). Conclusion: [18F]-JK-PSMA-7 PET showed a high detection rate in patients with PSA levels ≥ 0.3 ng/ml under ADT. The lower PSA threshold of 0.3 ng/ml for high detection rates was consistent across the three PSMA ligands. Thus, PSMA imaging is suitable for clinical follow-up of patients with increasing PSA levels under ADT. [ABSTRACT FROM AUTHOR]

5-Iodotubercidin is a prototype adenosine kinase (AK) inhibitor with potent anti-seizure activity in rodent epilepsy models. Using the chloramine-T method for radioiodination of tubercidin with 131I, we prepared no-carrier-added 5-[131I]iodotubercidin (5-[131I]IT) in a radiochemical yield of 61 ± 13% and with a radiochemical purity of > 99% (molar activity = 10–40 GBq/µmol). In vitro competition and saturation experiments demonstrated specific binding of 5-[131I]IT in rodent brain slices (KD ~ 31 nM), but ex vivo autoradiography revealed its accumulation in cerebral vessels. We conclude that 5-[131I]IT could be a useful tool for the detection and quantification of AK in in vitro studies. [ABSTRACT FROM AUTHOR]

Due to its favorable decay properties, the non-standard radionuclide 45Ti is a promising PET isotope for tumor imaging. Additionally, titanium complexes are widely used as anti-tumor agents and 45Ti could be used to study their in vivo distribution and metabolic fate. However, although 45Ti can be obtained using the 45Sc(p,n)45Ti nuclear reaction its facile production is offset by the high oxophilicity and hydrolytic instability of Ti4+ ions in aqueous solutions, which complicate recovery from the irradiated Sc matrix. Most available 45Ti recovery procedures rely on ion exchange chromatography or solvent extraction techniques which are time-consuming, produce large final elution volumes, or, in case of solvent extraction, cannot easily be automated. Thus a more widespread application of 45Ti for PET imaging has been hampered. Here, we describe a novel, solvent-free approach for recovery of 45Ti that involves formation of [45Ti]TiCl4 by heating of an irradiated Sc target in a gas stream of chlorine, followed by thermochromatographic separation of the volatile radiometal chloride from co-produced scandium chloride and trapping of [45Ti]TiCl4 in a glass vial at − 78 °C. The recovery of 45Ti amounted to 76 ± 5% (n = 5) and the radionuclidic purity was determined to be > 99%. After trapping, the [45Ti]TiCl4 could be directly used for 45Ti-radiolabeling, as demonstrated by the successful radiosynthesis of [45Ti][Ti(2,4-salan)]. [ABSTRACT FROM AUTHOR]

Purpose: A recent study reported on high, longer lasting and finally reversible cerebral uptake of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) induced by epileptic activity. Therefore, we examined cerebral [18F]FET uptake in two chemically induced rat epilepsy models and in patients with focal epilepsy to further investigate whether this phenomenon represents a major pitfall in brain tumor diagnostics and whether [18F]FET may be a potential marker to localize epileptic foci.Procedures: Five rats underwent kainic acid titration to exhibit 3 to 3.5 h of class IV-V motor seizures (status epilepticus, SE). Rats underwent 4× [18F]FET PET and 4× MRI on the following 25 days. Six rats underwent kindling with pentylenetetrazol (PTZ) 3 to 8×/week over 10 weeks, and hence, seizures increased from class I to class IV. [18F]FET PET and MRI were performed regularly on days with and without seizures. Four rats served as healthy controls. Additionally, five patients with focal epilepsy underwent [18F]FET PET within 12 days after the last documented seizure.Results: No abnormalities in [18F]FET PET or MRI were detected in the kindling model. The SE model showed significantly decreased [18F]FET uptake 3 days after SE in all examined brain regions, and especially in the amygdala region, which normalized within 2 weeks. Corresponding signal alterations in T2-weighted MRI were noted in the amygdala and hippocampus, which recovered 24 days post-SE. No abnormality of cerebral [18F]FET uptake was noted in the epilepsy patients.Conclusions: There was no evidence for increased cerebral [18F]FET uptake after epileptic seizures neither in the rat models nor in patients. The SE model even showed decreased [18F]FET uptake throughout the brain. We conclude that epileptic seizures per se do not cause a longer lasting increased [18F]FET accumulation and are unlikely to be a major cause of pitfall for brain tumor diagnostics. [ABSTRACT FROM AUTHOR]

Purpose: Integrated histomolecular diagnostics of gliomas according to the World Health Organization (WHO) classification of 2016 has refined diagnostic accuracy and prediction of prognosis. This study aimed at exploring the prognostic value of dynamic O-(2-[18F]-fluoroethyl)-l-tyrosine (FET) PET in newly diagnosed, histomolecularly classified astrocytic gliomas of WHO grades III or IV. Methods: Before initiation of treatment, dynamic FET PET imaging was performed in patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA). Static FET PET parameters such as maximum and mean tumour/brain ratios (TBRmax/mean), the metabolic tumour volume (MTV) as well as the dynamic FET PET parameters time-to-peak (TTP) and slope, were obtained. The predictive ability of FET PET parameters was evaluated concerning the progression-free and overall survival (PFS, OS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate Kaplan-Meier and multivariate Cox regression survival analyses were performed to assess the predictive power of these parameters for survival. Results: Sixty patients (45 GBM and 15 AA patients) of two university centres were retrospectively identified. Patients with isocitrate dehydrogenase (IDH)-mutant or O6-methylguanine-DNA-methyltransferase (MGMT) promoter-methylated tumours had a significantly longer PFS and OS (both P < 0.001). Furthermore, ROC analysis of IDH-wildtype glioma patients (n = 45) revealed that a TTP > 25 min (AUC, 0.90; sensitivity, 90%; specificity, 87%; P < 0.001) was highly prognostic for longer PFS (13 vs. 7 months; P = 0.005) and OS (29 vs. 12 months; P < 0.001). In contrast, at a lower level of significance, TBRmax, TBRmean, and MTV were only prognostic for longer OS (P = 0.004, P = 0.038, and P = 0.048, respectively). Besides complete resection and a methylated MGMT promoter, TTP remained significant in multivariate survival analysis (all P ≤ 0.02), indicating an independent predictor for OS. Conclusions: Our data suggest that dynamic FET PET allows the identification of patients with longer OS among patients with newly diagnosed IDH-wildtype GBM and AA. [ABSTRACT FROM AUTHOR]

