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Background: 68 Ga-EMP-100 is a novel positron emission tomography (PET) ligand that directly targets tumoral c-MET expression. Upregulation of the receptor tyrosin kinase c-MET in renal cell carcinoma (RCC) is correlated with overall survival in metastatic disease (mRCC). Clinicopathological staging of c-MET expression could improve patient management prior to systemic therapy with for instance inhibitors targeting c-MET such as cabozantinib. We present the first in-human data of 68 Ga-EMP-100 in mRCC patients evaluating uptake characteristics in metastases and primary RCC., Methods: Twelve patients with mRCC prior to anticipated cabozantinib therapy underwent 68 Ga-EMP-100 PET/CT imaging. We compared the biodistribution in normal organs and tumor uptake of mRCC lesions by standard uptake value (SUV mean ) and SUV max measurements. Additionally, metastatic sites on PET were compared to contrast-enhanced computed tomography (CT) and the respective, quantitative PET parameters were assessed and then compared inter- and intra-individually., Results: Overall, 87 tumor lesions were analyzed. Of these, 68/87 (79.3%) were visually rated c-MET-positive comprising a median SUV max of 4.35 and SUV mean of 2.52. Comparing different tumor sites, the highest uptake intensity was found in tumor burden at the primary site (SUV max 9.05 (4.86-29.16)), followed by bone metastases (SUV max 5.56 (0.97-15.85)), and lymph node metastases (SUV max 3.90 (2.13-6.28)) and visceral metastases (SUV max 3.82 (0.11-16.18)). The occurrence of visually PET-negative lesions (20.7%) was distributed heterogeneously on an intra- and inter-individual level; the largest proportion of PET-negative metastatic lesions were lung and liver metastases. The highest physiological 68 Ga-EMP-100 accumulation besides the urinary bladder content was seen in the kidneys, followed by moderate uptake in the liver and the spleen, whereas significantly lower uptake intensity was observed in the pancreas and the intestines., Conclusion: Targeting c-MET expression, 68 Ga-EMP-100 shows distinctly elevated uptake in mRCC patients with partially high inter- and intra-individual differences comprising both c-MET-positive and c-MET-negative lesions. Our first clinical results warrant further systemic studies investigating the clinical use of 68 Ga-EMP-100 as a biomarker in mRCC patients., (© 2021. The Author(s).)

Background: O-(2-[ 18 F]-fluoroethyl)-L-tyrosine ( 18 F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30% of low- and 5% of high-grade gliomas do not present enhanced 18 F-FET uptake at primary diagnosis (" 18 F-FET-negative gliomas") and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed 18 F-FET-negative gliomas and to compare them to a matched group of 18 F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 18 F-FET-negative (tumour-to-background ratio (TBR) < 1.6), n = 20 18 F-FET-positive gliomas (TBR > 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells (%) and the staining intensity (range 0-2) were multiplied to an overall score (H-score; range 0-200) and correlated to PET findings as well as progression-free survival (PFS)., Results: IHC staining of LAT1 expression was positive in both, 18 F-FET-positive as well as 18 F-FET-negative gliomas. No differences were found between the 18 F-FET-negative and 18 F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBR max , neither in the overall group nor in the 18 F-FET-positive group only (p = 0.651 and p = 0.140)., Conclusion: Although LAT1 is reported to mediate the uptake of 18 F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18 F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in 18 F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of 18 F-FET are necessary., (© 2021. The Author(s).)

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [ 18 F]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [ 18 F]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [ 18 F]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer's disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age- and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [ 18 F]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions.

Background: Surgeon's intraoperative estimation of meningioma extent of resection (Simpson Grade, SG) is widely used as a prognostic factor for recurrence. However, the validity of SG is still a matter of debate. In preoperative imaging, 68Ga-DOTATATE/PET-CT has been shown to detect meningioma tissue even more sensitively than magnetic resonance imaging (MRI)., Objective: To evaluate the Simpson grading within the framework of modern postoperative imaging techniques (MRI; PET-CT)., Methods: At first, patients with WHO grade I meningioma, surgical resection, and postoperative 68Ga-DOTATATE/PET-CT within 6 mo after surgery were retrospectively analyzed. Second, an analogous prospective cohort of patients with WHO grade I meningioma was investigated by comparing SG after meningioma removal with postoperative MRI and 68Ga-DOTATATE/PET-CT within 6 mo after surgery., Results: A total of 37 patients were retrospectively analyzed. In total, 5/8 patients with SG-I and II resections showed tumor remnants according to postoperative PET-CT (SG 62.5% false negative). In the prospective cohort of 52 tumors, PET-CT displayed tracer uptake in 15/37 SG-I or II resections indicating unexpected tumor remnants (SG 40.5% false negative). MRI was false negative in 7 of these 15 cases (MRI 18.9% false negative) (P = .037). Discordant results according to PET-CT were more often found in convexity (40%) and falcine (46.7%) meningiomas than in skull base meningiomas (18.2%)., Conclusion: Intraoperative Simpson grading is at risk to underestimate tumor remnants, predominantly in grade I and II resections. Postoperative PET-CT improves detection rates compared to MRI. Prognostic impact of postoperative meningioma remnants according to PET-CT needs to be investigated prospectively., (Copyright © 2020 by the Congress of Neurological Surgeons.)

A 25-year-old man presented with headache and intracranial pressure symptoms. On MRI, an intracranial lesion was detected in the right thalamus with exophytic growth into the third ventricle and inhomogeneous contrast enhancement without necrosis. Dual amino acid (F-FET) and TSPO (F-GE-180) PET imaging showed high tumor-to-background ratios in both scans and a short time-to-peak in F-FET uptake dynamics. Biopsy revealed a diffuse midline glioma, H3K27M-mutant (WHO grade IV), a novel entity in the 2016 WHO classification with poor clinical outcome. Our case shows that the highly aggressive features of this tumor entity can be visualized in vivo by both PET modalities.

