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Nonphysiologic overexpression of amyloid-β (Aβ) precursor protein in common transgenic Aβ mouse models of Alzheimer disease likely hampers their translational potential. The novel App NL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of Alzheimer disease for Aβ-targeting treatment trials. We aimed to establish serial small-animal PET of amyloidosis and neuroinflammation in App NL-G-F mice as a tool for therapy monitoring. Methods: App NL-G-F mice (20 homozygous and 21 heterogeneous) and 12 age-matched wild-type mice were investigated longitudinally from 2.5 to 10 mo of age with 18 F-florbetaben Aβ PET and 18 F-GE-180 18-kDa translocator protein (TSPO) PET. Voxelwise analysis of SUV ratio images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final scan. Quantification of fibrillar Aβ and activated microglia by immunohistochemistry and biochemistry served for validation of the PET results. Results: The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous App NL-G-F mice had a rising SUV ratio in cortex and hippocampus for Aβ (+9.1%, +3.8%) and TSPO (+19.8%, +14.2%) PET from 2.5 to 10 mo of age (all P < 0.05), whereas heterozygous App NL-G-F mice did not show significant changes with age. Significant voxelwise clusters of Aβ deposition and microglial activation in homozygous mice appeared at 5 mo of age. Immunohistochemical and biochemical findings correlated strongly with the PET data. Water maze escape latency was significantly elevated in homozygous App NL-G-F mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. Conclusion: Longitudinal PET in App NL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice but is insensitive to minor changes in heterozygous animals. The combination of PET with behavioral tasks in App NL-G-F treatment trials is poised to provide important insights in preclinical drug development., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

A 51-year-old man presented with recurrent gliosarcoma and increasing cough over the last months. On F-FDG PET/CT, solid lung masses with high F-FDG uptake were present. A biopsy taken from a lung lesion indicated distant metastases from gliosarcoma. Gliosarcoma, a rare malignant central nervous system tumor, presents with extracranial metastases in only less than 10%. As highlighted by this case, F-FDG PET/CT can be used for whole-body staging in patients with metastatic brain tumor. Vice versa, highly F-FDG-avid lung lesions in patients with brain tumors should lead to distant metastases as differential diagnosis despite their rare occurrence.

Purpose: According to the updated WHO classification of gliomas with its emphasis on molecular parameters, tumours with an IDH-wildtype status have a dismal prognosis. To ensure timely adjustment of treatment, demand for non-invasive prediction methods is high. 18 F-FET PET has been shown to be an important diagnostic tool for glioma management. The aim of this study was to assess the value of dynamic 18 F-FET PET for the non-invasive prediction of the IDH-mutation status., Methods: Newly diagnosed WHO grade II-IV glioma patients with MRI and dynamic 18 F-FET PET were included. The 18 F-FET PET parameters mean and maximal tumour-to-background ratio (TBR mean , TBR max ) and minimal time-to-peak (TTP min ) were evaluated. The diagnostic power for the prediction of the IDH genotype (positive/negative predictive value) was tested in the overall study group and in the subgroup of non-contrast enhancing gliomas., Results: Three hundred forty-one patients were evaluated. Molecular analyses revealed 178 IDH-mutant and 163 IDH-wildtype tumours. Overall, 270/341 gliomas were classified as 18 F-FET-positive (TBR max  > 1.6), 90.2% of the IDH-wildtype and 69.1% of IDH-mutant gliomas. Median TBR max was significantly higher in IDH-wildtype compared with IDH-mutant gliomas (2.9 vs. 2.3, p < 0.001); however, ROC-analyses revealed no reliable cutoff due to a high overlap (range 1.0-7.1 vs. 1.1-7.9). Dynamic analysis revealed a significantly shorter TTP min in IDH-wildtype gliomas; using TTP min  ≤ 12.5 min as indicator for IDH-wildtype gliomas, a positive predictive value of 87% was reached (negative predictive value 72%, AUC = 0.796, p ≤ 0.001). A total of 161/341 gliomas did not show contrast enhancement on MRI; even within this subgroup, TTP min  ≤ 12.5 min remained a good predictor of IDH-wildtype glioma (positive predictive value 83%, negative predictive value 90%; AUC = 0.868, p < 0.001)., Conclusion: A short TTP min in dynamic 18 F-FET PET serves as good predictor of highly aggressive IDH-wildtype status in gliomas. In particular, a high diagnostic power was observed in the subgroup of non-contrast enhancing gliomas, which helps to identify patients with worse prognosis.

Purpose: Oncocytic (Hürthle cell) papillary thyroid carcinoma (OPTC) is a rare variant of the papillary thyroid carcinoma (PTC) which comprises approximately 1 to 11 % of PTC cases. Its clinical course and prognosis have not been comprehensively documented and the clinical outcome remains a controversial issue. Therefore, we investigated the long-term prognosis after thyroidectomy and (adjuvant) initial radioactive iodine therapy (RIT) of OPTC compared to PTC., Methods: A total of 563 patients (47 with OPTC and 516 with PTC) with a median follow-up of 9.9 (0.3; 23.5) years were studied. All patients underwent thyroidectomy followed by (adjuvant) initial RIT. Data on the patients' demographics, pathology, laboratory findings, imaging studies, treatment, and follow-up including recurrence, and disease-specific survival were collected. Cox's multivariate regression model was used to identify independent prognostic factors for survival., Results: OPTC patients were significantly older (55.2 ± 12.3 years) than PTC patients (50.3 ± 13.5) at the time of initial diagnosis (p value 0.016). Initial tumor size was larger in the OPTC group (2.8 ± 1.8 cm for OPTC patients, 1.5 ± 1.2 cm for PTC patients, p value < 0.001). Before matching, OPTC patients presented more often with evidence of disease at the last visit of follow-up (p value 0.046). However, this difference was not observed anymore after matching for risk factors (p value 0.637). Disease-specific survival did not differ significantly. Age (HR, 1.183; 95% CI, 1.097-1.276) was identified as an independent prognostic factor for disease-specific survival. OPTC patients predominantly showed a recurrence of distant metastasis within a shorter time despite being not statistically significant., Conclusion: At initial diagnosis, OPTC shows significant differences in terms of age and initial tumor size compared to PTC. Patients suffering from OPTC present with the same clinical long-term outcome indifferent to PTC after (adjuvant) initial RIT after matching.

