Spleen Uptake Research Articles

Synthesis and Evaluation of 99mTc-Labeled PSMA-Targeted Tracers Based on the Lys-Urea-Aad Pharmacophore for Detecting Prostate Cancer with Single Photon Emission Computed Tomography.

Prostate-specific membrane antigen (PSMA) is a well-validated prostate cancer marker but reported PSMA-targeted tracers derived from the Lys-urea-Glu pharmacophore including the clinically validated [99mTc]Tc-EDDA/HYNIC-iPSMA have high off-target uptake in kidneys, spleen, and salivary glands. In this study, we synthesized and evaluated three novel 99mTc-labeled PSMA-targeted tracers and investigated if the tracers derived from the Lys-urea-Aad pharmacophore could have minimized uptake in off-target organs/tissues. In vitro competition binding assays showed that compared with HYNIC-iPSMA, the three novel ligands had slightly weaker PSMA binding affinity (average Ki = 3.11 vs. 8.96-11.6 nM). Imaging and ex vivo biodistribution studies in LNCaP tumor-bearing mice showed that [99mTc]Tc-EDDA/HYNIC-iPSMA and the three novel tracers successfully visualized LNCaP tumor xenografts in SPECT images and were excreted mainly via the renal pathway. The average tumor uptake at 1 h post-injection varied from 5.40 to 18.8%ID/g, and the tracers derived from the Lys-urea-Aad pharmacophore had much lower uptake in the spleen and salivary glands. Compared with the clinical tracer [99mTc]Tc-EDDA/HYNIC-iPSMA, the Lys-urea-Aad-derived [99mTc]Tc-EDDA-KL01127 had lower background uptake and superior tumor-to-background contrast ratios and is therefore promising for clinical translation to detect prostate cancer lesions with SPECT.

Reevaluación del diagnóstico y el tratamiento de las infecciones de dispositivos de electroestimulación cardiaca mediante [18F]FDG-PET/TC

Introduction and objectivesThe role of [18F]FDG-PET/CT in cardiac implantable electronic device (CIED) infections requires better evaluation, especially in the diagnosis of systemic infections. We aimed to determine the following: a) the diagnostic accuracy of [18F]FDG-PET/CT in each CIED topographical region, b) the added value of [18F]FDG-PET/CT over transesophageal echocardiography (TEE) in diagnosing systemic infections, c) spleen and bone marrow uptake in differentiating isolated local infections from systemic infections, and d) the potential application of [18F]FDG-PET/CT in follow-up. MethodsRetrospective single-center study including 54 cases and 54 controls from 2014 to 2021. The Primary endpoint was the diagnostic yield of [18F]FDG-PET/CT in each topographical CIED region. Secondary analyses described the performance of [18F]FDG-PET/CT compared with that of TEE in systemic infections, bone marrow and spleen uptake in systemic and isolated local infections, and the potential application of [18F]FDG-PET/CT in guiding cessation of chronic antibiotic suppression when completed device removal is not performed. ResultsWe analyzed 13 (24%) isolated local infections and 41 (76%) systemic infections. Overall, the specificity of [18F]FDG-PET/CT was 100% and sensitivity 85% (79% pocket, 57% subcutaneous lead, 22% endovascular lead, 10% intracardiac lead). When combined with TEE, [18F]FDG-PET/CT increased definite diagnosis o fsystemic infections from 34% to 56% (P=.04). Systemic infections with bacteremia showed higher spleen (P=.05) and bone marrow metabolism (P=.04) than local infections. Thirteen patients without complete device removal underwent a follow-up [18F]FDG-PET/CT, with no relapses after discontinuation of chronic antibiotic suppression in 6 cases with negative follow-up [18F]FDG-PET/CT. ConclusionsThe sensitivity of [18F]FDG-PET/CT for evaluating CIED infections was high in local infections but much lower in systemic infections. However, accuracy increased when [18F]FDG-PET/CT was combined with TEE in endovascular lead bacteremic infection. Spleen and bone marrow hypermetabolism could differentiate bacteremic systemic infection from local infection. Although further prospective studies are needed, follow-up [18F]FDG-PET/CT could play a potential role in the management of chronic antibiotic suppression therapy when complete device removal is unachievable.

