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Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive (90)Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose–response relationship to ultimately optimize the administered activity before treatment and image it after treatment. (90)Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging (90)Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE (90)Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose–volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10- and 13-mm diameters, consistent with its high spatial resolution and system sensitivity. The total liver-absorbed dose showed excellent agreement between the uEXPLORER and the mCT for both patients, with differences lower than 0.2%. Larger differences of up to 60% were observed when comparing the liver segment doses. All dose–volume histograms were in good agreement, with narrower tails for the uEXPLORER in all segments, indicating lower image noise. Conclusion: This patient study is compelling for the use of total-body (90)Y PET for liver dosimetry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT, especially in lower-count regions of interest, which is expected to improve dose quantification and tumor dosimetry.

The objective of this retrospective study was to determine the role of F-18-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with Lu-177- or Y-90-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both Ga-68-DOTATOC/TATE/NOC and F-18-FDG PET/CT before treatment and were followed 3-189 mo. Kaplan-Meier analysis, log-rank testing (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: One hundred ninety-nine patients (40.2%) presented with pancreatic NENs, 49 with cancer of unknown primary, and 139 with midgut NENs, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8, and in other locations in 42. F-18-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were Ga-68-DOTATOC/TATE/NOC-positive. For all patients, the median PFS and OS, defined from the start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive F-18-FDG results predicted shorter PFS (18.5 mo vs. 24.1 mo; P = 0.0015) and OS (53.2 mo vs. 83.1 mo; P

Cynthia De la Garza-Ramos,1,&ast; Cameron J Overfield,1,&ast; S Ali Montazeri,1 Harris Liou,2 Ricardo Paz-Fumagalli,1 Gregory T Frey,1 J Mark McKinney,1 Charles A Ritchie,1 Zlatko Devcic,1 Andrew R Lewis,1 Denise M Harnois,3 Tushar Patel,3 Beau B Toskich1 1Division of Interventional Radiology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Alix School of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA; 3Department of Transplant, Mayo Clinic Florida, Jacksonville, FL, USA&ast;These authors contributed equally to this workCorrespondence: Beau B ToskichDivision of Interventional Radiology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USATel +1 904-953-1496Email Toskich.Beau@mayo.eduPurpose: Transarterial radioembolization can serve as an ablative therapy for early-stage hepatocellular carcinoma (HCC). Given the volumetric variability of liver segments, this study aimed to characterize the safety of ablative radioembolization by determining percent liver treated (%LT) thresholds associated with biochemical toxicity.Patients and Methods: Patients with HCC receiving a single ablative radioembolization treatment using glass microspheres from 2017 through 2020 were reviewed. %LT was calculated as treatment angiosome volume divided by whole liver volume. Biochemical toxicities were defined as increases in Albumin-Bilirubin (ALBI) grade or Child-Pugh (CP) class compared to baseline and albumin or bilirubin adverse events (AEs) per the Common Terminology Criteria for Adverse Events. Receiver operating characteristic curves and multivariate logistic regression analyses were performed to assess the impact of %LT on toxicities.Results: Of 141 patients analyzed, 53% (n=75) were ALBI 1, 45% (n=64) ALBI 2, 79% (n=111) CP-A, and 21% (n=30) CP-B. A %LT ≥ 14.5% was associated with grade/class increases in ALBI 2 (p≤ 0.01) and CP-B patients (p=0.026). In multivariate analysis, a %LT ≥ 14.5% was an independent predictor of increases in the ALBI 2 and CP-B groups (p< 0.01). No significant %LT threshold was found for ALBI 1 and CP-A patients. No grade 3/4 albumin or bilirubin AEs were reported, while grade 2 AEs were related to an initial whole liver volume < 1.3 L (p≤ 0.01).Conclusion: Patients with ALBI 2 and CP-B liver function are less likely to have an increase in their respective grade/class when treating < 14.5% of the liver using glass microspheres. ALBI 1 and CP-A patients showed no definitive %LT threshold for biochemical toxicity within the range of this study.Keywords: hepatocellular carcinoma, radioembolization, Y-90, adverse events