Background: O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET has a sensitivity of more than 90% to detect gliomas. In the remaining small fraction of gliomas without increased tracer uptake, some tumors even show photopenic defects whose clinical significance is unclear., Methods: Glioma patients with a negative FET PET scan prior to neuropathological confirmation were identified retrospectively. Gliomas were rated visually as (i) having indifferent FET uptake or (ii) photopenic, if FET uptake was below background activity. FET uptake in the area of signal hyperintensity on the T2/fluid attenuated inversion recovery-weighted MRI was evaluated by mean standardized uptake value (SUV) and mean tumor-to-brain ratio (TBR). The progression-free survival (PFS) of photopenic gliomas was compared with that of gliomas with indifferent FET uptake., Results: Of 100 FET-negative gliomas, 40 cases with photopenic defects were identified. Fifteen of these 40 cases (38%) had World Health Organization (WHO) grades III and IV gliomas. FET uptake in photopenic gliomas was significantly decreased compared with both the healthy-appearing brain tissue (SUV, 0.89 ± 0.26 vs 1.08 ± 0.23; P < 0.001) and gliomas with indifferent FET uptake (TBR, 0.82 ± 0.09 vs 0.96 ± 0.13; P < 0.001). Irrespective of the applied treatment, isocitrate dehydrogenase (IDH)-mutated WHO grade II diffuse astrocytoma patients with indifferent FET uptake (n = 25) had a significantly longer PFS than patients with IDH-mutated diffuse astrocytomas (WHO grade II) with photopenic defects (n = 11) (51 vs 24 mo; P = 0.027). The multivariate survival analysis indicated that photopenic defects predict an unfavorable PFS (P = 0.009)., Conclusion: Photopenic gliomas in negative FET PET scans should be managed more actively, as they seem to have a higher risk of harboring a higher-grade glioma and an unfavorable outcome., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The role of bevacizumab (BEV) in the setting of reirradiation (reRT) of malignant glioma recurrences is poorly defined. At our institution, reRT plus BEV was routinely used until its disapproval for glioma treatment by the European Medical Agency. Accordingly, reRT was applied without the addition of BEV since 2017. Here we present for the first time outcome and toxicity profiles of reRT plus BEV and reRT alone for malignant glioma recurrences., Patients and Methods: All adult patients consecutively undergoing reRT of a recurrent malignant glioma (37 anaplastic astrocytoma, WHO III; 124 glioblastoma, WHO IV) between 2007 and 2017 were included. In one group of patients, BEV (10 mg/kg bodyweight) was applied concomitantly on days 1 and 15 of reRT. Radiation toxicity referred to clinically significant toxicities of proven symptomatic radionecrosis (RN) and symptomatic oedema (SE) requiring steroid treatment for more than six weeks after reRT. Post-recurrence survival (PRS) and freedom from RN/SE were estimated with the Kaplan-Meier method. Prognostic factors were obtained from proportional hazards models., Results: BEV plus reRT was applied in 124 and reRT alone in 37 patients. Both groups were comparable in terms of their patient-, tumour-, and RT/reRT-related variables. PRS was independent from the applied reRT protocols. RN/SE was less frequently seen after reRT plus BEV absolutely (27/124 (21.8%) vs. 14/37 (37.8%) patients; p = 0.025) and over time (1-year RN/SE rate: 23.9% vs. 54.1%; p = 0.013). The unadjusted and adjusted hazard ratio for RN/SE was doubled in case of reRT alone. Absence of BEV remained the only risk factor for RN/SE in multivariate models (p = 0.026)., Conclusion: Concomitant BEV effectively reduces treatment toxicity of reRT and should be reconsidered in future reRT protocols., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: The advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs)., Patients and Methods: Combined PET-MRI with the tracer O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (MRGTVs). BTVs were semi-automatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and MRGTVs were fused into union volume PET-MRGTVs. The Sørensen-Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the MRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the PET-MRGTVs with margins of 10, 8, 5 and 3 mm., Results: Seven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median MRGTV volume 41.8 cc. Median BTV volume was 36.6 cc and median PET-MRGTV volume 59.3 cc. The median Sørensen-Dice coefficient for the comparison between MRGTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the PET-MRGTV with a reduced margin of 3 mm., Conclusion: PET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning., Competing Interests: The authors have declared that no competing interests exist.

The tropomyosin receptor kinase TrkA/B/C family is responsible for human neuronal growth, survival, and differentiation from early nervous system development stages onward. Downregulation of TrkA/B/C receptors characterizes numerous neurological disorders including Alzheimer's disease (AD). Abnormally expressed Trk receptors or chimeric Trk fusion proteins are also well-characterized oncogenic drivers in a variety of neurogenic and non-neurogenic human neoplasms and are currently the focus of intensive clinical research. Previously, we have described the clinical translation of a highly selective and potent carbon-11-labeled pan-Trk radioligand and the preclinical characterization of the optimized fluorine-18-labeled analogue, [ 18 F]TRACK, for in vivo Trk positron emission tomography (PET) imaging. We describe herein central nervous system selectivity assessment and first-in-human study of [ 18 F]TRACK.

A 77-year-old woman with history of breast cancer presented with 2 unclear dural contrast-enhancing lesions on MRI; differential diagnoses were breast cancer metastases and meningiomas. On Ga-DOTATOC PET/CT, the temporal lesion showed high uptake and was classified as meningioma, whereas the lesion at the falx showed barely any Ga-DOTATOC uptake uncharacteristic for meningioma and suggestive for a brain metastasis. After resection, histological specimens from the temporal lesion showed meningioma tissue with distinct SSTR2A expression, whereas the falx lesion revealed a breast cancer metastasis without significant SSTR2A expression. Therefore, Ga-DOTATOC PET represents a powerful imaging modality for the evaluation of unclear dural lesions.

Background: PET represents a valuable tool for glioma imaging. In addition to amino acid tracers such as 18 F-FET, PET targeting the 18-kDa mitochondrial translocator-protein (TSPO) is of high interest for high-grade glioma (HGG) imaging due to its upregulation in HGG cells. 18 F-GE-180, a novel TSPO ligand, has shown a high target-to-background contrast in HGG. Therefore, we intra-individually compared its uptake characteristics to dynamic 18 F-FET PET and contrast-enhanced MRI in patients with HGG., Methods: Twenty HGG patients (nine IDH-wildtype, 11 IDH-mutant) at initial diagnosis (n = 8) or recurrence (n = 12) were consecutively included and underwent 18 F-GE-180 PET, dynamic 18 F-FET PET, and MRI. The maximal tumour-to-background ratios (TBR max ) and biological tumour volumes (BTV) were evaluated in 18 F-GE-180 and 18 F-FET PET. Dynamic 18 F-FET PET analysis included the evaluation of minimal time-to-peak (TTP min ). In MRI, the volume of contrast-enhancement was delineated (VOL CE ). Volumes were spatially correlated using the Sørensen-Dice coefficient., Results: The median TBR max tended to be higher in 18 F-GE-180 PET compared to 18 F-FET PET [4.58 (2.33-8.95) vs 3.89 (1.56-7.15); p = 0.062] in the overall group. In subgroup analyses, IDH-wildtype gliomas showed a significantly higher median TBR max in 18 F-GE-180 PET compared to 18 F-FET PET [5.45 (2.56-8.95) vs 4.06 (1.56-4.48); p = 0.008]; by contrast, no significant difference was observed in IDH-mutant gliomas [3.97 (2.33-6.81) vs 3.79 (2.01-7.15) p = 1.000]. Only 5/20 cases showed higher TBR max in 18 F-FET PET compared to 18 F-GE-180 PET, all of them being IDH-mutant gliomas. No parameter in 18 F-GE-180 PET correlated with TTP min (p > 0.05 each). There was a tendency towards higher median BTV GE-180 [32.1 (0.4-236.0) ml] compared to BTV FET [19.3 (0.7-150.2) ml; p = 0.062] with a moderate spatial overlap [median Sørensen-Dice coefficient 0.55 (0.07-0.85)]. In MRI, median VOL CE [9.7 (0.1-72.5) ml] was significantly smaller than both BTV FET and BTV GE180 (p < 0.001 each), leading to a poor spatial correlation with BTV GE-180 [0.29 (0.01-0.48)] and BTV FET [0.38 (0.01-0.68)]., Conclusion: PET with 18 F-GE-180 and 18 F-FET provides differing imaging information in HGG dependent on the IDH-mutational status, with diverging spatial overlap and vast exceedance of contrast-enhancement in MRI. Combined PET imaging might reveal new insights regarding non-invasive characterization of tumour heterogeneity and might influence patients' management.