Background: Recent studies reported on high uptake of the PSMA ligands [68Ga]HBED-CC (68Ga-PSMA) and 18F-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of 68Ga-PSMA and 18F-DCFPyL in three different rat glioma models. Methods: F98, 9 L, or U87 rat gliomas were implanted into the brains of 38 rats. After 13 days of tumor growth, 68Ga-PSMA (n = 21) or 18F-DCFPyL (n = 17) was injected intravenously, and animals were sacrificed 40 min later. Five animals for each tracer and tumor model were additionally investigated by micro-PET at 20–40 min post injection. Cryosections of the tumor bearing brains were analyzed by ex vivo autoradiography and immunofluorescence staining for blood vessels, microglia, astrocytes, and presence of PSMA. Blood-brain barrier (BBB) permeability was tested by coinjection of Evans blue dye (EBD). 68Ga-PSMA uptake after restoration of BBB integrity by treatment with dexamethasone (Dex) was evaluated in four animals with U87 gliomas. Competition experiments using the PSMA-receptor inhibitor 2-(phosphonomethyl)pentane-1,5-dioic acid (PMPA) were performed for both tracers in two animals each. Results: Autoradiography demonstrated a strong 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral area and moderate binding in the center of the tumors. PMPA administration led to complete inhibition of 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral region. Restoration of BBB by Dex treatment reduced EBD extravasation but 68Ga-PSMA binding remained unchanged. Expression of activated microglia (CD11b) was low in the intra- and peritumoral area but GFAP staining revealed strong activation of astrocytes in congruency to the tracer binding in the peritumoral area. All tumors were visualized in micro PET, showing a lower tumor/brain contrast with 68Ga-PSMA than with 18F-DCFPyL. Conclusions: High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of all glioma models is presumably caused by activated astrocytes. This may represent a limitation for the clinical application of PSMA ligands in gliomas. [ABSTRACT FROM AUTHOR]

Purpose: Positron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) improves the diagnostics of cerebral gliomas compared with conventional magnetic resonance imaging (MRI). Sodium MRI is an evolving method to assess tumor metabolism. In this pilot study, we explored the relationship of [18F]FET-PET and sodium MRI in patients with cerebral gliomas in relation to the mutational status of the enzyme isocitrate dehydrogenase (IDH).Procedures: Ten patients with untreated cerebral gliomas and one patient with a recurrent glioblastoma (GBM) were investigated by dynamic [18F]FET-PET and sodium MRI using an enhanced simultaneous single-quantum- and triple-quantum-filtered imaging of 23Na (SISTINA) sequence to estimate total (NaT), weighted non-restricted (NaNR, mainly extracellular), and restricted (NaR, mainly intracellular) sodium in tumors and normal brain tissue. [18F]FET uptake and sodium parameters in tumors with a different IDH mutational status were compared. After biopsy or resection, histology and the IDH mutational status were determined neuropathologically.Results: NaT (p = 0.05), tumor-to-brain ratios (TBR) of NaT (p = 0.02), NaNR (p = 0.003), and the ratio of NaT/NaR (p < 0.001) were significantly higher in IDH-mutated than in IDH-wild-type gliomas (n = 5 patients each) while NaR was significantly lower in IDH-mutated gliomas (p = 0.01). [18F]FET parameters (TBR, time-to-peak) were not predictive of IDH status in this small cohort of patients. There was no obvious relationship between sodium distribution and [18F]FET uptake. The patient with a recurrent GBM exhibited an additional radiation injury with strong abnormalities in sodium MRI.Conclusions: Sodium MRI appears to be more strongly related to the IDH mutational status than are [18F]FET-PET parameters. A further evaluation of the combination of the two methods in a larger group of high- and low-grade gliomas seems promising. [ABSTRACT FROM AUTHOR]

Purpose: Using PET imaging in a group of patients with Alzheimer's disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function. Methods: We included 38 patients with mild-to-moderate AD (mean age 67 ± 7 years, mean MMSE score 24 ± 4, mean years of education 14 ± 4; 20 men, 18 women) in whom a [18F]AV-1451 scan (a measure of tau pathology) and an [18F]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [18F]AV-1451 and [18F]FDG from healthy controls, and subsequently thresholded at a z-score of ≥3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates. Results: Years of education were positively associated with tau-specific volume (β = 0.362, p = 0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (β = 0.303, p = 0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction. Conclusion: In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life. [ABSTRACT FROM AUTHOR]

Purpose: Areas of contrast enhancement (CE) on MRI are usually the target for resection or radiotherapy target volume definition in glioblastomas. However, the solid tumour mass may extend beyond areas of CE. Amino acid PET can detect parts of the tumour that show no CE. We systematically investigated tumour volumes delineated by amino acid PET and MRI in patients with newly diagnosed, untreated glioblastoma.Methods: Preoperatively, 50 patients with neuropathologically confirmed glioblastoma underwent O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET, and fluid-attenuated inversion recovery (FLAIR) and contrast-enhanced MRI. Areas of CE were manually segmented. FET PET tumour volumes were segmented using a tumour-to-brain ratio of ≥1.6. The percentage overlap volumes, and Dice and Jaccard spatial similarity coefficients (DSC, JSC) were calculated. FLAIR images were evaluated visually.Results: In 43 patients (86%), the FET tumour volume was significantly larger than the CE volume (21.5 ± 14.3 mL vs. 9.4 ± 11.3 mL; P < 0.001). Forty patients (80%) showed both increased uptake of FET and CE. In these 40 patients, the spatial similarity between FET uptake and CE was low (mean DSC 0.39 ± 0.21, mean JSC 0.26 ± 0.16). Ten patients (20%) showed no CE, and one of these patients showed no FET uptake. In five patients (10%), increased FET uptake was present outside areas of FLAIR hyperintensity.Conclusion: Our results show that the metabolically active tumour volume delineated by FET PET is significantly larger than tumour volume delineated by CE. Furthermore, the results strongly suggest that the information derived from both imaging modalities should be integrated into the management of patients with newly diagnosed glioblastoma. [ABSTRACT FROM AUTHOR]

