European Journal of Nuclear Medicine and Molecular Imaging最新文献

The recently developed metabolically more stable minigastrin derivative, DOTA-CCK-66, displayed promising preclinical data when labeled either with ⁶⁸Ga or ¹⁷⁷Lu. First positron emission tomography/computed tomography (PET/CT) imaging using [⁶⁸Ga]Ga-DOTA-CCK-66 in two patients suffering from medullary thyroid carcinoma (MTC) displayed a favorable biodistribution profile. Here, we aim to investigate the therapeutic potential of [²²⁵Ac]Ac-DOTA-CCK-66 as a targeted α-therapy (TAT) agent in a comparative treatment study of [¹⁷⁷Lu]Lu- versus [²²⁵Ac]Ac-DOTA-CCK-66.

Methods: Treatment studies were performed (3 groups, n = 5, AR42J tumor-bearing 394-NOD SCID mice). Control group animals were injected with [⁶⁸Ga]Ga-DOTA-CCK-66 (1.1 MBq, PET/CT imaging), while treatment group animals received a single dose of either [¹⁷⁷Lu]Lu-DOTA-CCK-66 (37 MBq, radioligand therapy (RLT)) or [²²⁵Ac]Ac-DOTA-CCK-66 (37 kBq, TAT). All animals' tumor volume and body weight were monitored twice a week until end-point criteria were reached. Blood samples were evaluated (VetScan VS2, Abaxis) once mice were sacrificed.

Results: Upon treatment, an initial decline in tumor volume, followed by a significantly delayed tumor growth of treated cohorts, was observed. Mean survival of ¹⁷⁷Lu- as well as ²²⁵Ac-treated animals was increased by 3- (37 ± 3 d) and 4.5-fold (54 ± 6 d), respectively, when compared to non-treated animals (12 ± 3 d). Blood sample analysis did not indicate toxic side effects to the liver, kidney, or stomach upon ¹⁷⁷Lu and ²²⁵Ac-treatment.

Conclusion: We demonstrated a substantial therapeutic efficacy of ¹⁷⁷Lu- and ²²⁵Ac-labeled DOTA-CCK-66. As expected, treatment with the latter resulted in the highest mean survival rates. These results indicate a high therapeutic potential of ²²⁵Ac-labeled DOTA-CCK-66 for TAT in MTC patient management.

Purpose: To assess the trends in administered 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) doses, computed tomography (CT) radiation doses, and image quality over the last 15 years in children with drug-resistant epilepsy (DRE) undergoing hybrid positron emission tomography (PET) brain scans.

Methods: We retrospectively analyzed data from children with DRE who had [¹⁸F]FDG-PET/CT or magnetic resonance scans for presurgical evaluation between 2005 and 2021. We evaluated changes in injected [¹⁸F]FDG doses, administered activity per body weight, CT dose index volume (CTDIvol), and dose length product (DLP). PET image quality was assessed visually by four trained raters. Conversely, CT image quality was measured using region-of-interest analysis, normalized by signal-to-noise (SNR) and contrast-to-noise ratio (CNR).

Results: We included 55 children (30 male, mean age: 9 ± 6 years) who underwent 61 [¹⁸F]FDG-PET scans (71% as PET/CT). Annually, the injected [¹⁸F]FDG dose decreased by ~ 1% (95% CI: 0.92%-0.98%, p < 0.001), with no significant changes in administered activity per body weight (p = 0.51). CTDIvol and DLP decreased annually by 16% (95% CI: 9%-23%) and 15% (95% CI: 8%-21%, both p < 0.001), respectively. PET image quality improved by 9% year-over-year (95% CI: 6%-13%, p < 0.001), while CT-associated SNR and CNR decreased annually by 7% (95% CI: 3%-11%, p = 0.001) and 6% (95% CI: 2%-10%, p = 0.008), respectively.