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: Recent data suggest that diffuse gliomas carrying mutations in codon 34 of the H3 histone family 3A protein represent a very rare, distinct subgroup of IDH-wild type malignant astrocytic gliomas. However, characteristics detectable by MRI and F-FET PET in H3-G34-mutant gliomas are unknown., Methods: We report on MRI and F-FET PET findings in 8 patients from 4 German centers with H3-G34-mutant diffuse gliomas. MRI analyses included multifocality, contrast enhancement, necrosis, cysts, hemorrhages, calcification, and edema. F-FET PET characteristics were evaluated on the basis of static F-FET PET parameters, such as maximal tumor-to-background ratio (TBRmax) and biological tumor volume (BTV), as well as the minimal time-to-peak (TTPmin) obtained from dynamic F-FET PET data., Results: MRI showed multifocal lesions in 2 of 8, contrast enhancement in 6 of 8, necrosis in 3 of 8, cysts in 3 of 8, hemorrhage in 1 of 8, and calcifications in 1 of 8 patients. None of the tumors showed marked peritumoral edema. However, all 8 H3-G34-mutant gliomas were characterized by a high uptake intensity on F-FET PET with a median TBRmax of 3.4 (range, 2.5-11.7) and a relatively diffuse uptake pattern leading to a large BTV (median, 41.9 mL; range, 7.5-115.6). Dynamic PET data revealed a short median TTPmin of 12.5 minutes., Conclusions: MRI features of diffuse gliomas with H3-G34 mutation may present very heterogeneously with some cases not even fulfilling the imaging criteria of high-grade glioma. In contrast, in F-FET PET, these tumors show an extensive and diffuse tracer uptake resulting in large BTV with a high TBRmax and a short TTPmin, thus resembling PET characteristics of aggressive high-grade gliomas, namely, glioblastomas.

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.

Purpose: Although the mechanisms by which the central noradrenaline (NA) system influences appetite and controls energy balance are quite well understood, its relationship to changes in body weight remains largely unknown. The main goal of this study was to further clarify whether the brain NA system is a stable trait or whether it can be altered by dietary intervention., Methods: We aimed to compare central NA transporter (NAT) availability in ten obese, otherwise healthy individuals with a body mass index (BMI) of 42.4 ± 3.7 kg/m 2 (age 34 ± 9 years, four women) and ten matched non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m 2 , age 33 ± 10 years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[ 11 C]O-methylreboxetine (MRB) before and 6 months after dietary intervention., Results: MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BP ND ) in the insula and the hippocampus of obese individuals, which correlated well with changes in BMI (-3.3 ± 5.3%; p = 0.03) following completion of the dietary intervention. Furthermore, voxel-wise regression analyses showed that lower BP ND in these regions, but also in the midbrain and the prefrontal cortex, at baseline was associated with higher achieved weight loss (e.g., hippocampal area R 2  = 0.80; p < 0.0001). No changes were observed in non-obese controls., Conclusion: These first longitudinal interventional data on NAT availability in highly obese individuals indicate that the central NA system is modifiable. Our findings suggest that NAT availability before intervention could help predict the amount and success of weight loss in obese individuals and help adjust treatment options individually by allowing prediction of the benefit of a dietary intervention.

68 Ga-DOTATATE PET/CT enables detection of meningioma tissue based on somatostatin receptor 2 expression. Transosseous extension of intracranial meningiomas is known to be an important risk factor for tumor recurrence and patient mortality. We analyzed the diagnostic performance of 68 Ga-DOTATATE PET/CT and contrast-enhanced MRI (CE-MRI) for the detection of osseous infiltration using qualitative and quantitative imaging parameters. Methods: In this institutional review board-approved retrospective study, subjects were selected from 327 consecutive 68 Ga-DOTATATE PET/CT examinations for evaluation of confirmed or suspected meningioma. Inclusion criteria were CE-MRI within 30 d and pathology-confirmed meningioma diagnosis with inclusion or exclusion of transosseous extension as the standard of reference. Imaging was analyzed by two readers. Tracer uptake values and meningioma volumes were determined. χ 2 , Mann-Whitney U, Wilcoxon signed rank, and McNemar tests, as well as receiver-operating-characteristic analyses, were performed to compare variables and diagnostic performance. Results: Eighty-two patients fulfilled the inclusion criteria. Patients with transosseous extension of meningioma ( n = 67) showed significantly larger lesions (median, 12.8 vs. 3.3 mL; P < 0.001) and significantly higher tracer uptake values (median SUV max , 14.2 vs. 7.6; P = 0.011) than patients with extraosseous meningiomas ( n = 15). 68 Ga-DOTATATE PET/CT in comparison to CE-MRI performed at a higher sensitivity (98.5% vs. 53.7%) while maintaining high specificity (86.7% vs. 93.3%) in the detection of osseous involvement ( P < 0.001). In receiver-operating-characteristic analysis, PET/CT assessment performed better than CE-MRI (area under the curve, 0.932 vs. 0.773). PET/CT- and CE-MRI-based volume estimation yielded comparable results for extraosseous meningiomas ( P = 0.132) and the extraosseous part of transosseous meningiomas ( P = 0.636), whereas the volume of the intraosseous part was assessed as significantly larger by PET/CT ( P < 0.001). Conclusion: 68 Ga-DOTATATE PET/CT enables improved detection of the transosseous extension of intracranial meningiomas compared with CE-MRI., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)