Purpose: O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is an established positron emission tomography (PET) tracer for brain tumor imaging. This study explores the influence of dexamethasone therapy on [18F]FET uptake in the normal brain and its influence on the maximum and mean tumor-to-brain ratio (TBR).Procedures: [18F]FET PET scans of 160 brain tumor patients were evaluated (80 dexamethasone treated, 80 untreated; each group with 40 men/40 women). The standardized uptake value of [18F]FET uptake in the normal brain (SUVbrain) in the different groups was compared. Nine patients were examined repeatedly with and without dexamethasone therapy.Results: SUVbrain of [18F]FET uptake was significantly higher in dexamethasone-treated patients than in untreated patients (SUVbrain 1.33 ± 0.1 versus 1.06 ± 0.16 in male and 1.45 ± 0.25 versus 1.31 ± 0.28 in female patients). Similar results were observed in patients with serial PET scans. Furthermore, compared to men, a significantly higher SUVbrain was found in women, both with and without dexamethasone treatment. There were no significant differences between the different groups for TBRmax and TBRmean, which could have been masked by the high standard deviation. In a patient with a stable brain metastasis investigated twice with and without dexamethasone, the TBRmax and the biological tumor volume (BTV) decreased considerably after dexamethasone due to an increased SUVbrain.Conclusion: Dexamethasone treatment appears to increase the [18F]FET uptake in the normal brain. An effect on TBRmax, TBRmean, and BTV cannot be excluded which should be considered especially for treatment monitoring and the estimation of BTV using [18F]FET PET. [ABSTRACT FROM AUTHOR]

Purpose: Cis-4-[18F]fluoro-D-proline (D-cis-[18F]FPro) has been shown to pass the intact blood-brain barrier and to accumulate in areas of secondary neurodegeneration and necrosis in the rat brain while uptake in experimental brain tumors is low. This pilot study explores the uptake behavior of D-cis-[18F]FPro in human brain tumors after multimodal treatment.Procedures: In a prospective study, 27 patients with suspected recurrent brain tumor after treatment with surgery, radiotherapy, and/or chemotherapy (SRC) were investigated by dynamic positron emission tomography (PET) using D-cis-[18F]FPro (22 high-grade gliomas, one unspecified glioma, and 4 metastases). Furthermore, two patients with untreated lesions were included (one glioblastoma, one reactive astrogliosis). Data were compared with the results of PET using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) which detects viable tumor tissue. Tracer distribution, mean and maximum lesion-to-brain ratios (LBRmean, LBRmax), and time-to-peak (TTP) of the time activity curve (TAC) of tracer uptake were evaluated. Final diagnosis was determined by histology (n = 9), clinical follow-up (n = 10), or by [18F]FET PET (n = 10).Results: D-cis-[18F]FPro showed high uptake in both recurrent brain tumors (n = 11) and lesions classified as treatment-related changes (TRC) only (n = 16) (LBRmean 2.2 ± 0.7 and 2.1 ± 0.6, n.s.; LBRmax 3.4 ± 1.2 and 3.2 ± 1.3, n.s.). The untreated glioblastoma and the lesion showing reactive astrogliosis exhibited low D-cis-[18F]FPro uptake. Distribution of [18F]FET and D-cis-[18F]FPro uptake was discordant in 21/29 cases indicating that the uptake mechanisms are different.Conclusion: The high accumulation of D-cis-[18F]FPro in pretreated brain tumors and TRC supports the hypothesis that tracer uptake is related to cell death. Further studies before and after therapy are needed to assess the potential of D-cis-[18F]FPro for treatment monitoring. [ABSTRACT FROM AUTHOR]

A brief historical background of the development of the theranostic approach in nuclear medicine is given and seven theranostic pairs of radionuclides, namely 44gSc/47Sc, 64Cu/67Cu, 83Sr/89Sr, 86Y/90Y, 124I/131I, 152Tb/161Tb and 152Tb/149Tb, are considered. The first six pairs consist of a positron and a β−-emitter whereas the seventh pair consists of a positron and an α-particle emitter. The decay properties of all those radionuclides are briefly mentioned and their production methodologies are discussed. The positron emitters 64Cu, 86Y and 124I are commonly produced in sufficient quantities via the (p,n) reaction on the respective highly enriched target isotope. A clinical scale production of the positron emitter 44gSc has been achieved via the generator route as well as via the (p,n) reaction, but further development work is necessary. The positron emitters 83Sr and 152Tb are under development. Among the therapeutic radionuclides, 89Sr, 90Y and 131I are commercially available and 161Tb can also be produced in sufficient quantity at a nuclear reactor. Great efforts are presently underway to produce 47Sc and 67Cu via neutron, photon and charged particle induced reactions. The radionuclide 149Tb is unique because it is an α-particle emitter. The present method of production of 152Tb and 149Tb involves the use of the spallation process in combination with an on-line mass separator. The role of some emerging irradiation facilities in the production of special radionuclides is discussed. [ABSTRACT FROM AUTHOR]

Purpose: The molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2-F-fluoroethyl)-L-tyrosine (F-FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion. Methods: Ninety patients with newly diagnosed and untreated gliomas with a static and dynamic F-FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBR), as well as dynamic parameters (time-to-peak and slope) of F-FET uptake were calculated. Results: Sixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBR, TBR, TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas ( P < 0.01). TBR showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBR, TBR, TTP, and slope discriminated between gliomas with and without IDH mutation ( p < 0.01). The best diagnostic performance was obtained for the combination of TTP with TBR or slope (accuracy, 73%). Conclusion: Data suggest that static and dynamic F-FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by F-FET PET. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the potential of textural feature analysis of O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET to differentiate radiation injury from brain metastasis recurrence.Methods: Forty-seven patients with contrast-enhancing brain lesions (n = 54) on MRI after radiotherapy of brain metastases underwent dynamic 18F-FET PET. Tumour-to-brain ratios (TBRs) of 18F-FET uptake and 62 textural parameters were determined on summed images 20-40 min post-injection. Tracer uptake kinetics, i.e., time-to-peak (TTP) and patterns of time-activity curves (TAC) were evaluated on dynamic PET data from 0-50 min post-injection. Diagnostic accuracy of investigated parameters and combinations thereof to discriminate between brain metastasis recurrence and radiation injury was compared.Results: Diagnostic accuracy increased from 81 % for TBRmean alone to 85 % when combined with the textural parameter Coarseness or Short-zone emphasis. The accuracy of TBRmax alone was 83 % and increased to 85 % after combination with the textural parameters Coarseness, Short-zone emphasis, or Correlation. Analysis of TACs resulted in an accuracy of 70 % for kinetic pattern alone and increased to 83 % when combined with TBRmax.Conclusions: Textural feature analysis in combination with TBRs may have the potential to increase diagnostic accuracy for discrimination between brain metastasis recurrence and radiation injury, without the need for dynamic 18F-FET PET scans.Key Points: • Textural feature analysis provides quantitative information about tumour heterogeneity • Textural features help improve discrimination between brain metastasis recurrence and radiation injury • Textural features might be helpful to further understand tumour heterogeneity • Analysis does not require a more time consuming dynamic PET acquisition. [ABSTRACT FROM AUTHOR]