Purpose: The aims of the study were: 1) to compare two phases of dual-phase cone beam computed tomography (DPCBCT) achieved before and after Yttrium-90 (90Y) administration and to evaluate additional benefits during radioembolisation (RE) procedures; and 2) to compare DP-CBCT with pre-procedure contrast enhanced cross-sectional images in terms of tumour detection. Material and methods: Twenty-three hepatocellular carcinoma patients undergoing RE treatment were scanned with DPCBCT consisting of early arterial (EA) and late arterial (LA) phases before and after 90Y administration. The CT-like datasets were compared according to embolisation effect, enhancement patterns, lesion detectability, image quality, and artifacts by two interventional radiologists blinded to each other. The compatibility of the two radiologists was evaluated with kappa statistical analysis, and the difference between EA and LA phases was evaluated with marginal homogeneity test. Also, DP-CBCT images were compared with preprocedural cross-sectional images (CT/MRI). Results: For 23 patients 92 data were acquired. Thirteen patients showed a decrease on post-embolisation images both visually and on Hounsfield unit (HU) measurements. No statistical difference was found for tumour detection between EA and LA phases (p = 1.0). Tumour enhancement was visually superior at LA phases whereas EA phases were better for arterial mapping for selective catheterisation. DP-CBCT images were not inferior to preprocedural cross-sectional imaging findings. Conclusions: DP-CBCT is a promising tool for predicting tumour response to therapy and is not inferior to preprocedural cross-sectional imaging in terms of tumour detection. It allows better assessment during RE procedures because early phases provide good mapping for superselective catheterisation whereas late phases are better for visualisation of tumour enhancement.

OBJECTIVE: When handling Y-labelled and Lu-labelled radiopharmaceuticals, skin exposure is mainly due to β-particles. This study aimed to investigate the equivalent dose saving of the staff when changing from an essentially manual radiolabelling procedure to an automatic dose dispenser (ADD). MATERIALS AND METHODS: The chemist and physician were asked to wear thermoluminescence dosimeters on their fingertips to evaluate the quantity of Hp(0.07) on the skin. Data collected were divided into two groups: before introducing ADD (no ADD) and after introducing ADD. RESULTS: For the chemist, the mean values (95th percentile) of Hp(0.07) for no ADD and ADD are 0.030 (0.099) and 0.019 (0.076) mSv/GBq, respectively, for Y, and 0.022 (0.037) and 0.007 (0.023) mSv/GBq, respectively, for Lu. The reduction for ADD was significant (t-test with P

Since prostate-specific membrane antigen (PSMA) has been identified as a diagnostic target for prostate cancer, many urea-based small PSMA-targeting molecules were developed. First, the clinical application of these Ga-68 labelled compounds in positron emission tomography (PET) showed their diagnostic potential. Besides, the therapy of prostate cancer is a demanding field, and the use of radiometals with PSMA bearing ligands is a valid approach. In this work, we describe the synthesis of a new PSMA ligand, CHX-A''-DTPA-DUPA-Pep, the subsequent labelling with Ga-68, Lu-177 and Y-90 and the first in vitro characterization. In cell investigations with PSMA-positive LNCaP C4-2 cells, KD values of ≤14.67 ± 1.95 nM were determined, indicating high biological activities towards PSMA. Radiosyntheses with Ga-68, Lu-177 and Y-90 were developed under mild reaction conditions (room temperature, moderate pH of 5.5 and 7.4, respectively) and resulted in nearly quantitative radiochemical yields within 5 min.

Rational-designed multimerization of targeting ligands can be used to improve kinetic and thermodynamic properties. Multimeric targeting ligands may be produced by tethering multiple identical or two or more monomeric ligands of different binding specificities. Consequently, multimeric ligands may simultaneously bind to multiple receptor molecules. Previously, multimerization has been successfully applied on radiolabeled RGD peptides, which resulted in an improved tumor targeting activity in animal models. Multimerization of peptide-based ligands may improve the binding characteristics by increasing local ligand concentration and by improving dissociation kinetics. Here, we present a preclinical study on a novel radiolabeled bombesin (BN) homodimer, designated In-111-DOTA-[(Aca-BN(7-14)](2), that was designed for enhanced targeting of gastrin-releasing peptide receptor (GRPR)-positive prostate cancer cells. A BN homodimer was conjugated with DOTA-NHS and labeled with In-111. After HPLC purification, the GRPR targeting ability of In-111-DOTA-[(Aca-BN(7-14)](2) was assessed by microSPECT imaging in SCUD mice xenografted with the human prostate cancer cell line PC-3. In-111 labeling of DOTA-[(Aca-BN(7-14)](2) was achieved within 30 min at 85 C with a labeling yield of >40%. High radiochemical purity (>95%) was achieved by HPLC purification. In-111-DOTA-[(Aca-BN(7-14)](2) specifically bound to GRPR-positive PC-3 prostate cancer cells with favorable binding characteristics because uptake of In-111-DOTA-[Aca-BN(7-14)](2) in GRPR-positive PC-3 cells increased over time. A maximum peak with 30% radioactivity was observed after 2 h of incubation. The log D value was -1.8 +/- 0.1. In-111-DOTA-[(Aca-BN(7-14)](2) was stable in vitro both in PBS and human serum for at least 4 days. In vivo biodistribution analysis and microSPECT/CT scans performed after 1, 4, and 24 h of injection showed favorable binding characteristics and tumor-to-normal tissue ratios. This study identifies In-111-DOTA-[(Aca-BN(7-14)](2) as a promising radiotracer for nuclear imaging of GRPR in prostate cancer.

