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Purpose: This retrospective analysis evaluates baseline 18 F-flotufolastat positron emission tomography (PET) parameters as prognostic parameters for treatment response and outcome in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing treatment with [ 177 Lu]Lu-PSMA-I&T., Methods: A total of 188 mCRPC patients with baseline 18 F-flotufolastat PET scans were included. Tumor lesions were semiautomatically delineated, with imaging parameters including volume-based and standardized uptake value (SUV)-based metrics. Outcome measures included prostate-specific antigen (PSA) response, PSA-progression-free survival (PSA-PFS), and overall survival (OS). Univariate and multivariate regression analyses assessed the impact of baseline imaging and pretherapeutic clinical parameters on outcome. Event time distributions were estimated with the Kaplan-Meier method, and groups were compared with log-rank tests., Results: Significant prognostic parameters for PSA response and PSA-PFS included log-transformed whole-body SUVmax (odds ratio (OR), 3.26, 95% confidence interval (CI), 2.01-5.55 and hazard ratio (HR), 0.51, 95% CI, 0.4-0.66; both p < 0.001) and prior chemotherapy (OR 0.3, 95% CI, 0.12-0.72 and HR 1.64, 95% CI, 1.07-2.58; p = 0.008 and p = 0.028, respectively). For OS, significant prognosticators were the following log-transformed parameters: number of lesions (HR 1.38, 95% CI, 1.24-1.53; p < 0.001), TTV (HR 1.27, 95% CI, 1.18-1.37; p < 0.001), and ITLV (HR 1.24, 95% CI, 1.16-1.33; p < 0.001), with log-transformed TTV (HR 1.15, 95% CI, 1.04-1.27; p = 0.008) remaining significant in multivariate analysis., Conclusion: At baseline, SUV-based 18 F-flotufolastat PET metrics (e.g., whole-body SUVmax) serve as significant positive prognosticators for short-term outcomes (PSA response and PSA-PFS). In contrast, volume-based metrics (e.g., TTV) are significant negative prognosticators for long-term outcome (OS), in mCRPC patients treated with [ 177 Lu]Lu-PSMA-I&T., Competing Interests: Declerations. Ethics approval and consent to participate: The institutional ethics committee of the Technical University of Munich approved this retrospective analysis under the reference number 115/18S. We certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants. Consent for publication: Not applicable. Competing interests: ME&IR report fees from Blue Earth Diagnostics Ltd. (consultant, research funding). ME reports fees from Novartis/AAA (consultant, speaker), Telix (consultant), Bayer (consultant, research funding), RayzeBio (consultant), Point Biopharma (consultant), Eckert-Ziegler (speaker), ABX GmbH (speaker) and Janssen Pharmaceuticals (consultant, speakers bureau), Parexel (image review) and Bioclinica (image review) outside the submitted work and a patent application for rhPSMA. He and other inventors are entitled to royalties on sales of 18F-flotufolastat. WW reports research support from BlueEarth Diagnostics, ITM, Novartis, and Pentixapharm. He has also acted as consultant for these companies. WW is an Associate Editor of EJNMMI. RT: Advisory boards, speaking fees; travel support, conference access; author fees; shares: Astellas, AstraZeneca, Bayer, BMS, Eisai, EUSA, Ipsen, Janssen, Merck, MSD, Novartis, Orion, Philogen, Roche, Sanofi, Thieme. No other potential conflicts of interest relevant to this article exist., (© 2024. The Author(s).)