The neural cell adhesion molecule (NCAM)-derived peptide FG loop (FGL) modulates synaptogenesis, neurogenesis, and stem cell proliferation, enhances cognitive capacities, and conveys neuroprotection after stroke. Here we investigated the effect of subcutaneously injected FGL on cellular compartments affected by degeneration and regeneration after stroke due to middle cerebral artery occlusion (MCAO), namely endogenous neural stem cells (NSC), oligodendrocytes, and microglia. In addition to immunohistochemistry, we used non-invasive positron emission tomography (PET) imaging with the tracer [F]-fluoro-L-thymidine ([F]FLT) to visualize endogenous NSC in vivo. FGL significantly increased endogenous NSC mobilization in the neurogenic niches as evidenced by in vivo and ex vivo methods, and it induced remyelination. Moreover, FGL affected neuroinflammation. Extending previous in vitro results, our data show that the NCAM mimetic peptide FGL mobilizes endogenous NSC after focal ischemia and enhances regeneration by amplifying remyelination and modulating neuroinflammation via affecting microglia. Results suggest FGL as a promising candidate to promote recovery after stroke. [ABSTRACT FROM AUTHOR]

Purpose: Gallium-68 (Ga-68)-labeled tracers for imaging expression of the prostate-specific membrane antigen (PSMA) such as the [(68)Ga]Ga-PSMA-HBED-CC have already demonstrated high potential for the detection of recurrent prostate cancer. However, compared to Ga-68, a labeling with fluorine-18 (F-18) would offer advantages with respect to availability, production amount, and image resolution. [(18)F]DCFPyL is a promising F-18-labeled candidate for PSMA-positron emission tomography (PET) imaging that has been recently introduced. In the current study, we aimed to compare [(68)Ga]Ga-PSMA-HBED-CC and [(18)F]DCFPyL for clinical use in biochemically relapsed prostate cancer.Procedures: In 14 selected patients with PSA relapse of prostate cancer, [(18)F]DCFPyL PET/X-ray computed tomography (CT) was performed in addition to [(68)Ga]Ga-PSMA-HBED-CC PET/CT. A systematic comparison was carried out between results obtained with both tracers with regard to the number of detected PSMA-positive lesions, the standardized uptake value (SUV)max and the lesion to background ratios.Results: All suspicious lesions identified by [(68)Ga]Ga-PSMA-HBED-CC were also detected with [(18)F]DCFPyL. In three patients, additional lesions were observed using [(18)F]DCFPyL PET/CT. The mean SUVmax in the concordant [(18)F]DCFPyL PSMA-positive lesions was significantly higher as compared to [(68)Ga]Ga-PSMA-HBED-CC (14.5 vs. 12.2, p = 0.028, n = 15). The mean tumor to background ratios (n = 15) were significantly higher for [(18)F]DCFPyL compared to [(68)Ga]Ga-PSMA-HBED-CC using kidney, spleen, or parotid as reference organs (p = 0.006, p = 0.002, p = 0.008), but no significant differences were found using the liver (p = 0.167) or the mediastinum (p = 0.363) as reference organs.Conclusion: [(18)F]DCFPyL PET/CT provided a high image quality and visualized small prostate lesions with excellent sensitivity. [(18)F]DCFPyL represents a highly promising alternative to [(68)Ga]Ga-PSMA-HBED-CC for PSMA-PET/CT imaging in relapsed prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: Gallium-68 (Ga-68)-labeled tracers for imaging expression of the prostate-specific membrane antigen (PSMA) such as the [Ga]Ga-PSMA-HBED-CC have already demonstrated high potential for the detection of recurrent prostate cancer. However, compared to Ga-68, a labeling with fluorine-18 (F-18) would offer advantages with respect to availability, production amount, and image resolution. [F]DCFPyL is a promising F-18-labeled candidate for PSMA-positron emission tomography (PET) imaging that has been recently introduced. In the current study, we aimed to compare [Ga]Ga-PSMA-HBED-CC and [F]DCFPyL for clinical use in biochemically relapsed prostate cancer. Procedures: In 14 selected patients with PSA relapse of prostate cancer, [F]DCFPyL PET/X-ray computed tomography (CT) was performed in addition to [Ga]Ga-PSMA-HBED-CC PET/CT. A systematic comparison was carried out between results obtained with both tracers with regard to the number of detected PSMA-positive lesions, the standardized uptake value (SUV) and the lesion to background ratios. Results: All suspicious lesions identified by [Ga]Ga-PSMA-HBED-CC were also detected with [F]DCFPyL. In three patients, additional lesions were observed using [F]DCFPyL PET/CT. The mean SUV in the concordant [F]DCFPyL PSMA-positive lesions was significantly higher as compared to [Ga]Ga-PSMA-HBED-CC (14.5 vs. 12.2, p = 0.028, n = 15). The mean tumor to background ratios ( n = 15) were significantly higher for [F]DCFPyL compared to [Ga]Ga-PSMA-HBED-CC using kidney, spleen, or parotid as reference organs ( p = 0.006, p = 0.002, p = 0.008), but no significant differences were found using the liver ( p = 0.167) or the mediastinum ( p = 0.363) as reference organs. Conclusion: [F]DCFPyL PET/CT provided a high image quality and visualized small prostate lesions with excellent sensitivity. [F]DCFPyL represents a highly promising alternative to [Ga]Ga-PSMA-HBED-CC for PSMA-PET/CT imaging in relapsed prostate cancer. [ABSTRACT FROM AUTHOR]