Conclusion: Our findings indicate stability in [¹⁸F]FDG administered activity per body weight alongside improvements in PET image quality. Conversely, CT-associated radiation doses reduced. These results reaffirm [¹⁸F]FDG-PET as an increasingly safer and higher-resolution auxiliary imaging modality for children with DRE. These improvements, driven by technological advancements, may enhance the diagnostic precision and patient outcomes in pediatric epilepsy surgery.

Purpose: Achieving endocrine remission by gross total resection is challenging in pituitary neuroendocrine tumours (PitNETs) with cavernous sinus invasion. This study aims to assess the safety, feasibility, and optimal dose for intraoperative fluorescence imaging as an added instrument to discriminate PitNET from surrounding tissue using bevacizumab-800CW, targeting vascular endothelial growth factor A (VEGF-A).

Methods: In part I, dose-escalation (0-4∙5-10-25 mg) was performed in 4 groups of 3 patients with PitNETs Knosp grade 3-4. In part II, after interim analysis, the 10 mg and 25 mg groups were expanded to a total of 6 patients. Quantitative fluoroscence molecular endoscopy consisted of wide field fluorescence molecular endoscopy and multi-diameter single fiber reflectance / single fiber fluorescence spectroscopy. Mean fluorescence intensity (MFI) of the fresh surgical specimen was calculated and VEGF-staining was performed.

Results: Eighteen patients were included. All doses were well tolerated. Three serious adverse events were registered, but none were tracer-related. Part I showed an adequate in-vivo tumour-to-background ratio for both 10 mg (TBR 2∙00 [1∙86, 2∙19]) and 25 mg (TBR 2∙10, [1∙86, 2∙58]). Part II revealed a substantially higher MFI in the 25 mg group. With both 10 mg and 25 mg a statistically significant difference between tumour and surrounding tissue was detected (p < 0∙0001). All surgical specimens had VEGF-A expression.

Conclusion: This study demonstrates the safety and feasibility of quantitative fluorescence molecular endoscopy during PitNET surgery. Both 10 mg and 25 mg bevacizumab-800CW result in clear differentiation in-vivo, with improved contrast ex-vivo (MFI) in the 25 mg group.

Trial registration: NCT04212793 / Study Details| Detection of PitNET Tissue During TSS Using Bevacizumab800CW| ClinicalTrials.gov.

Purpose: The introduction of immunotherapy in pleural mesothelioma (PM) has highlighted the need for effective outcome predictors. This study explores the role of [18F]FDG PET/CT in predicting outcomes in PM treated with immunotherapy.

Methods: Patients from the NIPU trial, receiving ipilimumab and nivolumab +/- telomerase vaccine in second-line, were included. [18F]FDG PET/CT was obtained at baseline (n = 100) and at week-5 (n = 76). Metabolic tumour volume (MTV) and peak standardised uptake value (SUV_peak) were evaluated in relation to survival outcomes. Wilcoxon rank-sum test was used to assess differences in MTV, total lesion glycolysis (TLG), maximum standardised uptake value (SUV_max) and SUV_peak between patients exhibiting an objective response, defined as either partial response or complete response according to the modified Response Criteria in Solid Tumours (mRECIST) and immune RECIST (iRECIST), and non-responders, defined as either stable disease or progressive disease as their best overall response.

Results: Univariate Cox regression revealed significant associations of MTV with OS (HR 1.36, CI: 1.14, 1.62, p < 0.001) and PFS (HR 1.18, CI: 1.03, 1.34, p = 0.02), while multivariate analysis showed a significant association with OS only (HR 1.35, CI: 1.09, 1.68, p = 0.007). While SUV_peak was not significantly associated with OS or PFS in univariate analyses, it was significantly associated with OS in multivariate analysis (HR 0.43, CI: 0.23, 0.80, p = 0.008). Objective responders had significant reductions in TLG, SUV_max and SUV_peak at week-5.

Conclusion: MTV provides prognostic value in PM treated with immunotherapy. High SUV_peak was not associated with inferior outcomes, which could be attributed to the distinct mechanisms of immunotherapy. Early reductions in PET metrics correlated with treatment response.