A 43-year-old woman with suspected recurrence of atypical meningioma World Health Organization grade II presented extensive intracranial lesions with high Ga-DOTATATE uptake. Moreover, numerous Ga-DOTATATE-positive bone, lung, and liver lesions were seen. For final diagnosis, biopsies taken from a lung lesion revealed distant metastases of the atypical meningioma. This case underlines the high diagnostic power of Ga-DOTATATE PET/CT for the staging of meningioma even beyond cerebral or spinal lesions; in case of distant lesions in patients with known meningioma, differential diagnosis should also contain metastases despite their rare occurrence. Moreover, this case emphasizes radioligand therapy especially in metastatic meningioma.

Background: We aimed to elucidate the place of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) PET in prognostic models of gadolinium (Gd)-negative gliomas., Methods: In 98 patients with Gd-negative gliomas undergoing 18F-FET PET guided biopsy, time activity curves (TACs) of each tumor were qualitatively categorized as either increasing or decreasing. Additionally, post-hoc quantitative analyses were done using minimal time-to-peak (TTPmin) measurements. Prognostic factors were obtained from multivariate hazards models. The fit of the biospecimen- and imaging-derived models was compared., Results: A homogeneous increasing, mixed, and homogeneous decreasing TAC pattern was seen in 51, 19, and 28 tumors, respectively. Mixed TAC tumors exhibited both increasing and decreasing TACs. Corresponding adjusted 5-year survival was 85%, 47%, and 19%, respectively (P < 0.001). Qualitative and quantitative TAC measurements were highly intercorrelated (P < 0.0001). TTPmin was longest (shortest) in the homogeneous increasing (decreasing) TAC group and in between in the mixed TAC group. TTPmin was longer in isocitrate dehydrogenase (IDH)-mutant tumors (P < 0.001). Outcome was similarly precisely predicted by biospecimen- and imaging-derived models. In the biospecimen model, World Health Organization (WHO) grade (P < 0.0001) and IDH status (P < 0.001) were predictors for survival. Outcome of homogeneous increasing (homogeneous decreasing) TAC tumors was nearly identical, with both TTPmin > 25 min (TTPmin ≤ 12.5 min) tumors and IDH-mutant grade II (IDH-wildtype) gliomas. Outcome of mixed TAC tumors matched that of both intermediate TTPmin (>12.5 min and ≤25 min) and IDH-mutant, grade III gliomas. Each of the 3 prognostic clusters differed significantly from the other ones of the respective models (P < 0.001)., Conclusion: TAC measurements constitute a powerful biomarker independent from tumor grade and IDH status., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Many predictive or influencing factors have emerged in investigations of the cognitive reserve model of patients with Alzheimer's disease (AD). For example, neuronal injury, which correlates with cognitive decline in AD, can be assessed by [ 18 F]-fluorodeoxyglucose positron-emission-tomography (FDG-PET), structural magnetic resonance imaging (MRI) and total tau in cerebrospinal fluid (CSF t-tau ), all according to the A/T/N-classification. The aim of this study was to calculate residual cognitive performance based on neuronal injury biomarkers as a surrogate of cognitive reserve, and to test the predictive value of this index for the individual clinical course., Methods: 110 initially mild cognitive impaired and demented subjects (age 71 ± 8 years) with a final diagnosis of AD dementia were assessed at baseline by clinical mini-mental-state-examination (MMSE), FDG-PET, MRI and CSF t-tau . All neuronal injury markers were tested for an association with clinical MMSE and the resulting residuals were correlated with years of education. We used multiple regression analysis to calculate the expected MMSE score based on neuronal injury biomarkers and covariates. The residuals of the partial correlation for each biomarker and the predicted residualized memory function were correlated with individual cognitive changes measured during clinical follow-up (27 ± 13 months)., Results: FDG-PET correlated highly with clinical MMSE (R = -0.49, p < .01), whereas hippocampal atrophy to MRI (R = -0.15, p = .14) and CSF t-tau (R = -0.12, p = .22) showed only weak correlations. Residuals of all neuronal injury biomarker regressions correlated significantly with education level, indicating them to be surrogates of cognitive reserve. A positive residual was associated with faster cognitive deterioration at follow-up for the residuals of stand-alone FDG-PET (R = -0.36, p = .01) and the combined residualized memory function model (R = -0.35, p = .02)., Conclusions: These findings suggest that subjects with higher cognitive reserve had accumulated more pathology, which subsequently caused a faster cognitive decline over time. Together with previous findings suggesting that higher reserve is associated with slower cognitive decline, we propose a biphasic reserve effect, with an initially protective phase followed by more rapid decompensation once the protection is overwhelmed., (Copyright © 2019. Published by Elsevier Inc.)

We present a 45-year-old man with newly generalized tonic-clonic seizures due to a contrast-enhancing frontal lesion with perifocal edema suggestive for high-grade glioma (HGG). For further evaluation, a dynamic F-FET PET scan was performed, which showed high F-FET-uptake with early peak and constantly decreasing time-activity curves, a characteristic feature of HGG. Stereotactic biopsy and histological evaluation excluded a neoplastic lesion but confirmed a manifestation of neurosarcoidosis with strong expression of the L-amino-acid-transporter considered responsible for F-FET-uptake. Therefore, unknown manifestations of neurosarcoidosis represent a clinical pitfall in F-FET PET and can mimic HGG.

Background: Glioma grading with dynamic 18 F-FET PET (0-40 min p.i.) is typically performed by analysing the mean time-activity curve of the entire tumour or a suspicious area within a heterogeneous tumour. This work aimed to ensure a reader-independent glioma characterisation and identification of aggressive sub-volumes by performing a voxel-based analysis with diagnostically relevant kinetic and static 18 F-FET PET parameters. One hundred sixty-two patients with a newly diagnosed glioma classified according to histologic and molecular genetic properties were evaluated. The biological tumour volume (BTV) was segmented in static 20-40 min p.i. 18 F-FET PET images using the established threshold of 1.6 × background activity. For each enclosed voxel, the time-to-peak (TTP), the late slope (Slope 15-40 ), and the tumour-to-background ratios (TBR 5-15, TBR 20-40 ) obtained from 5 to 15 min p.i. and 20 to 40 min p.i. images were determined. The percentage portion of these values within the BTV was evaluated with percentage volume fractions (PVFs) and cumulated percentage volume histograms (PVHs). The ability to differentiate histologic and molecular genetic classes was assessed and compared to volume-of-interest (VOI)-based parameters., Results: Aggressive WHO grades III and IV and IDH-wildtype gliomas were dominated by a high proportion of voxels with an early peak, negative slope, and high TBR, whereby the PVHs with TTP < 20 min p.i., Slope 15-40 < 0 SUV/h, and TBR 5-15 and TBR 20-40 > 2 yielded the most significant differences between glioma grades. We found significant differences of the parameters between WHO grades and IDH mutation status, where the effect size was predominantly higher for voxel-based PVHs compared to the corresponding VOI-based parameters. A low overlap of BTV sub-volumes defined by TTP < 20 min p.i. and negative Slope 15-40 with TBR 5-15 > 2 - and TBR 20-40 > 2 -defined hotspots was observed., Conclusions: The presented approach applying voxel-wise analysis of dynamic 18 F-FET PET enables an enhanced characterisation of gliomas and might potentially provide a fast identification of aggressive sub-volumes within the BTV. Parametric 3D 18 F-FET PET information as investigated in this study has the potential to guide individual therapy instrumentation and may be included in future biopsy studies.