The neural cell adhesion molecule (NCAM) plays a role in neurite outgrowth, synaptogenesis, and neuronal differentiation. The NCAM mimetic peptide FG Loop (FGL) promotes neuronal survival in vitro and enhances spatial learning and memory in rats. We here investigated the effects of FGL on neural stem cells (NSC) in vitro and in vivo. In vitro, cell proliferation of primary NSC was assessed after exposure to various concentrations of NCAM or FGL. The differentiation potential of NCAM- or FGL-treated cells was assessed immunocytochemically. To investigate its influence on endogenous NSC in vivo, FGL was injected subcutaneously into adult rats. The effects on NSC mobilization were studied both via non-invasive positron emission tomography (PET) imaging using the tracer [F]-fluoro- l-thymidine ([F]FLT), as well as with immunohistochemistry. Only FGL significantly enhanced NSC proliferation in vitro, with a maximal effect at 10 μg/ml. During differentiation, NCAM promoted neurogenesis, while FGL induced an oligodendroglial phenotype; astrocytic differentiation was neither affected by NCAM or FGL. Those differential effects of NCAM and FGL on differentiation were mediated through different receptors. After FGL-injection in vivo, proliferative activity of NSC in the subventricular zone (SVZ) was increased (compared to placebo-treated animals). Moreover, non-invasive imaging of cell proliferation using [F]FLT-PET supported an FGL-induced mobilization of NSC from both the SVZ and the hippocampus. We conclude that FGL robustly induces NSC mobilization in vitro and in vivo, and supports oligodendroglial differentiation. This capacity renders FGL a promising agent to facilitate remyelinization, which may eventually make FGL a drug candidate for demyelinating neurological disorders. [ABSTRACT FROM AUTHOR]

Purpose: Angiogenesis is a key event in the progression of glioblastomas (GBM). Our goal was to measure different anatomical and physiological parameters of GBM vessels using steady-state contrast-enhanced magnetic resonance imaging (SSCE-MRI), together with the assessment of biochemical parameters on GBM proliferation and angiogenesis using [C]methyl- L-methionine (MET) and 3′-deoxy-3′-[F]fluorothymidine (FLT) and positron emission tomography (PET). We focused on how these anatomical and biochemical read-outs correlate with one another and with immunohistochemistry. Methods: SSCE-MRI together with C-MET and F-FLT PET were performed 3 weeks after intracranial implantation of human GBM spheroids in nude rats ( n = 8). Total cerebral blood volume (tCBV), blood volume present in microvessels (μCBV), vessel density and size were calculated. Rats were treated with bevacizumab ( n = 4) or vehicle ( n = 4) for 3 weeks. Imaging was repeated at week 6, and thereafter immunohistochemistry was performed. Results: Three weeks after implantation, MRI showed an increase of vessel density and μCBV in the tumour compared to the contralateral brain. At week 6, non-treated rats showed a pronounced increase of C-MET and F-FLT tumour uptake. Between weeks 3 and 6, tCBV and vessel size increased, whereas vessel density and μCBV decreased. In rats treated with bevacizumab μCBV values were significantly smaller at week 6 than in non-treated rats, whereas the mean vessel size was higher. Accumulation of both radiotracers was lower for the treated versus the non-treated group. Most importantly, non-invasive measurement of tumour vessel characteristics and tumour proliferation correlated to immunohistochemistry findings. Conclusion: Our study demonstrates that SSCE-MRI enables non-invasive assessment of the anatomy and physiology of the vasculature of experimental gliomas. Combined SSCE-MRI and C-MET/F-FLT PET for monitoring biochemical markers of angiogenesis and proliferation in addition to vessel anatomy could be useful to improve our understanding of therapy response of gliomas. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the predictive value of early and late residual F-fluorodeoxyglucose (FDG) and F-fluorothymidine (FLT) uptake using different SUV measurements in PET in patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib. Methods: We retrospectively reviewed data from 30 patients with untreated stage IV NSCLC who had undergone a combined FDG PET and FLT PET scan at 1 week (early) and 6 weeks (late) after the start of erlotinib treatment. Early and late residual FDG and FLT uptake were measured in up to five lesions per scan with different quantitative standardized uptake values (SUV, SUV, SUV, SUV, SUV, SUV) and compared with short-term outcome (progression vs. nonprogression after 6 weeks of erlotinib treatment). Receiver-operating characteristics (ROC) curve analysis was used to determine the optimal cut-off value for detecting nonprogression after 6 weeks. Kaplan-Meier analysis and the log-rank test were used to evaluate the association between residual uptake and progression-free survival (PFS). Results: Nonprogression after 6 weeks was associated with a significantly lower early and late residual FDG uptake, measured with different quantitative parameters. In contrast, nonprogression after 6 weeks was not associated with early and late residual FLT uptake. Furthermore, patients with a lower early residual FDG uptake measured in terms of SUV and SUV had a significantly prolonged PFS (282 days vs. 118 days; p = 0.022) than patients with higher values. Similarly, lower late residual FDG uptake and early residual FLT uptake measured in terms of SUV, SUV and SUV, and late FLT uptake measured in terms of SUV and SUV was associated with an improved PFS. Conclusion: Early and late residual FDG uptake, measured using different quantitative SUV parameters, are predictive factors for short-term outcome in patients with advanced NSCLC treated with erlotinib. Additionally, low residual FDG and FLT uptake early and late in the course of erlotinib treatment is associated with improved PFS. [ABSTRACT FROM AUTHOR]

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In detecting pheochromocytoma (PHEO), positron emission tomography (PET) with the radiolabelled amine precursor 18F-fluorodihydroxyphenylalanine (18F-DOPA) offers excellent specificity, while computed tomography (CT) provides high sensitivity and ability to localize lesions; therefore, the combination of these modalities could be advantageous in this setting. The aim of this study was to investigate whether combined 18F-DOPA PET/CT more accurately detects and localizes PHEO lesions than does each modality alone. 18F-DOPA PET, CT and 18F-DOPA PET/CT images of 25 consecutive patients undergoing diagnostic scanning of suspected sporadic or multiple endocrine neoplasia type 2 syndrome-associated PHEO were reviewed retrospectively in randomized sequence. Two blinded observers scored the images regarding the likelihood of PHEO being present and localizable. Results were correlated with subsequent clinical history and, when available, histology. Of the 19 lesions detected by all three modalities, PET identified each as positive for PHEO, but was unable to definitively localize 15 of 19 (79%). CT could definitively localize all 19 lesions, but could not definitively diagnose or exclude PHEO in 18 of 19 (95%) lesions. Furthermore, CT falsely identified as negative for PHEO one lesion which was judged to be positive for this tumor by both PET and PET/CT. Only in PET/CT scans were all 19 lesions accurately characterized and localized. On a per-patient basis, the sensitivity of 18F-DOPA PET/CT for PHEO was 100% and the specificity 88%, with a 100% positive predictive value and an 88% negative predictive value. 18F-DOPA PET/CT more accurately diagnoses and localizes adrenal and extra-adrenal masses suspicious for PHEO than do 18F-DOPA PET or CT alone. [ABSTRACT FROM AUTHOR]