Size effect of fluorescent thiol-organosilica particles on their distribution in the mouse spleen

We investigated the distribution of intravenously administered thiol-organosilica particle (thiol-OS) in the spleen to evaluate their size effect in mice. A single administration of particles of thiol-OS containing rhodamine B (Rh) (90, 280, 340, 450, 630, 1110, 1670, and 3030 nm in diameter) was performed. After 24 h, we conducted a combination analysis using histological studies by fluorescent microscopy and quantitative inductively coupled plasma optical emission spectrometry (ICP-OES), which revealed no clear correlation between the particle size and spleen uptake of particle weight and number per tissue weight, and the injection dose. Moreover, Rh with 450 nm diameter (Rh450) showed the highest uptake, and Rh with 340 nm diameter (Rh340) showed the lowest uptake. Histologically, large fluorescent areas in the marginal zone (MZ) and red pulp (RP) of the spleen were observed for all particle sizes, but less in the follicle of white pulp. Using combination analysis using the particle weights of ICP-OES and the fluorescent area, we compared the distributions of each particle in each region. Rh450 had the largest accumulated weight in the MZ and RP. Particles larger than Rh450 showed negative correlations between their sizes and accumulated weight in the MZ and RP. Simultaneous dual administration of particles using Rhs and thiol-OS containing fluorescein (90 nm in diameter) showed the size-dependent difference in cellular distribution and intracellular localization. Immunohistochemical staining against macrophage markers, CD169, and F4/80 showed various colocalization patterns with macrophages that uptook particles, indicating differences in particle uptake in each macrophage may have novel significance.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction and Aim: Recently, in an ancillary study of FOLL12 trial (NCT02063685), total Metabolic Tumor Volume (tMTV) assessed before treatment has been demonstrated to be an independent predictor of PFS in patients receiving frontline immune chemotherapy (1). During the segmentation procedure, it has been observed that frequently spleen MTV (sMTV) heavily influenced the tMTV value, particularly in case of diffuse spleen uptake included in tMTV calculation. High tMTV could be a negative prognostic factor as it represents the tumor burden. On this basis, the aim of the current study was to evaluate the effect of the sMTV defined on baseline PET on tMTV calculation and its impact on outcome, particularly 5y-PFS (Progression Free Survival), in follicular lymphoma patients. Methods and Results: Overall, 690 patients with baseline PET were included in the analysis, 48% were older than 60 years, 89% had stage III-IV disease and 40% had a high-risk FLIPI-2 score. Overall, the 5y-PFS was 79% (95% CI, 76%–82%). Among 690 patients 469 (67.9%) did not have spleen involvement while 128 (18.5%) and 93 (13.4%) showed focal and diffuse spleen involvement, respectively. The 5y-PFS (95% CI) according the spleen status was 67% (62–72), 58% (48–67) and 61% (49–61) in patients without, with focal and with diffuse spleen involvement, respectively (p not significant). MTV calculation was performed with a threshold of 41% for segmentation. In the whole population of 690 patients, the tMTV threshold to categorized low and high tumor burden was 224 and 194 ml with and without sMTV, respectively. Assuming 200 ml as a tMTV threshold, only 16/693 pts (2.3%) changed from low to high tumor burden when the sMTV was included in the tMTV. Including sMTV in tMTV, with a threshold of 200 ml, the 5y-PFS in patients with low and high tMTV was 73% (95% CI: 67–78) and 58% (95% CI: 53–64), respectively, with a HR of 1.83 (p < 0.001). Excluding sMTV from tMTV, the 5y-PFS in patients with low and high tMTV was 72% (95% CI: 67–77) and 58% (95% CI: 52–64) with a HR of 1.80 (p < 0.001). In the two groups, HRs values for tMTV >200 ml showed negligible difference, independently from sMTV inclusion. Conclusion: These preliminary data of the FOLL12 trial showed that tMTV correlated with outcome in terms of PFS; on the contrary the metabolic spleen status defined in the baseline PET do not seem to show any prognostic added value, neither in case of focal nor in case of diffuse uptake. Finally, the inclusion/exclusion of the sMTV into the tMTV did not significantly change either the risk classification of the patients or the outcome in terms of PFS. Larger patients population are needed to confirm these data.

Evaluation of Candidate Theranostics for 227Th/89Zr Paired Radioimmunotherapy of Lymphoma.

227Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223Ra as its first daughter. There is an ample supply of 227Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227Th4+ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability invitro and invivo. Tumor targeting of the lead 227Th-labeled compound invivo was performed in CD20-expressing models and compared with a companion 89Zr-labeled PET agent. Results: 227Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227Th-HEHA-ofatumumab showed moderate invitro stability. 227Th-DFOcyclo*-ofatumumab presented excellent 227Th labeling efficiency; however, high liver and spleen uptake was revealed invivo, indicative of aggregation. 227Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term invitro stability (<80%). 227Th-L804-ofatumumab coordinated 227Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89Zr-L804-ofatumumab, showed organ distribution matching that of 227Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89Zr/227Th quantitative imaging and α-particle therapy.

Reappraisal of [18F]FDG-PET/CT for diagnosis and management of cardiac implantable electronic device infections

Introduction and objectivesThe role of [18F]FDG-PET/CT in cardiac implantable electronic device (CIED) infections requires better evaluation, especially in the diagnosis of systemic infections. We aimed to determine the following: a) the diagnostic accuracy of [18F]FDG-PET/CT in each CIED topographical region, b) the added value of [18F]FDG-PET/CT over transesophageal echocardiography (TEE) in diagnosing systemic infections, c) spleen and bone marrow uptake in differentiating isolated local infections from systemic infections, and d) the potential application of [18F]FDG-PET/CT in follow-up. MethodsRetrospective single-center study including 54 cases and 54 controls from 2014 to 2021. The Primary endpoint was the diagnostic yield of [18F]FDG-PET/CT in each topographical CIED region. Secondary analyses described the performance of [18F]FDG-PET/CT compared with that of TEE in systemic infections, bone marrow and spleen uptake in systemic and isolated local infections, and the potential application of [18F]FDG-PET/CT in guiding cessation of chronic antibiotic suppression when completed device removal is not performed. ResultsWe analyzed 13 (24%) isolated local infections and 41 (76%) systemic infections. Overall, the specificity of [18F]FDG-PET/CT was 100% and sensitivity 85% (79% pocket, 57% subcutaneous lead, 22% endovascular lead, 10% intracardiac lead). When combined with TEE, [18F]FDG-PET/CT increased definite diagnosis o fsystemic infections from 34% to 56% (P=.04). Systemic infections with bacteremia showed higher spleen (P=.05) and bone marrow metabolism (P=.04) than local infections. Thirteen patients without complete device removal underwent a follow-up [18F]FDG-PET/CT, with no relapses after discontinuation of chronic antibiotic suppression in 6 cases with negative follow-up [18F]FDG-PET/CT. ConclusionsThe sensitivity of [18F]FDG-PET/CT for evaluating CIED infections was high in local infections but much lower in systemic infections. However, accuracy increased when [18F]FDG-PET/CT was combined with TEE in endovascular lead bacteremic infection. Spleen and bone marrow hypermetabolism could differentiate bacteremic systemic infection from local infection. Although further prospective studies are needed, follow-up [18F]FDG-PET/CT could play a potential role in the management of chronic antibiotic suppression therapy when complete device removal is unachievable.

Ultrasound-Responsive Biomimetic Superhydrophobic Drug-Loaded Mesoporous Silica Nanoparticles for Treating Prostate Tumor.

Interfacial nanobubbles on a superhydrophobic surface can serve as ultrasound cavitation nuclei for continuously promoting sonodynamic therapy, but their poor dispersibility in blood has limited their biomedical application. In this study, we proposed ultrasound-responsive biomimetic superhydrophobic mesoporous silica nanoparticles, modified with red blood cell membrane and loaded with doxorubicin (DOX) (F-MSN-DOX@RBC), for RM-1 tumor sonodynamic therapy. Their mean size and zeta potentials were 232 ± 78.8 nm and -35.57 ± 0.74 mV, respectively. The F-MSN-DOX@RBC accumulation in a tumor was significantly higher than in the control group, and the spleen uptake of F-MSN-DOX@RBC was significantly reduced in comparison to that of the F-MSN-DOX group. Moreover, the cavitation caused by a single dose of F-MSN-DOX@RBC combined with multiple ultrasounds provided continuous sonodynamic therapy. The tumor inhibition rates in the experimental group were 71.5 8 ± 9.54%, which is significantly better than the control group. DHE and CD31 fluorescence staining was used to assess the reactive oxygen species (ROS) generated and the broken tumor vascular system induced by ultrasound. Finally, we can conclude that the combination of anti-vascular therapy, sonodynamic therapy by ROS, and chemotherapy promoted tumor treatment efficacy. The use of red blood cell membrane-modified superhydrophobic silica nanoparticles is a promising strategy in designing ultrasound-responsive nanoparticles to promote drug-release.

Abstract 3579: Assessment of target-mediated biodistribution of an 89Zr labeled PD-L1/4-1BB bispecific Mabcalin protein