Background: Monitoring treatment response after chemotherapy of gadolinium-(Gd)-negative gliomas is challenging as conventional MRI often indicates no radiological changes. We hypothesize that 18 F-FET-PET can be used as a biomarker for response assessment in Gd-negative gliomas undergoing chemotherapy., Methods: Sixty-one patients harboring Gd-negative WHO grade II or III glioma receiving alkylating agents (temozolomide or CCNU/procarbacine) were included. All patients underwent MRI and 18 F-FET-PET before chemotherapy and 6 months later. We calculated T 2 -volume, 18 F-FET-PET based biological tumour volume (BTV) and maximal tumour-to-brain ratio (TBR max ). Moreover, dynamic PET acquisition was performed using time-activity-curves (TACs) analysis. For MRI-based response assessment, RANO criteria for low-grade glioma were used. For 18 F-FET-PET, following classification scheme was tested: responsive disease (RD) when a decrease in either BTV ≥ 25% and/or TBR max ≥ 10% occurred, an increase in BTV ≥ 25% and/or TBR max increase > 10% characterized progressive disease (PD), minor changes ± 25% for BTV and ± 10% for TBR max were regarded as stable disease (SD). Post-chemotherapy survival (PCS) and time-to-treatment failure (TTF) were calculated using the Kaplan-Meier method., Results: 18 F-FET-PET based response has shown patients with RD to have the longest TTF time (78.5 vs 24.6 vs 24.1 months, p = 0.001), while there was no significant difference between patients with a SD and PD. A comparable pattern was observed for PCS (p < 0.001). T 2 -volume based assessment was not associated with outcome., Conclusion: 18 F-FET-PET is a promising biomarker for early response assessment in Gd-negative gliomas undergoing chemotherapy. It might be helpful for a timely adjustment of potentially ineffective treatment concepts and overcomes limitations of conventional structural imaging.

PET targeting the translocator protein (TSPO) represents an interesting approach for glioma visualization, as TSPO is highly expressed in tumor cells. We present a 32-year-old man with recurrent glioblastoma after multimodal treatment. PET with the novel TSPO ligand F-GE-180 was performed after reirradiation. Here, the previously reirradiated tumor showed a remaining circular TSPO expression. Moreover, cerebrospinal fluid dissemination was detected by a high focal uptake at the right lateral and at the fourth ventricle, whereas only a faint contrast enhancement was present in MRI. This case demonstrated the diagnostic potential of TSPO-PET for glioma imaging by visualizing even minimal disease burden.

Purpose: Expression of the translocator protein (TSPO) is upregulated in activated macrophages/microglia and is considered to be a marker of neuroinflammation. We investigated the novel TSPO ligand [ 18 F]GE-180 in patients with relapsing-remitting multiple sclerosis (RRMS) to determine the feasibility of [ 18 F]GE-180 PET imaging in RRMS patients and to assess its ability to detect active inflammatory lesions in comparison with the current gold standard, contrast-enhanced magnetic resonance imaging (MRI)., Methods: Nineteen RRMS patients were prospectively included in this study. All patients underwent TSPO genotyping and were classified as high-affinity, medium-affinity or low-affinity binders (HAB/MAB/LAB). PET scans were performed after administration of 189 ± 12 MBq [ 18 F]GE-180, and 60-90 min summation images were used for visual analysis and assessment of standardized uptake values (SUV). The frontal nonaffected cortex served as a pseudoreference region (PRR) for evaluation of SUV ratios (SUVR). PET data were correlated with MRI signal abnormalities, i.e. T2 hyperintensity or contrast enhancement (CE). When available, previous MRI data were used to follow the temporal evolution of individual lesions., Results: Focal lesions were identified as hot spots by visual inspection. Such lesions were detected in 17 of the 19 patients and overall 89 [ 18 F]GE-180-positive lesions were found. TSPO genotyping revealed 11 patients with HAB status, 5 with MAB status and 3 with LAB status. There were no associations between underlying binding status (HAB, MAB and LAB) and the signal intensity in either lesions (SUVR 1.87 ± 0.43, 1.95 ± 0.48 and 1.86 ± 0.80, respectively; p = 0.280) or the PRR (SUV 0.36 ± 0.03, 0.40 ± 0.06 and 0.37 ± 0.03, respectively; p = 0.990). Of the 89 [ 18 F]GE-180-positive lesions, 70 showed CE on MRI, while the remainder presented as T2 lesions without CE. SUVR were significantly higher in lesions with CE than in those without (2.00 ± 0.53 vs. 1.60 ± 0.15; p = 0.001). Notably, of 19 [ 18 F]GE-180-positive lesions without CE, 8 previously showed CE, indicating that [ 18 F]GE-180 imaging may be able to detect lesional activity that is sustained beyond the blood-brain barrier breakdown., Conclusion: [ 18 F]GE-180 PET can detect areas of focal macrophage/microglia activation in patients with RRMS in lesions with and without CE on MRI. Therefore, [ 18 F]GE-180 PET imaging is a sensitive and quantitative approach to the detection of active MS lesions. It may provide information beyond contrast-enhanced MRI and is readily applicable to all patients. [ 18 F]GE-180 PET imaging is therefore a promising new tool for the assessment of focal inflammatory activity in MS.

Background: F-18-fluordeoxyglucose positron emission tomography (FDG-PET) is widely used for discriminative diagnosis of tau-positive atypical parkinsonian syndromes (T+APS). This approach now stands to be augmented with more specific tau tracers. Therefore, we retrospectively analyzed a large clinical routine dataset of FDG-PET images for evaluation of the strengths and limitations of stand-alone FDG-PET. Methods: A total of 117 patients (age 68.4 ± 11.1 y) underwent an FDG-PET exam. Patients were followed clinically for a minimum of one year and their final clinical diagnosis was recorded. FDG-PET was rated visually (positive/negative) and categorized as high, moderate or low likelihood of T+APS and other neurodegenerative disorders. We then calculated positive and negative predictive values (PPV/NPV) of FDG-PET readings for the different subgroups relative to their final clinical diagnosis. Results: Suspected diagnoses were confirmed by clinical follow-up (≥1 y) for 62 out of 117 (53%) patients. PPV was excellent when FDG-PET indicated a high likelihood of T+APS in combination with low to moderate likelihood of another neurodegenerative disorder. PPV was distinctly lower when FDG-PET indicated only a moderate likelihood of T+APS or when there was deemed equal likelihood of other neurodegenerative disorder. NPV of FDG-PET with a low likelihood for T+APS was high. Conclusions: FDG-PET has high value in clinical routine evaluation of suspected T+APS, gaining satisfactory differential diagnosis in two thirds of the patients. One third of patients would potentially profit from further evaluation by more specific radioligands, with FDG-PET serving gatekeeper function for the more expensive methods.