Purpose: Positron emission tomography (PET) is a powerful tool in small animal research, enabling noninvasive quantitative imaging of biochemical processes in living subjects. However, the dosimetric characteristics of small animal PET imaging are usually overlooked, although the radiation dose may be significant. The variations of anatomical characteristics between the various computational models may result in differences in the dosimetric outcome. Methods: We used five different anatomical rat models (two stylized and three voxel based) to compare calculated absorbed fractions and S values for eight positron-emitting radionuclides (C-11, N-13, O-15, F-18, Cu-64, Ga-68, Y-86, and I-124) commonly used to label various probes for small animal PET imaging. The MCNPX radiation transport code was used for radiation dose calculations. Results: For most source/target organ pairs, O-15 and Ga-68 produce the highest self-absorbed S values because of the high-energy and high-frequency of positron emissions, while Y-86 produces the highest cross-absorbed S values because of the high energy and high frequency of γ-rays emission. Anatomical models produced from different rat strains or modeling techniques exhibit different organ masses, volumes, and thus give rise to different S values and absorbed dose. The variations of absorbed fractions between models of the same type are less than those between models with different types. The calculated S values depend strongly on organ mass, and as such, different models produce similar S values for organs of comparable masses. In most source organs presenting with high cumulated activity, the absorbed dose is less affected by model difference compared with other organs. Conclusions: The produced S values for common positron-emitting radionuclides can be exploited in the assessment of radiation dose to rats from different radiotracers used in small animal PET experiments. This work contributes to a better understanding of the influence of different computational models on small animal dosimetry

Introduction: The aim of this study was to find out if Y-90 could form a stabile complex with meso-2,3-dimercaptosuccinic acid (DMSA) and if Y-90-DMSA may have potential for tumor therapy in the palliative treatment of bone metastases. Methods: The preparing of Y-90-DMSA was carried out by varying experimental parameters, such as ligand concentration, pH, time, and temperature of the reaction, in order to maximize the labeling yield. Analysis of the complexes enclosed the radiochemical quality control (instant thin-layer chromatography, paper chromatography, and high-performance liquid chromatography), determination of pharmacokinetical parameters as well as biodistrbution study in health male Wistar rats. In vitro stability of the complexes was tested too. Results: Y-90-DMSA could be prepared in high yields ( GT 95%) under optimized conditions of reaction. Stability studies in saline and human serum in vitro showed no significant release of activity from the ligand over 24 hours and 10 days, respectively. The preliminary biodistribution results in rat at 2 hours indicated that Y-90-DMSA, at both pH levels, was significantly retained into bone. The uptake in the kidneys was lower for Y-90-DMSA at pH 8.0 then at pH 3.0. The retention in other organs was negligible. Conclusions: Y-90 complexes could be made with ease with DMSA. Y-90-DMSA was obtained in good yield and was found to be very stable. A promising biodistribution result of this complex pointed at potential in the palliative treatment of bone metastases.

Background Selective arterial radioembolisation of liver tumours has increased, because of encouraging efficacy reports; however, therapeutic parameters used in external beam therapy are not applicable for understanding and predicting potential toxicity and efficacy, necessitating further studies of the physical and biological characteristics of radioembolisation. The aim was to characterise heterogeneity in the distribution of microspheres on a therapeutically relevant geometric scale considering the range of yttrium-90 (90Y) β-particles. Methods Two patients with intrahepatic cholangiocarcinoma, marginally resectable, were treated by selective arterial embolisation with 90Y resin microspheres (SIRTEX®), followed 9 days post-infusion by resection, including macroscopic tumour tissue and surrounding normal liver parenchyma. Formalin-fixed, sectioned resected tissues were exposed to autoradiographic films, or tissue biopsies of various dimensions were punched out for activity measurements and microscopy. Results Autoradiography and activity measurements revealed a higher activity in tumour tissue compared to normal liver parenchyma. Heterogeneity in activity distribution was evident in both normal liver and tumour tissue. Activity measurements were analysed in relation to the sample mass (5 to 422 mg), and heterogeneities were detected by statistical means; the larger the tissue biopsies, the smaller was the coefficient of variation. The skewness of the activity distributions increased with decreasing biopsy mass. Conclusions The tissue activity distributions in normal tissue were heterogeneous on a relevant geometric scale considering the range of the ionising electrons. Given the similar and repetitive structure of the liver parenchyma, this finding could partly explain the tolerance of a relatively high mean absorbed dose to the liver parenchyma from β-particles.