Abstract Background: PRS-344/S095012 is a novel 4-1BB (CD137) and programmed death-ligand 1 (PD-L1) bispecific antibody-Anticalin® fusion protein (MabcalinTM protein) designed to cluster 4-1BB on activated T cells exclusively in the presence of PD-L1 expressing cells. We aimed to study PRS-344/S095012 in vivo biodistribution and pharmacokinetics with 89Zr-positron emission tomography (PET) at a dose with antitumoral activity in mice and evaluate the contribution of each targeting arm. Methods: PRS-344/S095012 lacks cross-reactivity to murine 4-1BB and PD-L1. To explore the PRS-344/S095012 biodistribution in a humanized 4-1BB knock-in mouse model, we synthesized the surrogate 89Zr-Atezo-J10 with the same 4-1BB building block and cross-reactivity to murine PD-L1. Humanized 4-1BB knock-in C57BL/6J (h4-1BB KI B6) and C57BL/6J (B6) mice (n=4-6 per group) were subcutaneously engrafted with murine wildtype MC38 colon adenocarcinoma cells. Tumors were grown to a minimum of ≥50 mm3 (average 163 mm3) before tracer injection. Mice received intravenously 30 µg (2.5 MBq) of 89Zr-PRS-344/S095012 or 89Zr-Atezo-J10 supplemented with PRS-344/S095012 or Atezo-J10 up to 10 mg/kg. Four mice groups were formed to distinguish between bispecific (Atezo-J10 in h4-1BB KI B6), monospecific PD-L1 (Atezo-J10 in B6), monospecific 4-1BB (PRS-344/S095012 in h4-1BB KI B6), and isotype (PRS-344/S095012 in B6) binding up to 4 days post-injection (pi). In addition, a fifth group (5 MBq 89Zr-Atezo-J10) was studied to visualize the bispecific biodistribution up to 7 days pi. At days 1, 2, 4, or 2, 4, 7 pi, mice underwent serial PET imaging to obtain mean and maximum standardized uptake (SUVmean/max) and retro-orbital blood sampling, followed by ex vivo biodistribution. Results: PET imaging showed 89Zr-Atezo-J10 specific tumor accumulation with higher tumor-to-blood ratios of respectively 2.2-, 2.6-, and 2.4-fold (p&amp;lt;0.01) at 4 days pi compared to monospecific binding of PD-L1, 4-1BB, and isotype. The ex vivo biodistribution demonstrated the same trend with respectively 4.2-, 5.5-, and 6.8-fold (p&amp;lt;0.01) increase in tumor-to-blood uptake for 89Zr-Atezo-J10 versus monospecific binding of PD-L1, 4-1BB, and isotype 89Zr-Atezo-J10 spleen uptake was comparable (ns) with monospecific binding of PD-L1 but elevated (p&amp;lt;0.01) compared to 4-1BB or isotype distribution. The uptake in lymph nodes (axillary, cervical, tumor-draining, and mesenteric) did not differ between the groups. Conclusion: 89Zr-Atezo-J10 specific accumulation in PD-L1 expressing tumors is due to both PD-L1 and 4-1BB binding and is higher than with PD-L1 and 4-1BB mono-targeting. This preclinical study supports the clinical evaluation of 89Zr-PRS-344/S095012’s whole-body distribution and the development of tumor-specific 4-1BB targeting bispecifics. Citation Format: Claudia A. van Winkel, Xiaoyu Fan, Danique Giesen, Glenn Gauderat, Lucia Pattarini, Thomas Jaquin, Anissa Barakat, Anne-Marie De La Bigne, Marleen Richter, Nicole Andersen, Julie Legrand, Helene Lelièvre, Elisabeth G. de Vries, Aizea Morales-Kastresana, Marjolijn N. Lub- de Hooge. Assessment of target-mediated biodistribution of an 89Zr labeled PD-L1/4-1BB bispecific Mabcalin protein. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3579.

Metabolic patterns on [18F]FDG PET/CT in patients with unresectable stage III NSCLC undergoing chemoradiotherapy ± durvalumab maintenance treatment

PurposeIn patients with unresectable stage III non-small-cell lung cancer (NSCLC), durvalumab maintenance treatment after chemoradiotherapy (CRT) significantly improves survival. So far, however, metabolic changes of tumoral lesions and secondary lymphoid organs under durvalumab are unknown. Hence, we assessed changes on [18F]FDG PET/CT in comparison to patients undergoing CRT alone.MethodsForty-three patients with [18F]FDG PET/CT both before and after standard CRT for unresectable stage III NSCLC were included, in 16/43 patients durvalumab maintenance treatment was initiated (CRT-IO) prior to the second PET/CT. Uptake of tumor sites and secondary lymphoid organs was compared between CRT and CRT-IO. Also, readers were blinded for durvalumab administration and reviewed scans for findings suspicious for immunotherapy-related adverse events (irAE).ResultsInitial uptake characteristics were comparable. However, under durvalumab, diverging metabolic patterns were noted: There was a significantly higher reduction of tumoral uptake intensity in CRT-IO compared to CRT, e.g. median decrease of SUVmax –70.0% vs. –24.8%, p = 0.009. In contrast, the spleen uptake increased in CRT-IO while it dropped in CRT (median + 12.5% vs. –4.4%, p = 0.029). Overall survival was significantly longer in CRT-IO compared to CRT with few events (progression/death) noted in CRT-IO. Findings suggestive of irAE were present on PET/CT more often in CRT-IO (12/16) compared to CRT (8/27 patients), p = 0.005.ConclusionDurvalumab maintenance treatment after CRT leads to diverging tumoral metabolic changes, but also increases splenic metabolism and leads to a higher proportion of findings suggestive of irAE compared to patients without durvalumab. Due to significantly prolonged survival with durvalumab, survival analysis will be substantiated in correlation to metabolic changes as soon as more clinical events are present.

Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [18F]LUZ5-d8.

The development of cannabinoid receptor type 2 (CB2R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB2R radioligands, a carborane moiety was used as a bioisostere. Here we report the synthesis and characterization of carborane-based 1,8-naphthyridinones and thiazoles as novel CB2R ligands. All tested compounds showed low nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide (LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity CB2R ligands, while the in vivo pharmacology still needs to be addressed.

A physiologically based pharmacokinetic model for [68Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients

BackgroundLittle is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various 68Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed.MethodsA PBPK model was developed for [68Ga]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect.ResultsData of 39 and 59 patients receiving [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than ~ 550 mL.ConclusionThe developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [68Ga]Ga-DOTATATE and [68Ga]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant.

СИНТЕЗ И ДОКЛИНИЧЕСКАЯ ОЦЕНКА ВИЗУАЛИЗАЦИОННЫХ ВОЗМОЖНОСТЕЙ 99mТс-ДТПА-ГДОФ КАК НОВОГО ОТЕЧЕСТВЕННОГО ГЕПАТОТРОПНОГО ПРЕПАРАТА ДЛЯ СЦИНТИГРАФИЧЕСКИХ И ОФЭКТ-ИССЛЕДОВАНИЙ

Purpose: Was to obtain a radiopharmaceutical (RPH) ‒ 99mTc bound with DTPA-GDOF (2-(2-carboxymethyl-(4-hexa-decyloxyphenyl-carbamoyl-methyl)-aminoethyl)-aminoethyl-(4-hexadecyl-oxyphenyl-carbamoyl methyl)-aminoacetic acid) and evaluate in an in vivo experiment on laboratory rats the possibility of using as hepatotropic RPH for scintigraphy and SPECT. Material and methods: The synthesis of DTPA-GDOF was carried out according to the original method of M.L. Belyanin e.a. at the N.M. Kizhner Center of TPU, by the interaction of 4-hexadecyloxyaniline with diethylenetriaminopentaacetic acid (d-DTPA) anhydride in dimethylformamide medium. Then 2 mg of GDOF-DTPA powder was mixed with 0.5 ml of 5 % sodium bicarbonate solution and heated to 100 oC until completely dissolved. 2 mg of tin dichloride powder were added to the solution, stirred and incubated at 25 oC for at least 20 minutes. The resulting solution was mixed with 99mTc eluate with an activity of 3 MBq and incubated for 10 min at 25 oC. Control of the labelling efficiency of 99mTc with DTPA-GDOF was carried out by chromatography on paper, according to the method of Zimmer and Pavel (1977). An in vivo study of the absorption kinetics of 99mTc-DTPA-GDOF was performed on male rats of the Wistar line (n = 12) 300–350 g. 99mTc-DTPA-GDOF at a dosage of 0.025 mmol/kg, 3 MBq was injected into the femoral vein. All scans are performed using the SPECT/CT Siemens Symbia T. Dynamic planar study included recording 4 sec/frame for the first two minutes, 128 × 128 pixels, and then up to 20 min – as 15 s/frame, followed by a SPECT/CT of the whole body. The value of the fraction of extraction (retention) of RPH in the liver was calculated. The values of the organ accumulation of RPH were determined as the organ fraction of uptake of the agent relative to the total dose administered to the animal Results. The labeling efficiency of DTPA-GDOF with 99mTc in fresh eluate of a standard molybdenum generator was in all cases more than 94 % (on average 95.6 ± 2.1 %, thus the proportion of free technetium was up to 4‒4.5 %). When storing 99mTc-DTPA-GDOF at room temperature on a shelf for up to 5 hours, the release of 99mTc-from the complex with DTPA-GDOF did not exceed 3.1 ± 0.3 %. The extraction fraction of 99mTc-DTPA-GDOF in the liver is as high as 0.78 ± 0.04. The fraction of the injected dose taken up by the liver is up to 70 % (68.9 ± 8.9). The quota of the spleen uptake is 14.1 ± 4.2 %. The level of accumulation of 99mTc-DTPA-GDOF in the liver was then maintained steadily without a significant decrease for up to 16‒18 hours. Conclusion: The 99mTc-DTPA-GDOF complex is a original RFP, with a high 99mTc labeling efficiency, long-lasting stability after labelling, and providing in vivo highly specific long-term imaging of the liver and spleen with gamma scintigraphy and SPECT.

Enhanced Efficacy of Radiopharmaceuticals When Using Technetium-99m-Labeled Liposomal Agents: Synthesis and Pharmacokinetic Properties.

Challenges posed by the retention of radiopharmaceuticals in unintended organs affect the quality of patient procedures when undergoing diagnostics and therapeutics. The aim of this study was to formulate a suitable tracer encapsulated in liposomes using different techniques and compounds to enhance the stability, uptake, clearance, and cytotoxic effect of the radiopharmaceutical. Cationic liposomes were prepared by a thin-film method using dipalmitoyl phosphatidylcholine (DPPC) and cholesterol. Whole-body gamma camera images were acquired of intravenously injected New Zealand rabbits. Additionally, liposomes were assessed using stability, toxicity, zeta potential, and particle size tests. In the control cases, Technetium-99m (99mTc)-sestamibi exhibited the lowest heart uptake the blood pool and delayed images compared to both 99mTc-liposomal agents. Liver and spleen uptake in the control samples with 99mTc-sestamibi increased in 1-h-delayed images, unlike with 99mTc-liposomal agents, which were decreased in delayed images. The mean maximum count in the bladder for 99mTc-sestamibi loaded liposomes 1 h post-injection was 2354.6 (±2.6%) compared to 178.4 (±0.54%) for 99mTc-sestamibi without liposomes. Liposomal encapsulation reduced the cytotoxic effect of the sestamibi. 99mTc-MIBI-cationic liposomes exhibited excellent early uptake and clearance compared to 99mTc-MIBI without liposomes. Adding cholesterol during liposome formation enhanced the stability and specificity of the targeted organs.

18F]FDG PET/CT in Patients Affected by SARS-CoV-2 and Lymphoproliferative Disorders and Treated with Tocilizumab.

Interstitial pneumonia is a severe complication induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Several treatments have been proposed alone or, more often, in combination, depending, also, on the presence of other organ disfunction. The most frequently related, well-described, and associated phenomenon is pan-lymphopenia with circulating, high levels of cytokines. We report, here, on two patients with COVID-19 and lymphoproliferative disorders treated with Tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor) and followed by an [18F]FDG PET/CT to early evaluate the therapy's efficacy. One patient with angioimmunoblastic T-lymphoma (A), one with Hodgkin lymphoma (A), and both with positive RT-PCR for SARS-CoV-2 and with similar clinical findings of interstitial pneumonia at the CT scan, were imaged by [18F]FDG PET/CT before and 14 days after a single dose of Tocilizumab. In both patients, the basal [18F]FDG PET/CT showed a diffused lung parenchyma uptake, corresponding to the hyperdense areas at the CT scan. After 2 weeks of a Tocilizumab infusion, patient B had an improvement of symptoms, with normalization of the [18F]FDG uptake. By contrast, patient A, who was still symptomatic, showed a persisting and abnormal distribution of [18F]FDG. Interestingly, both patients showed a low bone marrow uptake of [18F]FDG at the diagnosis and after 15 days, while the spleen uptake was low only in lymphopenic patient A; both are indirect signs of an immune deficiency. In conclusion, in these two patients, interstitial pneumonia was efficiently treated with Tocilizumab, as demonstrated by the [18F]FDG PET/CT. Our results confirm that interleukin-6 (IL6) has a role in the COVID-19 disease and that anti-cytokine treatment can also be performed in patients with lymphoproliferative disorders.

18F-FDG-based radiomics and machine learning: a useful help for aortic prosthetic valve infective endocarditis diagnosis?

Abstract Introduction FDG PET/CT allows for a better sensitivity in the prosthetic valve endocartitis (PVE) diagnostic when integrated to ESC 2015 criteria, but visual image analysis results in a weaker specificity and is subject to an inter-observer variability. We therefore aimed to evaluate the interest of quantitative analysis using radiomics and machine learning of FDG PET/CT scans in the PVE diagnostic. Material and methods Between 2015 and 2021, patients referred for a FDG PET/CT in our nuclear medicine department with suspected PVE were retrospectively included. The initial development of the model was focused on aortic prosthetic valve (aPV). The aPV was segmented and 31 radiomics features were extracted using the IBSI compliant PyRadiomics framework. Radiomics features were first tested by shuffling 50 times the signal within the aortic segmentation and non-contributive (i.e. identical results within 2×1,96σ over 50 iterations) were excluded. Correlated features were further removed using the variable inflation factor blinded to outcome and remaining features were standardized. Four machine learning algorithms (Ridge and LASSO logistic regression, support vector classifier and random forest) were evaluated and tuned through the use of a training database of patients with aPV included from 2015 to 2019 (excluding positive patient with a mitral and aortic valve). The procedure was further tested through 100 loops on an additional cohort of patients with only aPV included after 2019. ROC curves were subsequently computed and sensitivity was derived based on a fixed specificity of 0.7. Gold standard consisted in an expert consensus from the Endocarditis team. Primary objective was to assess the diagnostic performances of our combined approach using radiomics features and clinical features related to the PET exam (i.e time between aPV implantation and FDG PET/CT, time between antibiotics initiation and FDG PET/CT, extracardiac positive foci, spleen uptake and bone marrow uptake greater than liver uptake). Results 108 patients were included, for a total of 65 definite PVE and 43 rejected PVE according to the expert consensus. The four algorithms were trained on a total of 68 patients and further tested on a cohort of 40 patients. The performance metrics are reported in the table. Support vector classifier achieved the best scores with an AUC of 0.79±0.01 (sensitivity 0.74±0.03; specificity 0.7). When adding clinical features, AUC was 0.82±0.02 (sensitivity 0.78±0.02; specificity 0.7). Conclusion When analyzed with our machine learning-based algorithms, FDG PET/CT reached acceptable diagnostic performances in terms of sensitivity for a specificity corresponding to the results reported by the ENDOPET study (1). These preliminary results obtained on a small test dataset suggest that an artificial intelligence-based algorithm may then guide the final diagnosis especially in this area of subjective visual assessment of PVE. Funding Acknowledgement Type of funding sources: None.

PET/CT-Based Characterization of 18F-FDG Uptake in Various Tissues Reveals Novel Potential Contributions to Coronary Artery Disease in Psoriatic Arthritis

Background and ObjectivesPsoriasis is a heterogeneous inflammatory disease that involves the skin, joints, liver, heart, and other organs. Psoriatic arthritis (PsA) is associated with cardiovascular disease (CVD), but the relative contributions of inflammatory and metabolic dysregulation to CVD are incompletely understood. We set out to discover novel potential contributors to CVD in PsA patients by comprehensively phenotyping a cohort of PsA patients using these advanced technologies.MethodsIn this cross-sectional analysis of a cohort study, we investigated associations of systemic inflammation and metabolic dysregulation with Coronary CT angiography (CCTA)-proven coronary artery disease (CAD) in 39 subjects with PsA. We measured traditional CVD risk factors [blood pressure, Body Mass Index (BMI), diabetes, age, sex, smoking], serum markers of systemic inflammation (hsCRP, GlycA) and metabolic dysfunction (cholesterol efflux capacity), and inflammatory cytokines (IL-1β, IL-6, IL-12/IL-23, IL-17A, TNF-α, IFN-γ). We also incorporated radiographic measures of metabolic dysfunction (visceral and subcutaneous adipose volume) and tissue-specific inflammation (positron emission tomography-computed tomography, PET-CT). To quantify relative contributions of FDG (fluorodeoxyglucose) uptake and adiposity to coronary plaque, we performed multiple linear regression, controlling for Framingham risk score (FRS) and FRS + visceral adiposity.ResultsCompared with non-psoriatic volunteers, subjects with PsA had elevated markers of metabolic and inflammatory disease, which was more pronounced in subjects with moderate-to-severe skin disease. This included visceral (p = 0.005) and subcutaneous (p = 0.004) adiposity, BMI (p = 0.001), hemoglobin A1C (p = 0.037), high sensitivity C-reactive protein (p = 0.005), IL-6 (p = 0.003), IFN-γ (p = 0.006), and liver FDG uptake (p = 0.03). In subjects with PsA, visceral adiposity correlated significantly with subclinical CAD (standardized β = 0.681, p = 0.002), as did FDG uptake in bone marrow (standardized β = 0.488, p = 0.008), liver (standardized β = 0.619, p < 0.001), spleen (standardized β = 0.523, p = 0.004), and subcutaneous adipose (standardized β = 0.524, p = 0.003).InterpretationTogether, these findings reveal inflammatory and metabolic potential contributors to subclinical CAD in PsA, including adipose inflammation, and suggesting novel targets for CVD prevention and treatment in PsA.

Biodistribution of Intra-Arterial and Intravenous Delivery of Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in a Rat Model to Guide Delivery Strategies for Diabetes Therapies.

Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) have become an emerging strategy for treating various autoimmune and metabolic disorders, particularly diabetes. Delivery of UC-MSC-EVs is essential to ensure optimal efficacy of UC-MSC-EVs. To develop safe and superior EVs-based delivery strategies, we explored nuclear techniques including positron emission tomography (PET) to evaluate the delivery of UC-MSC-EVs in vivo. In this study, human UC-MSC-EVs were first successfully tagged with I-124 to permit PET determination. Intravenous (I.V.) and intra-arterial (I.A.) administration routes of [124I]I-UC-MSC-EVs were compared and evaluated by in vivo PET-CT imaging and ex vivo biodistribution in a non-diabetic Lewis (LEW) rat model. For I.A. administration, [124I]I-UC-MSC-EVs were directly infused into the pancreatic parenchyma via the celiac artery. PET imaging revealed that the predominant uptake occurred in the liver for both injection routes, and further imaging characterized clearance patterns of [124I]I-UC-MSC-EVs. For biodistribution, the uptake (%ID/gram) in the spleen was significantly higher for I.V. administration compared to I.A. administration (1.95 ± 0.03 and 0.43 ± 0.07, respectively). Importantly, the pancreas displayed similar uptake levels between the two modalities (0.20 ± 0.06 for I.V. and 0.24 ± 0.03 for I.A.). Therefore, our initial data revealed that both routes had similar delivery efficiency for [124I]I-UC-MSC-EVs except in the spleen and liver, considering that higher spleen uptake could enhance immunomodulatory application of UC-MSC-EVs. These findings could guide the development of safe and efficacious delivery strategies for UC-MSC-EVs in diabetes therapies, in which a minimally invasive I.V. approach would serve as a better delivery strategy. Further confirmation studies are ongoing.

Relationship between Biodistribution and Tracer Kinetics of 11C-Erlotinib, 18F-Afatinib and 11C-Osimertinib and Image Quality Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis in Advanced Stage Non-Small Cell Lung Cancer Patients.

Background: Patients with non-small cell lung cancer (NSCLC) driven by activating epidermal growth factor receptor (EGFR) mutations are best treated with therapies targeting EGFR, i.e., tyrosine kinase inhibitors (TKI). Radiolabeled EGFR-TKI and PET have been investigated to study EGFR-TKI kinetics and its potential role as biomarker of response in NSCLC patients with EGFR mutations (EGFRm). In this study we aimed to compare the biodistribution and kinetics of three different EGFR-TKI, i.e., 11C-erlotinib, 18F-afatinib and 11C-osimertinib. Methods: Data of three prospective studies and 1 ongoing study were re-analysed; data from thirteen patients (EGFRm) were included for 11C-erlotinib, seven patients for 18F-afatinib (EGFRm and EGFR wild type) and four patients for 11C-osimertinib (EGFRm). From dynamic and static scans, SUV and tumor-to-blood (TBR) values were derived for tumor, lung, spleen, liver, vertebra and, if possible, brain tissue. AUC values were calculated using dynamic time-activity-curves. Parent fraction, plasma-to-blood ratio and SUV values were derived from arterial blood data. Tumor-to-lung contrast was calculated, as well as (background) noise to assess image quality. Results: 11C-osimertinib showed the highest SUV and TBR (AUC) values in nearly all tissues. Spleen uptake was notably high for 11C-osimertinib and to a lesser extent for 18F-afatinib. For EGFRm, 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-lung contrast, compared to an inverse contrast observed for 11C-osimertinib. Tumor-to-lung contrast and spleen uptake of the three TKI ranked accordingly to the expected lysosomal sequestration. Conclusion: Comparison of biodistribution and tracer kinetics showed that 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-background contrast in EGFRm positive tumors. Image quality, based on contrast and noise analysis, was superior for 11C-erlotinib and 18F-afatinib (EGFRm) scans compared to 11C-osimertinib and 18F-afatinib (EGFR wild type) scans.

Evaluation of Spleen Function in Renal Transplant Patients and Controls by Liver-Spleen Scanning Using Qualitative and Quantitative Methods

Objective: The purpose of this study was to compare renal transplant recipients healthy controls, in order to find scintigraphic signs of hyposplenism or hypersplenism by using qualitative and quantitative liver-spleen scan parameters. Material and Methods: Scanning parameters were evaluated in 88 renal transplant recipients and 59 controls after administration of 5-mCi of 99mTc-stannous colloid. Spleen uptake was characterized as normal, low, or high in comparison to the liver and bone marrow pattern uptake was described as normal or high. The images were drawn over the liver and spleen for counting scintillations and measuring the area. Spleen/liver ratio from controls was correlated with qualitative spleen uptake of renal transplant recipients. Immunosuppressive regimens consisted of combinations of azathioprine or mycophenolate mofetil and rapamycin, tacrolimus or cyclosporine. Results: renal transplant recipients took up more radiocolloid and had larger livers and spleens than controls. Cases of lower (hyposplenism) and higher (hypersplenism) uptake in the spleen were more frequent in renal transplant recipients than in controls. There was a good correlation between spleen uptake of renal transplant recipients and spleen/liver ratio of controls. Discussion: renal transplant recipients liver and spleen took up more radiocolloid consistent with their enlarged state, likely due to activation of the mononuclear phagocyte system, probably by repeated exposure to infection. Low and high splenic uptake were found in renal transplant recipients, these findings are consistent with diagnosis of hyposplenism and hypersplenism respectively. Quantitative methods validated visual assessment.

PET Imaging of Small Extracellular Vesicles via [89Zr]Zr(oxinate)4 Direct Radiolabeling.

Exosomes or small extracellular vesicles (sEVs) are increasingly gaining attention for their potential as drug delivery systems and biomarkers of disease. Therefore, it is important to understand their in vivo biodistribution using imaging techniques that allow tracking over time and at the whole-body level. Positron emission tomography (PET) allows short- and long-term whole-body tracking of radiolabeled compounds in both animals and humans and with excellent quantification properties compared to other nuclear imaging techniques. In this report, we explored the use of [89Zr]Zr(oxinate)4 (a cell and liposome radiotracer) for direct and intraluminal radiolabeling of several types of sEVs, achieving high radiolabeling yields. The radiosynthesis and radiolabeling protocols were optimized for sEV labeling, avoiding sEV damage, as demonstrated using several characterizations (cryoEM, nanoparticle tracking analysis, dot blot, and flow cytometry) and in vitro techniques. Using pancreatic cancer sEVs (PANC1) in a healthy mouse model, we showed that it is possible to track 89Zr-labeled sEVs in vivo using PET imaging for at least up to 24 h. We also report differential biodistribution of intact sEVs compared to intentionally heat-damaged sEVs, with significantly reduced spleen uptake for the latter. Therefore, we conclude that 89Zr-labeled sEVs using this method can reliably be used for in vivo PET tracking and thus allow efficient exploration of their potential as drug delivery systems.