Data in this article show radioligand uptake (to gamma counter and positron-emission-tomography) as well as polymerase chain reaction analyses of 18 kDa translocator protein (TSPO) quantification. We confirmed specificity of [ 18 F]GE180 binding of rodent brain and myocardium by blocking experiments with prior application of non-radioactive GE180, using dynamic in vivo positron-emission-tomography and ex vivo gamma counter measurements. Expression of TSPO was compared between rodent brain and myocardium by quantitative polymerase chain reaction.

In this case of suspected sphenoid wing meningioma, Ga-DOTATATE PET/CT showed a somatostatin receptor (SSR)-expressing tumor with extension to the nasopharynx and SSR-expressing cervical lymph nodes. Subsequent biopsy from the nasopharynx revealed an Epstein-Barr virus (EBV)-associated, undifferentiated World Health Organization type 3 nasopharyngeal carcinoma (NPC), a potential clinical pitfall due to the reported high SSR expression of this tumor subtype. In consideration of the high target-to-background contrast, SSR ligands might be superior to F-FDG for EBV-associated NPC PET imaging, particularly at the skull base. Somatostatin receptor ligands might furthermore offer interesting theranostic possibilities for patients with advanced/extensive EBV-associated NPC.

Background: Stratification of glioma according to isocitrate dehydrogenase 1/2 (IDH1/2) mutation and 1p/19q codeletion status has gained major importance in the new World Health Organization (WHO) classification. Parameters derived from uptake dynamics of 18F-fluoro-ethyl-tyrosine PET (18F-FET-PET) such as minimal time-to-peak (TTPmin) allow discrimination between different prognostic glioma subgroups, too. The present study is aimed at exploring whether TTPmin analysis provides prognostic information beyond the WHO classification., Methods: Three hundred patients with newly diagnosed WHO 2007 grades II-IV gliomas with 18F-FET-PET imaging at diagnosis were grouped into 4 subgroups (IDH1/2 mut-1p/19q codel; IDH1/2 mut-1p/19q non-codel; IDH1/2 wildtype WHO grade II and III tumors; and glioblastoma). Clinical and imaging factors such as age, Karnofsky performance score, treatment, TTPmin, and maximal tumor-to-brain ratio (TBRmax) were analyzed with regard to progression-free and overall survival (PFS and OS) via univariate and multivariate regression analysis., Results: PFS and OS were longest in the IDH1/2 mut-1p/19q codel subgroup, followed by IDH1/2 mut-1p/19q non-codel, IDH1/2 wildtype, and GBM (P < 0.001). Further, outcome stratified by TTPmin with a cutoff of 17.5 minutes revealed significantly longer PFS and OS in patients with TTPmin >17.5 minutes (P < 0.001 for PFS and OS). Lower TBRmax values or the absence of 18F-FET uptake was also associated with favorable outcome in the entire group. In the subgroup analyses, longer median TTPmin was associated with improved outcome specifically in the IDH1/2 mut-1p/19q non-codel group., Conclusion: 18F-FET-PET-derived dynamic analysis defines prognostically distinct subgroups of IDH1/2 mutant-1p/19q non-codel gliomas which cannot be distinguished as yet by molecular marker analysis., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objectives: PET imaging of the 18 kDa translocator protein (TSPO), a biomarker of microglial activity, receives growing interest in clinical and preclinical applications of neuroinflammatory and neurodegenerative brain diseases. In globally affected brains, intra-cerebral pseudo reference regions are not feasible. Consequently, many brain-independent approaches have been attempted, including SUV analysis and normalization to muscle- or heart uptake, aiming to stabilize quantitative analysis. In this study, we systematically compared different image normalization methods for static late phase TSPO-PET imaging of rodent brain., Methods: We first obtained gamma counter measurements for gold standard quantitation of [ 18 F]GE180 uptake in brain of C57Bl/6 mice (N = 10) after PET, aiming to identify factors contributing significantly to the quantitative results. Subsequently, data from a large cohort of C57Bl/6 mice (N = 79) were compiled to precisely determine the weighted influence and variance attributable these factors by regression analysis. Scan-rescan variability and agreement with histology were used to validate the tested normalization methods in an Alzheimer's disease (AD) mouse model with pathologically increased TSPO expression (PS2APP; N = 24). Longitudinal data from AD model mice (N = 10) scanned at four different ages were used to challenge and validate the different normalization methods in a practical application., Results: Gamma counter results revealed that injected dose, body weight and PET-measured radioactivity concentration in the ventral myocardium all significantly accounted for [ 18 F]GE180 activity in the brain. Skeletal muscle activity had high test-retest variance in this PET only application and was therefore pursued no further. Regression analysis of the large scale evaluation showed that scaling to injected dose or SUV analysis accounted for little variance in brain activity (R 2  < 0.5), but inclusion of myocardial activity together with injected dose and body weight in the regression model accounted for most of the variance in brain uptake (R 2  = 0.94). Scan-rescan stability, correlation with histology and applicability for longitudinal examination in the disease model were also significantly improved by inclusion of myocadial uptake in the quantitative model., Conclusion: Cerebral and myocardial TSPO expression are highly coupled under physiological conditions. Myocardial uptake has great potential for stabilization of static late phase [ 18 F]GE180 quantification in brain in the absence of a valid intra-cerebral pseudo-reference region., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The functional relevance of reactive gliosis for recovery from acute unilateral vestibulopathy is unknown. In the present study, glial activation was visualized in vivo by [ 18 F]GE180-PET in a rat model of unilateral labyrinthectomy (UL) and compared to behavioral vestibular compensation (VC) overtime. 14 Sprague-Dawley rats underwent a UL by transtympanic injection of bupivacaine/arsenilate, 14 rats a SHAM UL (injection of normal saline). Glial activation was depicted with [ 18 F]GE180-PET and ex vivo autoradiography at baseline and 7, 15, 30 days after UL/SHAM UL. Postural asymmetry and nystagmus were registered at 1, 2, 3, 7, 15, 30 days after UL/SHAM UL. Signs of vestibular imbalance were found only after UL, which significantly decreased until days 15 and 30. In parallel, [ 18 F]GE180-PET and ex vivo autoradiography depicted glial activation in the ipsilesional vestibular nerve and nucleus on days 7 and 15 after UL. Correlation analysis revealed a strong negative association of [ 18 F]GE180 uptake in the ipsilesional vestibular nucleus on day 7 with the rate of postural recovery ( R  = -0.90, p  < 0.001), suggesting that glial activation accelerates VC. In conclusion, glial activation takes place in the ipsilesional vestibular nerve and nucleus within the first 30 days after UL in the rat and can be visualized in vivo by [ 18 F]GE180-PET.