Background and Objective: Treatment planning through the diagnostic dimension of theranostics provides insights into predicting the absorbed dose of RPT, with the potential to individualize radiation doses for enhancing treatment efficacy. However, existing studies focusing on dose prediction from diagnostic data often rely on organ-level estimations, overlooking intra-organ variations. This study aims to characterize the intra-organ theranostic heterogeneity and utilize artificial intelligence techniques to localize them, i.e. to predict voxel-wise absorbed dose map based on pre-therapy PET., Methods: 23 patients with metastatic castration-resistant prostate cancer treated with [ 177 Lu]Lu-PSMA I&T RPT were retrospectively included. 48 treatment cycles with pre-treatment PET imaging and at least 3 post-therapeutic SPECT/CT imaging were selected. The distribution of PET tracer and RPT dose was compared for kidney, liver and spleen, characterizing intra-organ heterogeneity differences. Pharmacokinetic simulations were performed to enhance the understanding of the correlation. Two strategies were explored for pre-therapy voxel-wise dosimetry prediction: (1) organ-dose guided direct projection; (2) deep learning (DL)-based distribution prediction. Physical metrics, dose volume histogram (DVH) analysis, and identity plots were applied to investigate the predicted absorbed dose map., Results: Inconsistent intra-organ patterns emerged between PET imaging and dose map, with moderate correlations existing in the kidney (r = 0.77), liver (r = 0.5), and spleen (r = 0.58) (P < 0.025). Simulation results indicated the intra-organ pharmacokinetic heterogeneity might explain this inconsistency. The DL-based method achieved a lower average voxel-wise normalized root mean squared error of 0.79 ± 0.27%, regarding to ground-truth dose map, outperforming the organ-dose guided projection (1.11 ± 0.57%) (P < 0.05). DVH analysis demonstrated good prediction accuracy (R 2  = 0.92 for kidney). The DL model improved the mean slope of fitting lines in identity plots (199% for liver), when compared to the theoretical optimal results of the organ-dose approach., Conclusion: Our results demonstrated the intra-organ heterogeneity of pharmacokinetics may complicate pre-therapy dosimetry prediction. DL has the potential to bridge this gap for pre-therapy prediction of voxel-wise heterogeneous dose map., (© 2024. The Author(s).)

Purpose: Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure., Methods: A pilot study was conducted in 12 patients (age range 64-86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter 213 Bi coupled to an anti-EGFR antibody (366-821 MBq). The primary aims of the study were to determine the feasibility of treatment with the 213 Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter., Results: The study proved that intravesical instillation of the 213 Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment., Conclusion: Intravesical instillation of 213 Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the 213 Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.

Purpose: Integrins are transmembrane receptors responsible for cell-cell adhesion and cell-extracellular matrix binding and play an important role in angiogenesis and tumour metastasis. For this reason, integrins are increasingly used as targets for molecular imaging. Up to now interest has mostly been focused on the integrin subtype αvβ3. However, targeting of other subtypes such as the integrin α5β1 is also of high interest due to its central role in colonization of metastatic cells, resistance of tumour cells to chemotherapy and ionizing radiation, and tumour aggressiveness. Recently, a highly active antagonist ligand (2,2'-(7-(1-carboxy-4-((6-((3-(4-(((S)-1-carboxy-2-(2-(3-guanidinobenzamido)acetamido)ethyl)carbamoyl)-3,5-dimethylphenoxy)propyl)amino)-6-oxohexyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid, FR366) for the integrin subtype α5β1 with high selectivity versus αvβ3, has been developed and tested successfully in preliminary in vitro and in vivo experiments. Here, we present our results of an investigation of the use of (68)Ga-labelled α5β1 ligand in PET imaging., Methods: The free α5β1 peptidomimetic ligand was functionalized with a spacer (6-aminohexanoic acid) and the bifunctional chelator 1-((1,3-dicarboxy)propyl)-4,7-(carboxymethyl)-1,4,7-triazacyclononane (NODAGA) to yield FR366 and labelled with (68)Ga. To confirm selective in vivo targeting of α5β1, female BALB/c nude mice xenografted with α5β1-expressing RKO cells in the right shoulder and α5β1/αvβ3-expressing M21 cells in the left shoulder were subjected to PET/CT scans and biodistribution experiments. Specificity of tracer uptake was proven by blocking studies. Metabolic stability of the injected tracer was measured in urine and in plasma., Results: MicroPET/CT scans with radiolabelled FR366 showed a good tumour-to-normal tissue ratio with low uptake in the liver (0.32 ± 0.14 %ID/g) and good retention of (68)Ga-NODAGA-FR366 in the tumour (0.71 ± 0.20 %ID/g and 0.40 ± 0.12 %ID/g for RKO and M21 tumours, respectively, at 90 min after injection). Biodistribution experiments showed uptake in the α5β1-expressing RKO tumour of 1.05 ± 0.23 %ID/g at 90 min after injection. Specificity of tracer uptake was demonstrated by injection of 5 mg/kg unlabelled ligand 10 min prior to tracer injection, resulting in a 67 % reduction in uptake in the RKO tumour. The tracer was found to be metabolically stable in urine and plasma 30 min after injection., Conclusion: Our results show that PET imaging of α5β1 expression with the (68)Ga-labelled α5β1-specific ligand is feasible with good image quality. Thus, FR366 is a promising new tool for investigating the role of α5β1 in angiogenesis and the influence of this integrin subtype on cancer aggressiveness and metastatic potential.