Compartmental modelling of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. Based on the analysis of 11 patients with glioma (WHO grade II–IV) a procedure for the automated extraction of an input function from 18F-FLT brain PET data was derived. The time–activity curve of the volume of interest with the maximum difference in 18F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K1 (transport across the blood–brain barrier) and Ki (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K1,img and K1,sample, r = 0.95, p < 10−5; Ki,img and Ki,sample, r = 0.86, p < 0.001). A paired t-test showed no significant differences in the parameters derived with the two methods (K1,img and K1,sample, p = 0.20; Ki,img and Ki,sample, p = 0.92). Furthermore, a significant correlation between Ki,img and the percentage of Ki-67-positive cells was observed ( r = 0.73, p = 0.01). Kinetic modelling of 18F-FLT brain PET data using image-derived input functions extracted from human brain PET data with the practical procedure described here provides information about the proliferative activity of brain tumours which might have clinical relevance especially for monitoring of therapy response in future clinical trials. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether the thymidine analogue 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is adequate for early evaluation of the response of malignant lymphoma to antiproliferative treatment in a mouse xenotransplant model. Immunodeficient mice bearing a follicular lymphoma xenotransplant were treated with high-dose chemotherapy (cyclophosphamide, n = 10), immunotherapy (CD20 mAb, ibritumomab-tiuxetan, n = 10) or radioimmunotherapy ([90Y]CD20 mAb, Zevalin, n = 10). Forty-eight hours after treatment, antiproliferative effects were assessed with [18F]FLT. Ninety minutes after i.v. injection of 5–10 MBq [18F]FLT, mice were sacrificed and radioactivity within the tumour and normal organs was measured using a gamma counter and calculated as % ID/g. The proliferation fraction in tissue samples derived from treated and untreated tumours was evaluated by Ki-67 immunohistochemistry, which served as the reference for proliferative activity. In untreated lymphoma, the mean proliferation fraction was 83.6%. After chemotherapy, the mean proliferation fraction decreased to 39.3% ( p = 0.0001), after immunotherapy to 77.6% ( p = 0.0078) and after radioimmunotherapy to 78.8% ( p = 0.014). In none of the animals was a significant change in tumour size observed. In untreated lymphoma, tumoural [18F]FLT uptake was 5.4% ID/g, after chemotherapy it was 1.5% ( p = 0.0005), after immunotherapy, 3.9% (non-significant), and after radioimmunotherapy, 5.8% (non-significant). In a lymphoma xenotransplant model, [18F]FLT detects early antiproliferative drug activity before changes in tumour size are visible. These findings further support the use of [18F]FLT-PET for imaging early response to treatment in malignant lymphoma. [ABSTRACT FROM AUTHOR]

The purpose of this retrospective, blinded study was to evaluate the additional value of [18F]FDG PET/CT in comparison with PET alone and with side-by-side PET and CT in patients with malignant melanoma (MM). A total of 127 consecutive studies of patients with known MM referred for a whole-body PET/CT examination were included in this study. PET alone, side-by-side PET and CT and integrated PET/CT study were independently and separately interpreted without awareness of the clinical information. One score each was applied for certainty of lesion localisation and for certainty of lesion characterisation. Verification of the findings was subsequently performed using all available clinical, pathological ( n = 30) and follow-up information. The number of lesions with an uncertain localisation was significantly ( p < 0.001) reduced by PET/CT and side-by-side PET and CT ( p < 0.05) in comparison with PET alone. In line with this increase in certainty integrated PET/CT reading also improved certainty in characterisation of lesions, however, this did not reach significance ( p = 0.057) compared versus PET alone. Respectively, PET, side-by-side PET and CT and PET/CT showed a sensitivity of 86%, 89% and 91%, a specificity of 94%, 94% and 94%, a positive predictive value of 96%, 96% and 96% and a negative predictive value of 80%, 83% and 87%. Integrated PET/CT offers a significant benefit in lesion localisation and an improvement in lesion characterisation compared with PET alone or with side-by-side PET and CT. The benefit is not as great as that reported for other tumour entities, which may be due to the high avidity of MM for [18F]FDG. [ABSTRACT FROM AUTHOR]

Purpose: Recently, the thymidine analogue 3′- deoxy-3′[18F]fluorothymidine (FLT) has been introduced for imaging proliferation with positron emission tomography (PET). In this prospective study, we examined the accuracy of FLT for differentiation of benign from malignant lung lesions and for tumour staging. Methods: A total of 47 patients with newly diagnosed pulmonary nodules on chest CT suspicious for malignancy were examined with FLT-PET in addition to routine staging procedures. A total of 43 patients also underwent 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET imaging. Within 2 weeks, patients underwent resective surgery or core biopsy of the pulmonary lesion. Results: Histopathology revealed malignant lung tumours in 32 patients (20 non-small cell lung cancer, 1 small cell lung cancer, 1 pulmonary carcinoid, 1 non- Hodgkin's lymphoma, nine metastases from extrapulmonary tumours) and benign lesions in 15 patients. Increased FLT uptake was exclusively related to malignant tumours. FLT-PET was false negative in two patients with non-small cell lung cancer, in the patient with a pulmonary carcinoid and in three patients with lung metastases. The sensitivity of FLT-PET for detection of lung cancer was 90%, the specificity 100% and the accuracy 94%. Fifteen out of 21 patients with lung cancer had mediastinal lymph node metastases. FLT-PET was true positive in 7/15 patients, resulting in a sensitivity of 53% for N-staging (specificity 100%, accuracy 67%). Clinical TNM stage was correctly identified in 67% (20/30) patients, compared to 85% (23/27) with FDG-PET. Conclusion: FLT-PET has a high specificity for the detection of malignant lung tumours. Compared with FDG, FLT-PET is less accurate for N-staging in patients with lung cancer and for detection of lung metastases. FLTPET therefore cannot be recommended for staging of lung cancer. [ABSTRACT FROM AUTHOR]

We investigated the potential of [[sup 11] C]acetate positron emission tomography (PET) to detect local recurrence in prostate cancer (PCA) in patients with increasing PSA following complete prostatectomy. A total of 31 patients were studied and compared with the results of transrectal ultrasound (TRUS) combined with biopsy and clinical follow-up. Whole-body PET scan was performed 5 min after injection of 0.8 GBq [[sup 11] C]acetate and completed within 1 h. Focally increased tracer uptake below the urinary bladder or in an abdominal lymph node region was considered as relapse. TRUS followed by biopsy verified recurrence in 18 patients and ruled it out in 13 patients. PET demonstrated local recurrence in 15 out of the aforementioned 18 patients. PET also demonstrated distant lymph node involvement and bone metastases in five patients each. No focal [[sup 11] C]acetate uptake was demonstrated in the prostate bed in patients with negative biopsy. These patients had no evidence of disease during 6 months of follow-up. In the subgroup of patients with PSA <2.0 ng/ml (n=8), five patients had positive PET findings, with four of them verified by biopsy. It is concluded that [[sup 11] C]acetate PET is a promising new tool for the diagnosis of PCA recurrence and can influence patient management. [ABSTRACT FROM AUTHOR]