Background: PET with O-(2- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) has reached increasing clinical significance for patients with brain neoplasms. For quantification of standard PET-derived parameters such as the tumor-to-background ratio, the background activity is assessed using a region of interest (ROI) or volume of interest (VOI) in unaffected brain tissue. However, there is no standardized approach regarding the assessment of the background reference. Therefore, we evaluated the intra- and inter-reader variability of commonly applied approaches for clinical 18 F-FET PET reading. The background activity of 20 18 F-FET PET scans was independently evaluated by 6 readers using a (i) simple 2D-ROI, (ii) spherical VOI with 3.0 cm diameter, and (iii) VOI consisting of crescent-shaped ROIs; each in the contralateral, non-affected hemisphere including white and gray matter in line with the European Association of Nuclear Medicine (EANM) and German guidelines. To assess intra-reader variability, each scan was evaluated 10 times by each reader. The coefficient of variation (CoV) was assessed for determination of intra- and inter-reader variability. In a second step, the best method was refined by instructions for a guided background activity assessment and validated by 10 further scans., Results: Compared to the other approaches, the crescent-shaped VOIs revealed most stable results with the lowest intra-reader variabilities (median CoV 1.52%, spherical VOI 4.20%, 2D-ROI 3.69%; p < 0.001) and inter-reader variabilities (median CoV 2.14%, spherical VOI 4.02%, 2D-ROI 3.83%; p = 0.001). Using the guided background assessment, both intra-reader variabilities (median CoV 1.10%) and inter-reader variabilities (median CoV 1.19%) could be reduced even more., Conclusions: The commonly applied methods for background activity assessment show different variability which might hamper 18 F-FET PET quantification and comparability in multicenter settings. The proposed background activity assessment using a (guided) crescent-shaped VOI allows minimization of both intra- and inter-reader variability and might facilitate comprehensive methodological standardization of amino acid PET which is of interest in the light of the anticipated EANM technical guidelines.

Purpose: In recent years, several [ 18 F]-labeled amyloid-PET tracers have been developed and have obtained clinical approval. Despite their widespread scientific use, studies in routine clinical settings are limited. We therefore investigated the impact of [ 18 F]-florbetaben (FBB)-PET on the diagnostic management of patients with suspected dementia that was still unclarified after [ 18 F]-fluordeoxyglucose (FDG)-PET., Methods: All subjects were referred in-house with a suspected dementia syndrome due to neurodegenerative disease. After undergoing an FDG-PET exam, the cases were discussed by the interdisciplinary dementia board, where the most likely diagnosis as well as potential differential diagnoses were documented. Because of persistent diagnostic uncertainty, the patients received an additional FBB-PET exam. Results were interpreted visually and classified as amyloid-positive or amyloid-negative, and we then compared the individual clinical diagnoses before and after additional FBB-PET., Results: A total of 107 patients (mean age 69.4 ± 9.7y) were included in the study. The FBB-PET was rated as amyloid-positive in 65/107. In 83% of the formerly unclear cases, a final diagnosis was reached through FBB-PET, and the most likely prior diagnosis was changed in 28% of cases. The highest impact was observed for distinguishing Alzheimer's dementia (AD) from fronto-temporal dementia (FTLD), where FBB-PET altered the most likely diagnosis in 41% of cases., Conclusions: FBB-PET has a high additive value in establishing a final diagnosis in suspected dementia cases when prior investigations such as FDG-PET are inconclusive. The differentiation between AD and FTLD was particularly facilitated by amyloid-PET, predicting a considerable impact on patient management, especially in the light of upcoming disease-modifying therapies.

Background: PET ligands targeting the translocator protein (TSPO) represent promising tools to visualise neuroinflammation. Here, we analysed parameters obtained in dynamic and static PET images using the novel TSPO ligand [ 18 F]GE-180 in patients with relapsing remitting multiple sclerosis (RRMS) and an approach for semi-quantitative assessment of this disease in clinical routine. Seventeen dynamic [ 18 F]GE-180 PET scans of RRMS patients were evaluated (90 min). A pseudo-reference region (PRR) was defined after identification of the least disease-affected brain area by voxel-based comparison with six healthy controls (HC) and upon exclusion of voxels suspected of being affected in static 60-90 min p.i. images. Standardised uptake value ratios (SUVR) obtained from static images normalised to PRR were correlated to the distribution volume ratios (DVR) derived from dynamic data with Logan reference tissue model., Results: Group comparison with HC revealed white matter and thalamus as most affected regions. Fewest differences were found in grey matter, and normalisation to frontal cortex (FC) yielded the greatest reduction in variability of healthy grey and white matter. Hence, FC corrected for affected voxels was chosen as PRR, leading to time-activity curves of FC which were congruent to HC data (SUV 60-90 0.37, U test P = 0.42). SUVR showed a very strong correlation with DVR (Pearson ρ > 0.9). Focal MS lesions exhibited a high SUVR (range, 1.3-3.2)., Conclusions: This comparison with parameters from dynamic data suggests that SUVR normalised to corrected frontal cortex as PRR is suitable for the quantification of [ 18 F]GE-180 uptake in lesions and different brain regions of RRMS patients. This efficient diagnostic protocol based on static [ 18 F]GE-180 PET scans acquired 60-90 min p.i. allows the semi-quantitative assessment of neuroinflammation in RRMS patients in clinical routine.

We report a woman with multifocal lesions suggestive of meningiomas in MRI, which also presented with high Ga-DOTATATE uptake in PET, a finding characteristic for meningioma. A whole-body staging due to a pathological fracture revealed multiple neoplastic lesions throughout the body without detection of a primary site. Subsequent pathological workup of a lung lesion revealed multifocal metastases from follicular thyroid cancer despite thyroidectomy 10 years ago (without pathological finding), and posttreatment scans after radioiodine therapy confirmed the multiple brain lesions to be metastases as well. Our case shows that epidural metastases from endocrine origin might represent a clinical pitfall in Ga-DOTATATE PET.

The interobserver agreement for 68 Ga-PSMA-11 PET/CT study interpretations in patients with prostate cancer is unknown. Methods: 68 Ga-PSMA-11 PET/CT was performed in 50 patients with prostate cancer for biochemical recurrence ( n = 25), primary diagnosis ( n = 10), biochemical persistence after primary therapy ( n = 5), or staging of known metastatic disease ( n = 10). Images were reviewed by 16 observers who used a standardized approach for interpretation of local (T), nodal (N), bone (Mb), or visceral (Mc) involvement. Observers were classified as having a low (<30 prior 68 Ga-PSMA-11 PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 6). Histopathology ( n = 25, 50%), post-external-beam radiation therapy prostate-specific antigen response ( n = 15, 30%), or follow-up PET/CT ( n = 10, 20%) served as a standard of reference. Observer groups were compared by overall agreement (% patients matching the standard of reference) and Fleiss' κ with mean and corresponding 95% confidence interval (CI). Results: Agreement among all observers was substantial for T (κ = 0.62; 95% CI, 0.59-0.64) and N (κ = 0.74; 95% CI, 0.71-0.76) staging and almost perfect for Mb (κ = 0.88; 95% CI, 0.86-0.91) staging. Level of experience positively correlated with agreement for T (κ = 0.73/0.66/0.50 for high/intermediate/low experience, respectively), N (κ = 0.80/0.76/0.64, respectively), and Mc staging (κ = 0.61/0.46/0.36, respectively). Interobserver agreement for Mb was almost perfect irrespective of prior experience (κ = 0.87/0.91/0.88, respectively). Observers with low experience, when compared with intermediate and high experience, demonstrated significantly lower median overall agreement (54% vs. 66% and 76%, P = 0.041) and specificity for T staging (73% vs. 88% and 93%, P = 0.032). Conclusion: The interpretation of 68 Ga-PSMA-11 PET/CT for prostate cancer staging is highly consistent among observers with high levels of experience, especially for nodal and bone assessments. Initial training on at least 30 patient cases is recommended to ensure acceptable performance., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