Study registration: The NIPU trial (NCT04300244) is registered at clinicaltrials.gov. https://classic.

Clinicaltrials: gov/ct2/show/NCT04300244?cond=Pleural+Mesothelioma&cntry=NO&draw=2&rank=4.

Purpose: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with ²²⁵Ac or ¹³¹I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB).

Methods: We studied the biodistribution and tumour uptake of [¹³¹I]I-GMIB-4AH29 and [²²⁵Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [¹³¹I]I-GMIB-4AH29 and [²²⁵Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [²²⁵Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [²²⁵Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB.

Results: The biodistribution showed high tumour uptake of [¹³¹I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [²²⁵Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [¹³¹I]I-GMIB-4AH29 or [²²⁵Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [²²⁵Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [²²⁵Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy.

Conclusion: [²²⁵Ac]Ac-DOTA-4AH29 and [¹³¹I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [²²⁵Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy.

Purpose: Epithelial cell adhesion molecule (EpCAM) is a potential therapeutic target and anchoring molecule for circulating and disseminated tumour cells (CTC/DTC) in liquid biopsy. In this study, we aimed to construct EpCAM-specific immuno-positron emission tomography (immunoPET) imaging probes and assess the diagnostic abilities in preclinical cancer models.

Methods: By engineering six single-domain antibodies (e.g., EPCD1 - 6) targeting EpCAM of different binding properties and labelling with ⁶⁸Ga (T_1/2 = 1.1 h) and ¹⁸F (T_1/2 = 110 min), we developed a series of EpCAM-targeted immunoPET imaging probes. The probes' pharmacokinetics and diagnostic accuracies were investigated in cell-derived human colorectal (LS174T) and esophageal cancer (OE19) tumour models.

Results: Based on in vitro binding affinities and in vivo pharmacokinetics of the first three tracers ([⁶⁸Ga]Ga-NOTA-EPCD1, [⁶⁸Ga]Ga-NOTA-EPCD2, and [⁶⁸Ga]Ga-NOTA-EPCD3), we selected [⁶⁸Ga]Ga-NOTA-EPCD3 for tumour imaging which showed an average tumour uptake of 2.06 ± 0.124%ID/g (n = 3) in LS174T cell-derived tumour model. Development and characterisation of [¹⁸F]AIF-RESCA-EPCD3 showed comparable tumour uptake of 1.73 ± 0.0471%ID/g (n = 3) in the same tumour model. Further validation of [⁶⁸Ga]Ga-NOTA-EPCD3 in OE19 cell-derived tumour model showed an average tumour uptake of 4.27 ± 1.16%ID/g and liver uptake of 13.5 ± 1.30%ID/g (n = 3). Near-infrared fluorescence imaging with Cy7-EPCD3 confirmed the in vivo pharmacokinetics and relatively high liver accumulation. We further synthesized another three ¹⁸F-labeled nanobody tracers ([¹⁸F]AIF-RESCA-EPCD4, [¹⁸F]AIF-RESCA-EPCD5, and [¹⁸F]AIF-RESCA-EPCD6) and found that [¹⁸F]AIF-RESCA-EPCD6 had the best pharmacokinetics with low background. [¹⁸F]AIF-RESCA-EPCD6 showed explicit uptake in the subcutaneously inoculated OE19 tumour model with an average uptake of 4.70 ± 0.26%ID/g (n = 3). In comparison, the corresponding tumour uptake (0.17 ± 0.25%ID/g, n = 3) in the EPCD6 blocking group was substantially lower (P < 0.001), indicating the targeting specificity of the tracer.

Conclusions: We developed a series of ⁶⁸Ga/¹⁸F-labeled nanobody tracers targeting human EpCAM. ImmunoPET imaging with [¹⁸F]AIF-RESCA-EPCD6 may facilitate better use of EpCAM-targeted therapeutics by noninvasively displaying the target's expression dynamics.