Here we report the expression of major pyrimidine metabolising enzymes in pancreatic cancer cell lines, chronic pancreatitis tissue and human pancreatic cancer and the in vitro uptake of 3'-[[sup 18]F]fluoro-3'-deoxythymidine ([[sup 18]F]FLT). The expression of pyrimidine metabolising enzymes was evaluated with real-time PCR, Western blot and immunostaining. Thymidine kinase 1 (TK-1) activity was measured with a fluorocytometric assay. The cellular uptake and intracellular metabolism of [[sup 18]F]FLT were evaluated in pancreatic lobules and in transformed cancer cell lines. TK-1 and thymidine synthetase mRNA were increased in six pancreatic cancer cell lines, while mRNA levels of thymidine kinase 2 and deoxycytidine kinase were down-regulated. High TK-1 activity was confirmed in all cell lines. Furthermore, TK-1 was overexpressed in human pancreatic cancer as compared with normal pancreatic tissue and samples from patients with chronic pancreatitis. The cellular uptake of [[sup 18]F]FLT was 18.4%±3.6% and 5.2%±1.4% of the applied radioactivity after 240 min in SW-979 and BxPc-3 cells, respectively, while uptake of [[sup 18]F]fluorodeoxyglucose ([[sup 18]F]FDG) was only 0.6%±0.04% (SW979) and 0.3%±0.13% (BxPc-3) after 240 min of incubation. In contrast, cellular uptake of [[sup 18]F]FLT in isolated pancreatic lobules and growth-arrested HT1080 cells was lower as compared with the uptake of [[sup 18]F]FDG and with the malignant pancreatic cancer cell lines. HPLC analysis of the perchloric acid-soluble cell fraction demonstrated the phosphorylation of [[sup 18]F]FLT to the respective monophosphate in both cell lines. Furthermore, 0.8%±0.12% (BxPc-3) and 1.3%±0.38% (SW-979) of the applied radioactivity was detected in the perchloric acid-insoluble cell fraction, indicating the incorporation of [[sup 18]F]FLT into the DNA. Our results demonstrate the cellular uptake, intracellular trapping and incorporation into the DNA of... [ABSTRACT FROM AUTHOR]

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates ([sup 188] Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2±2.1 (range 6.9–15.8) GBq [sup 188] Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5–22) to bone marrow, 11.6 (1.7–31.1) to spleen, 5.0 (2.0–11.7) to liver, 7.0 (2.3–11.6) to kidneys, 0.7 (0.3–1.3) to lungs and 1.4 (0.8–2.1) to the whole body. Stem cells engrafted in all patients within 9–18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4±5.3 (range 18–34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking [sup 188] Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia. [ABSTRACT FROM AUTHOR]

Abstract. We simultaneously determined global myocardial blood flow (MBF) by the argon inert gas technique and by nitrogen-13 ammonia positron emission tomography (PET) to validate PET-derived MBF values in humans. A total of 19 patients were investigated at rest (n=19) and during adenosine-induced hyperaemia (n=16). Regional coronary artery stenoses were ruled out by angiography. The argon inert gas method uses the difference of arterial and coronary sinus argon concentrations during inhalation of a mixture of 75% argon and 25% oxygen to estimate global MBF. It can be considered as valid as the microspheres technique, which, however, cannot be applied in humans. Dynamic PET was performed after injection of 0.8+/-0.2 GBq [sup 13]N-ammonia and MBF was calculated applying a two-tissue compartment model. MBF values derived from the argon method at rest and during the hyperaemic state were 1.03+/-0.24 mi min[sup -1]g[sup -1] and 2.64+/-1.02 ml min[sup -1]g[sup -1], respectively. MBF values derived from ammonia PET at rest and during hyperaemia were 0.95+/-0.23 ml min[sup -1]g[sup -1] and 2.44+/-0.81 ml min[sup -1]g[sup -1] respectively. The correlation between the two methods was close (y=0.92x+0.14, r=0.96; P<0.0001). No indication was found for limited extraction of ammonia in the myocardium. The high concordance of global MBF values derived with argon and ammonia indicates that the implicit correction of spillover and recovery effects,... [ABSTRACT FROM AUTHOR]

Abstract. We investigated the potential of carbon-11 choline positron emission tomography (PET) for the detection of lymph node and bone metastases in prostate cancer. A total of 23 patients were studied (known metastases: 8; suspicion of metastases: 3; primary staging: 12). Whole-body PET imaging was performed 5 min after injection of the tracer and completed within I h. Focally increased tracer uptake in bone or abdominal lymph node regions was interpreted as representing tumour involvement. All known bone and lymph node metastases could be recognized by [[sup 11]C]choline PET. One out of ten negative scans for primary staging was false-negative (lymph node <1 cm) and one out of two positive scans was false-positive with regard to lymph node involvement (focal bowel activity). It is concluded that [[sup 11]C]choline PET is a promising new tool for the primary staging of prostate cancer, with lymph node and bone metastases demonstrating high tracer uptake. Therapeutic management could be influenced by these results in that the technique may permit avoidance of surgical lymph node exploration. [ABSTRACT FROM AUTHOR]

Anti-NCA antigen antibody BW 250/183 (Anti-Granulocyte) localizes more than 50% of injected antibody dose to the bone marrow. Therefore, this antibody is promising for adjuvant conditioning radioimmunotherapy of bone marrow before bone marrow transplantation. To examine its potential use for radioimmunotherapy, we developed an efficient and reproducible technical protocol for labelling anti-NCA antigen antibody BW 250/183 with generator-produced rhenium-188, aiming at both high radiochemical yield and high specific activity. 188Re-labelled BW 250/183 antibody was used in 12 patients with advanced leukaemia. Labelling of BW 250/183 with 188Re was accomplished by the direct radiolabelling method using tris-(2-carboxyethyl) phosphine (TCEP) as the reducing agent. Twelve patients with recurrent acute or chronic leukaemia were treated with activities of 6.5–12.4 GBq of 188Re-labelled BW 250/183. Standard gamma camera scintigraphy was used to evaluate the biodistribution, and a region of interest analysis together with the MIRDOSE 3.1 software was applied to determine the radiation doses to relevant tissues. The 188Re-BW 250/183 antibody was labelled in high radiochemical yield, with high radiochemical purity (94%±3%) and specific activity (5.55–7.4 GBq/mg) within 1 h. The preliminary biodistribution studies showed persistent uptake of 188Re-BW 250/183 in bone marrow. The radiation absorbed doses (mGy/MBq) delivered to the total body, red marrow, liver, spleen and kidneys were 0.13±0.02, 1.45±0.71, 0.43±0.21, 1.32±0.99 and 0.71±0.17, respectively. TCEP reduction enabled the direct, fast and effective labelling of the monoclonal antibody BW 250/183 with 188Re. Preliminary clinical results suggest delivery of a significant radiation dose to bone marrow and thus the potential for adjuvant conditioning therapy before BMT. [ABSTRACT FROM AUTHOR]