In patients with brain metastasis, PET using labeled amino acids has gained clinical importance, mainly regarding the differentiation of viable tumor tissue from treatment-related effects. However, there is still limited knowledge concerning the uptake characteristics in patients with newly diagnosed and untreated brain metastases. Hence, we evaluated the uptake characteristics in these patients using dynamic O -(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) PET. Methods: Patients with newly diagnosed brain metastases without prior local therapy and 18 F-FET PET scanning were retrospectively identified in 2 centers. Static and dynamic PET parameters (maximal/mean tumor-to-brain-ratio [TBR max /TBR mean ], biologic tumor volume [BTV], and time-activity curves with minimal time to peak [TTP min ]) were evaluated and correlated with MRI parameters (maximal lesion diameter, volume of contrast enhancement) and originating primary tumor. Results: Forty-five brain metastases in 30 patients were included. Forty of 45 metastases (89%) had a TBR max ≥ 1.6 and were classified as 18 F-FET-positive (median TBR max , 2.53 [range, 1.64-9.47]; TBR mean , 1.86 [range, 1.63-5.48]; and BTV, 3.59 mL [range, 0.04-23.98 mL], respectively). In 39 of 45 brain metastases eligible for dynamic analysis, a wide range of TTP min was observed (median, 22.5 min; range, 4.5-47.5 min). All 18 F-FET-negative metastases had a diameter of ≤ 1.0 cm, whereas metastases with a > 1.0 cm diameter all showed pathologic 18 F-FET uptake, which did not correlate with lesion size. The highest variability of uptake intensity was observed within the group of melanoma metastases. Conclusion: Untreated metastases predominantly show increased 18 F-FET uptake, and only a third of metastases < 1.0 cm were 18 F-FET-negative, most likely because of scanner resolution and partial-volume effects. In metastases > 1.0 cm, 18 F-FET uptake intensity was highly variable and independent of tumor size (even intraindividually). 18 F-FET PET might provide additional information beyond the tumor extent by reflecting molecular features of a metastasis and might be a useful tool for future clinical applications, for example, response assessment., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Most high-grade gliomas (HGG) recur after initial multimodal therapy and re-irradiation (Re-RT) has been shown to be a valuable re-treatment option in selected patients. We evaluated the prognostic value of dynamic time-to-peak analysis and early static summation images in O-(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) PET for patients treated with Re-RT ± concomitant bevacizumab. We retrospectively analyzed 72 patients suffering from recurrent HGG with 18 F-FET PET prior to Re-RT. PET analysis revealed the maximal tumor-to-background-ratio (TBR max ), the biological tumor volume, the number of PET-foci and pattern of time-activity-curves (TACs; increasing vs. decreasing). Furthermore, the novel PET parameters early TBR max (at 5-15 min post-injection) and minimal time-to-peak (TTP min ) were evaluated. Additional analysis was performed for gender, age, KPS, O6-methylguanine-DNA methyltransferase methylation status, isocitrate dehydrogenase 1 mutational status, WHO grade and concomitant bevacizumab therapy. The influence of PET and clinical parameters on post-recurrence survival (PRS) was investigated. Shorter TTP min was related to shorter PRS after Re-RT with 6 months for TTP min  < 12.5 min, 7 months for TTP min 12.5-25 min and 11 months for TTP min >25 min (p = 0.027). TTP min had a significant impact on PRS both on univariate (p = 0.027; continuous) and multivariate analysis (p = 0.011; continuous). Other factors significantly related to PRS on multivariate analysis were increasing vs. decreasing TACs (p = 0.008) and Karnofsky Performance Score (p = 0.015; <70 vs. ≥70). Early TBR max as well as the other conventional PET parameters were not significantly related to PRS on univariate analysis. Dynamic 18 F-FET PET with TTP min provides a high prognostic value for recurrent HGG prior to Re-RT, whereas early TBR max does not. Dynamic 18 F-FET PET using TTP min might help to personalize Re-RT treatment regimens in future through voxelwise TTP min analysis for dose painting purposes and PET-guided dose escalation.

Background: After focused high dose radiotherapy of brain metastases, differentiation between tumor recurrence and radiation-induced lesions by conventional MRI is challenging. This study investigates the usefulness of dynamic O-(2- 18 F-Fluoroethyl)-L-Tyrosine positron emission tomography ( 18 F-FET PET) in patients with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy of brain metastases., Methods: Twenty-two patients with 34 brain metastases (median age 61.9 years) were included. Due to follow-up scan evaluations after repeated treatment in a subset of patients, a total of 50 lesions with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy could be evaluated. 18 F-FET PET analysis included the assessment of maximum and mean tumor-to-background ratio (TBR max and TBR mean ) and analysis of time-activity-curves (TAC; increasing vs. decreasing) including minimal time-to-peak (TTP min ). PET parameters were correlated with histological findings and radiological-clinical follow-up evaluation., Results: Tumor recurrence was found in 21/50 cases (15/21 verified by histology, 6/21 by radiological-clinical follow-up) and radiation-induced changes in 29/50 cases (5/29 verified by histology, 24/29 by radiological-clinical follow-up). Median clinical-radiological follow-up was 28.3 months (range 4.2-99.1 months). 18 F-FET uptake was higher in tumor recurrence compared to radiation-induced changes (TBR max 2.9 vs. 2.0, p < 0.001; TBR mean 2.2 vs. 1.7, p < 0.001). Receiver-operating-characteristic (ROC) curve analysis revealed optimal cut-off values of 2.15 for TBR max and 1.95 for TBR mean (sensitivity 86 %, specificity 79 %). Increasing TACs and long TTP min were associated with radiation-induced changes, decreasing TACs with tumor recurrence (p = 0.01). By combination of TBR and TACs, sensitivity and specificity could be increased to 93 and 84 %., Conclusions: In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18 F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions.