Purpose: Few radiopharmaceuticals have been described for the study of lymphocyte trafficking despite its high clinical relevance. The main difficulty resides in the identification of a suitable highly specific probe to target these cells. Interleukin-12 (IL12) is a heterodimeric cytokine which plays a key role in the development of Th(1) lymphocytes. The aims of the present study were to label IL12 with (99m)Tc, to evaluate its ability to bind to activated T lymphocytes in vitro and to study its biodistribution in normal mice and mice affected by autoimmune colitis., Methods: IL12 was derivatised with HYNIC-NHS and labelled with( 99m)Tc. An in vitro binding assay was performed on KIT225 cells, an IL12 receptor-positive cell line. (99m)Tc-IL12 biodistribution in normal mice was studied. Targeting experiments were performed in Balb/c mice injected with KIT225 cells and in mice with chemically induced chronic colitis., Results: (99m)Tc-IL12 labelling efficiency ranged between 75% and 85%. Saturation binding analysis revealed a K (d) of 2.09 nM. Results of biodistribution studies showed a predominant hepatic route of excretion. A significant degree of uptake in the spleen and thymus was also observed. In mice injected with KIT225 cells, (99m)Tc-IL12-specific uptake in these cells increased over time. (99m)Tc-IL12 also accumulated significantly in bowel of mice affected by TNBS-induced colitis showing T lymphocyte infiltration at histology, while accumulation in colon from control animals was negligible., Conclusion: We conclude that this radiolabelled cytokine is a suitable candidate for specific in vivo imaging of T lymphocytes: a step forward in molecular imaging of immune-mediated processes.

Purpose: Several histopathological studies have demonstrated that vulnerable plaques are enriched in inflammatory cells. The aims of this study were: (1a) to test the ability of 99mTc-labelled interleukin-2 (99mTc-IL2) to bind to IL2R-positive (IL2R+) cells in carotid plaques and (1b) to correlate the plaque uptake of 99mTc-IL2, measured in vivo, with the number of IL2R+ cells within the plaque, measured ex vivo by histology (transversal study, TS), and (2) to evaluate changes in 99mTc-IL2 uptake in plaques, before and after treatment with a statin or a hypocholesterolaemic diet (longitudinal study, LS)., Methods: Ultrasound scan was performed for plaque characterisation and localisation. Fourteen patients (16 plaques) eligible for endoarterectomy were recruited for the TS and underwent 99mTc-IL2 scintigraphy before surgery. Nine patients (13 plaques) were recruited for the LS; these patients received atorvastatin or a standard hypocholesterolaemic diet and 99mTc-IL2 scintigraphy was performed before and after 3 months of treatment., Results: The degree of 99mTc-IL2 uptake was expressed as the plaque/background (T/B) ratio. In patients from TS, T/B ratios correlated with the percentage of IL2R+ cells at histology (r = 0.707; p = 0.002) and the number of IL2R+ cells at flow cytometry (r = 0.711; p = 0.006). No correlations were observed between ultrasound scores and either scintigraphic or histological findings. In patients from the LS, the mean 99mTc-IL2 uptake decreased in statin-treated patients (1.75+/-0.50 vs 2.16+/-0.44; p = 0.012), while it was unchanged in the patients on the hypocholesterolaemic diet (2.33+/-0.45 vs 2.34+/-0.5)., Conclusion: 99mTc-IL2 accumulates in vulnerable carotid plaques; this accumulation is correlated with the amount of IL2R+ cells and is influenced by lipid-lowering treatment with a statin.