Yttrium-90 is used for palliative therapy for the treatment of skeletal metastases, but because it is a pure β- emitter, data on the pharmacokinetics and radiation doses to metastases and unaffected organs are lacking. To obtain such data, the present study employed yttrium-86 as a substitute forY, with detection by positron emission tomography (PET). The study compared the properties of two differentY complexes -y-citrate andY -ethylene diamine tetramethylene phosphonate (EDTMP) - in ten patients with prostatic cancer who had developed multiple bone metastases (the ten patients being divided into two groups of five). Early dynamics were measured up to 1 h post injection (p.i.) over the liver region, followed by subsequent whole-body PET scans up to 3 days p.i. Absolute uptake data were determined for normal bone, bone metastases, liver and kidney. Radiation doses were calculated according to the MIRD recommendations. Based on the pharmacokinetic measurements of the distribution of theY complexes, it was possible to calculate radiation doses for the bone metastases and the red bone marrow delivered by complexes containingY. In 1 cm of bone metastasis, doses of 26±11 mGy/MBq and 18±2 mGy/MBq were determined per MBq of injectedY- citrate andY- EDTMP, respectively. The doses to the bone marrow were 2.5±0.4 mGy/MBq forY- citrate and 1.8±0.6 mGy/MBq forY-EDTMP.Y and PET provide quantitative information applicable to the clinical use ofY. This method may also be useful for the design of otherY radiopharmaceuticals and for planning radiotherapy dosages. [ABSTRACT FROM AUTHOR]

Aim: We investigated the whole-body distribution and the radiation dosimetry of [18F]-JK-PSMA-7, a novel 18F-labeled PSMA-ligand for PET/CT imaging of prostate cancer. Methods: Ten patients with prostate cancer and biochemical recurrence or radiologic evidence of metastatic diseases were examined with 329–384 MBq (mean 359 ± 17 MBq) [18F]-JK-PSMA-7. Eight sequential positron emission tomography (PET) scans were acquired from 20 min to 3 h after injection with IRB approval. The kidneys, liver, lungs, spleen, and salivary glands were segmented into volumes of interest using the QDOSE dosimetry software suite (ABX-CRO, Germany). Absorbed and effective dose were calculated using the ICRP-endorsed IDAC 1.0 package. The absorbed dose of the salivary glands was determined using the spherical model of OLINDA 1.1. PSMA-positive lesions were evaluated separately. Quantitative assessment of the uptake in suspicious lesions was performed by analysis of maximum (max) and peak SUV values. The gluteus maximus muscle (SUVmean) served as a reference region for the calculation of tumor-to-background ratios (TBR's). Results: Physiologic radiotracer accumulation was observed in the salivary and lacrimal glands, liver, spleen, and intestines, in a pattern resembling the distribution known from other PSMA-tracers with excretion via urinary and biliary pathways. The effective dose from [18F]-JK-PSMA-7 for the whole body was calculated to be 1.09E−02 mGy/MBq. The highest radiation dose was observed in the kidneys (1.76E−01 mGy/MBq), followed by liver (7.61E−02 mGy/MBq), salivary glands (4.68E−02 mGy/MBq), spleen (1.89E−02 mGy/MBq), and lungs (1.10E-2 mGy/MBq). No adverse effects of tracer injection were observed. Six out of ten patients were scored as PSMA-positive. A total of 18 suspicious lesions were analyzed, which included six bone lesions, nine lymph nodes, and three local lesions within the prostate fossa. The values for the SUVmax and SUVpeak in the PSMA-positive lesions increased until 60 min p.i. and remained at this intensity in the PET/CT scans until 140 min. In the period between 170 and 200 min after injection, a further significant increase in SUVmax and SUVpeak within the PSMA-positive lesions was observed. Conclusions: The highest TBR of [18F]-JK-PSMA-7 was found 3 h after injection. From the kinetically collected data, it can be concluded that this trend may also continue in the further course. The start of the PET/CT acquisition should be chosen as late as possible. The high uptake in suspicious lesions in terms of absolute SUVmax and relative TBR values indicates potentially high sensitivity of the tracer for detection of prostate cancer manifestations. [ABSTRACT FROM AUTHOR]

Mutations in the isocitrate dehydrogenase (IDH mut) gene have gained paramount importance for the prognosis of glioma patients. To date, reliable techniques for a preoperative evaluation of IDH genotype remain scarce. Therefore, we investigated the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET radiomics using textural features combined with static and dynamic parameters of FET uptake for noninvasive prediction of IDH genotype. Prior to surgery, 84 patients with newly diagnosed and untreated gliomas underwent FET PET using a standard scanner (15 of 56 patients with IDH mut) or a dedicated high-resolution hybrid PET/MR scanner (11 of 28 patients with IDH mut). Static, dynamic and textural parameters of FET uptake in the tumor area were evaluated. Diagnostic accuracy of the parameters was evaluated using the neuropathological result as reference. Additionally, FET PET and textural parameters were combined to further increase the diagnostic accuracy. The resulting models were validated using cross-validation. Independent of scanner type, the combination of standard PET parameters with textural features increased significantly diagnostic accuracy. The highest diagnostic accuracy of 93% for prediction of IDH genotype was achieved with the hybrid PET/MR scanner. Our findings suggest that the combination of conventional FET PET parameters with textural features provides important diagnostic information for the non-invasive prediction of the IDH genotype. [ABSTRACT FROM AUTHOR]

A correction to the article "Direct comparison of [18F]FDG PET/CT with PET alone and with side-by-side PET and CT in patients with malignant melanoma" that was published in the 2007 issue is presented.