Unlabelled: PET with O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) has gained increasing importance for glioma management. With regard to the occurrence of (18)F-FET-negative glioma, we investigated the value of (18)F-FET PET monitoring of primarily (18)F-FET-negative gliomas concerning the detection of progression and malignant transformation., Methods: We included 31 patients (26 World Health Organization [WHO] grade II, 5 WHO grade III) with primarily (18)F-FET-negative glioma and available (18)F-FET PET follow-up. (18)F-FET PET analysis comprised maximal tumor-to-background ratio (TBRmax) and dynamic analysis of tumoral (18)F-FET uptake over time (increasing vs. decreasing) including minimal time to peak (TTPmin). PET findings were correlated with MRI and clinical findings of progression as well as histology of recurrent tumors., Results: Twenty-three of 31 patients experienced tumor progression (median progression-free survival, 41.7 mo). Fourteen of 23 patients showed tumoral (18)F-FET uptake concurrent to and 4 of 23 before MRI-derived or clinical signs of tumor progression; 2 of 23 patients presented signs of progression in MRI when no concomitant (18)F-FET PET was available, but subsequent follow-up PET was positive. In 3 of 23 patients, no (18)F-FET uptake was detected at tumor progression. Overall, 20 of 31 primarily (18)F-FET-negative glioma turned (18)F-FET-positive during the follow-up. At first occurrence of tumoral (18)F-FET uptake, TBRmax was significantly higher in patients with malignant transformation (11/20) than in those without malignant progression (3.2 ± 0.9 vs. 1.9 ± 0.5; P = 0.001), resulting in a high detection rate for malignant transformation (for TBRmax > 2.46: sensitivity, 82%; specificity, 89%; negative predictive value, 80%; positive predictive value, 90%; and accuracy, 85%). Although static evaluation was superior to dynamic analysis for the detection of malignant transformation (for TTPmin ≤ 17.5 min: sensitivity, 73%; specificity, 67%; negative predictive value, 67%; positive predictive value, 73%; and accuracy, 70%), short TTPmin was associated with an early malignant transformation in the further disease course. Overall, 18 of 31 patients experienced malignant transformation; of these, 16 of 17 (94%) evaluable patients showed (18)F-FET uptake at the time of malignant transformation., Conclusion: (18)F-FET PET monitoring with static and dynamic evaluation is useful even in primarily (18)F-FET-negative glioma, providing a high detection rate of both tumor progression and malignant transformation, partly before further signs of progression in MRI. Hence, (18)F-FET uptake indicating malignant transformation might influence the patient management., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: Even though [(123)I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS with previously inconclusive findings can be improved by the use of iterative reconstruction algorithms and an improved semiquantitative evaluation which additionally implemented a correction algorithm for patient age and gamma camera dependency (EARL-BRASS; Hermes Medical Solutions, Sweden)., Methods: We identified 101 patients with inconclusive findings who underwent an [(123)I]FP-CIT SPECT between 2003 and 2010 as part of the diagnostic process of suspected PS at the University of Munich, and re-evaluated these scans using iterative reconstruction algorithms and the new corrected EARL-BRASS. Clinical follow-up was obtained in 62 out of the 101 patients and constituted the gold standard for the re-evaluation to assess the possible improvement in diagnostic accuracy., Results: Clinical follow-up confirmed the diagnosis of PS in 11 of the 62 patients. In patients in whom both visual and semiquantitative analysis showed concordant findings (48 patients), a high negative predictive value (93 %), positive predictive value (100 %) and accuracy (94 %) were found, and thus a correct diagnosis was obtained in 45 of the 48 patients. Among the 14 patients with discordant findings, the additional semiquantitative analysis correctly identified all five of nine patients patients without PS by nonpathological semiquantitative findings in visually pathological or inconclusive scans. In contrast, four of the remaining five patients with decreased semiquantitative values but visually normal scans did not show a PS during follow-up., Conclusion: The age-corrected and camera-corrected mode of evaluation using EARL-BRASS provided a notable improvement in the diagnostic accuracy of [(123)I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [(123)I]FP-CIT binding due to age-related loss of the dopamine transporter or pathological loss of binding.

Noninvasive tumor growth monitoring is of particular interest for the evaluation of experimental glioma therapies. This study investigates the potential of positron emission tomography (PET) using O-(2-(18)F-fluoroethyl)-L-tyrosine ([(18)F]-FET) to determine tumor growth in a murine glioblastoma (GBM) model-including estimation of the biological tumor volume (BTV), which has hitherto not been investigated in the pre-clinical context. Fifteen GBM-bearing mice (GL261) and six control mice (shams) were investigated during 5 weeks by PET followed by autoradiographic and histological assessments. [(18)F]-FET PET was quantitated by calculation of maximum and mean standardized uptake values within a universal volume-of-interest (VOI) corrected for healthy background (SUVmax/BG, SUVmean/BG). A partial volume effect correction (PVEC) was applied in comparison to ex vivo autoradiography. BTVs obtained by predefined thresholds for VOI definition (SUV/BG: ≥1.4; ≥1.6; ≥1.8; ≥2.0) were compared to the histologically assessed tumor volume (n = 8). Finally, individual "optimal" thresholds for BTV definition best reflecting the histology were determined. In GBM mice SUVmax/BG and SUVmean/BG clearly increased with time, however at high inter-animal variability. No relevant [(18)F]-FET uptake was observed in shams. PVEC recovered signal loss of SUVmean/BG assessment in relation to autoradiography. BTV as estimated by predefined thresholds strongly differed from the histology volume. Strikingly, the individual "optimal" thresholds for BTV assessment correlated highly with SUVmax/BG (ρ = 0.97, p < 0.001), allowing SUVmax/BG-based calculation of individual thresholds. The method was verified by a subsequent validation study (n = 15, ρ = 0.88, p < 0.01) leading to extensively higher agreement of BTV estimations when compared to histology in contrast to predefined thresholds. [(18)F]-FET PET with standard SUV measurements is feasible for glioma imaging in the GBM mouse model. PVEC is beneficial to improve accuracy of [(18)F]-FET PET SUV quantification. Although SUVmax/BG and SUVmean/BG increase during the disease course, these parameters do not correlate with the respective tumor size. For the first time, we propose a histology-verified method allowing appropriate individual BTV estimation for volumetric in vivo monitoring of tumor growth with [(18)F]-FET PET and show that standardized thresholds from routine clinical practice seem to be inappropriate for BTV estimation in the GBM mouse model.

Deep brain stimulation (DBS) is an invasive technique designed to stimulate certain deep brain regions for therapeutic purposes and is currently used mainly in patients with neurodegenerative disorders, such as Parkinson's disease. However, DBS is also used increasingly for other experimental applications, such as the treatment of psychiatric disorders (e.g. severe depression), weight reduction. Apart from its therapeutic potential, DBS can cause severe adverse effects, some that might also have a significant impact on the patient's personality and autonomy by the external stimulation of DBS which effects lie beyond the individual's control and free will. The article's purpose is to outline the procedures of DBS currently used in therapeutic and experimental applications and to discuss the ethical concerns regarding this procedure. It will address the clinical benefit-risk-ratio, the particular ethics of research in this field, and the ethical issues raised by affecting a patient's or an individual's personality and autonomous behaviour. Moreover, a potential ethical guideline, the Ulysses contract is discussed for the field of clinical application as well as the question of responsibility.

Purpose: Apart from binding to the dopamine transporter (DAT), [(123)I]FP-CIT shows moderate affinity for the serotonin transporter (SERT), allowing imaging of both monoamine transporters in a single imaging session in different brain areas. The aim of this study was to systematically evaluate extrastriatal binding (predominantly due to SERT) and its age and gender dependencies in a large cohort of healthy controls., Methods: SPECT data from 103 healthy controls with well-defined criteria of normality acquired at 13 different imaging centres were analysed for extrastriatal binding using volumes of interest analysis for the thalamus and the pons. Data were examined for gender and age effects as well as for potential influence of striatal DAT radiotracer binding., Results: Thalamic binding was significantly higher than pons binding. Partial correlations showed an influence of putaminal DAT binding on measured binding in the thalamus but not on the pons. Data showed high interindividual variation in extrastriatal binding. Significant gender effects with 31 % higher binding in women than in men were observed in the thalamus, but not in the pons. An age dependency with a decline per decade (±standard error) of 8.2 ± 1.3 % for the thalamus and 6.8 ± 2.9 % for the pons was shown., Conclusion: The potential to evaluate extrastriatal predominant SERT binding in addition to the striatal DAT in a single imaging session was shown using a large database of [(123)I]FP-CIT scans in healthy controls. For both the thalamus and the pons, an age-related decline in radiotracer binding was observed. Gender effects were demonstrated for binding in the thalamus only. As a potential clinical application, the data could be used as a reference to estimate SERT occupancy in addition to nigrostriatal integrity when using [(123)I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors.