No abstract available

No abstract available

[en] For dosimetry in radioligand therapy, the time-integrated activity coefficients (TIACs) for organs at risk and for tumour lesions have to be determined. The used sampling scheme affects the TIACs and therefore the calculated absorbed doses. The aim of this work was to develop a general and flexible method, which analyses numerous clinically applicable sampling schedules using true time-activity curves (TACs) of virtual patients. Nine virtual patients with true TACs of the tumours were created using a physiologically-based pharmacokinetic (PBPK) model and individual biokinetic data of five patients with neuroendocrine tumours and four with meningioma. ${}^{111}$In-DOTATATE was used for pre-therapeutic dosimetry. In total, 15,120 sampling schemes, each consisting of 4 time points, were investigated. Gaussian noise of different levels was added to the corresponding true time-activity points. A bi-exponential function was used to fit the simulated time-activity data. For each investigated sampling schedule, 1000 replications were performed. Patient-specific and population-specific optimal sampling schedules were determined using the relative root-mean-square error (rRMSE). Furthermore, the fractions of TIACs ã deviating >5% ($f_{\mathrm{\Delta <!--\; ??\; -->}\text{ã<!-- ?? -->}>5\mathrm{\%<!--\; \%\; -->}}$) and >10% ($f_{\mathrm{\Delta <!--\; ??\; -->}\text{ã<!-- ?? -->}>10\mathrm{\%<!--\; \%\; -->}}$) from the true TIAC ã${}_{true}$ were used for additional evaluations e.g. to investigate the effect of varying single time points. Almost all patient-specific and all population-specific optimal sampling schedules have t${}_4$ ≥ 96 h for all noise levels. Changing the latest time point from the population-specific optimal time to e.g. 48 h leads to a median increase of $f_{\mathrm{\Delta <!--\; ??\; -->}\text{ã<!-- ?? -->}>10\mathrm{\%<!--\; \%\; -->}}$ from 0.1% to 88% for the lowest investigated noise level. Using the determined population-specific optimal schedules, results in more accurate and precise results than established schedules from the literature. A method of determining the optimal sampling schedule for dosimetry, which considers clinical working hours and measurement uncertainties, has been developed and applied. The simulation study shows that optimised sampling schedules result in high accuracy and precision of the determined TIACs.

[en] Estimation of accurate time-integrated activity coefficients (TIACs) and radiation absorbed doses (ADs) is desirable for treatment planning in peptide-receptor radionuclide therapy (PRRT). This study aimed to investigate the accuracy of a simplified dosimetry using a physiologically-based pharmacokinetic (PBPK) model, a nonlinear mixed effect (NLME) model, and single-time-point imaging to calculate the TIACs and ADs of ${}^{90}$Y-DOTATATE in various organs of dosimetric interest and tumors. Biokinetic data of ${}^{111}$In-DOTATATE in tumors, kidneys, liver, spleen, and whole body were obtained from eight patients using planar scintigraphic imaging at T1 = (2.9 ± 0.6), T2 = (4.6 ± 0.4), T3 = (22.8 ± 1.6), T4 = (46.7 ± 1.7) and T5 = (70.9 ± 1.0) h post injection. Serum activity concentration was measured at 5 and 15 min; 0.5, 1, 2, and 4 h; and 1, 2, and 3 d p.i.. A published PBPK model for PRRT, NLME, and a single-time-point imaging datum at different time points were used to calculate TIACs in tumors, kidneys, liver, spleen, whole body, and serum. Relative deviations (RDs) (median [min, max]) between the calculated TIACs from single-time-point imaging were compared to the TIACs calculated from the all-time-points fit. The root mean square error (RMSE) of the difference between the computed ADs from the single-time-point imaging and reference ADs from the all-time point fittings were analyzed. A joint root mean square error RMSE${}_{joint}$ of the ADs was calculated with the RSME from both the tumor and kidneys to sort the time points concerning accurate results for the kidneys and tumor dosimetry. The calculations of TIACs and ADs from the single-time-point dosimetry were repeated using the sum of exponentials (SOE) approach introduced in the literature. The RDs and the RSME of the PBPK approach in our study were compared to the SOE approach. Using the PBPK and NLME models and the biokinetic measurements resulted in a good fit based on visual inspection of the fitted curves and the coefficient of variation CV of the fitted parameters (<50%). T4 was identified being the time point with a relatively low median and range of TIACs RDs, i.e., 5 [1, 21]% and 2 [-15, 21]% for kidneys and tumors, respectively. T4 was found to be the time point with the lowest joint root mean square error of the ADs. Based on the RD and RMSE, our results show a similar performance as the SOE and NLME model approach. In this study, we introduced a simplified calculation of TIACs/ADs using a PBPK model, an NLME model, and a single-time-point measurement. Our results suggest a single measurement might be used to calculate TIACs/ADs in the kidneys and tumors during PRRT.

[en] PET/MR is a new multimodal imaging technique that is expected to improve diagnostic performance of imaging in conditions in which assessment of changes in soft tissue is important such as prostate cancer. Despite substantial changes in PET technology compared to PET/CT, initial studies have demonstrated that integrated PET/MR provides comparable image quality to that of PET/CT, retaining PET quantification efficacy. In this review we briefly describe technological changes compared to PET/CT that made integrated PET/MR possible, propose acquisition protocols for evaluation of prostate cancer with this new multimodal approach, present initial results concerning the application of PET/MR in prostate cancer, and outline the potential for further clinical applications, focusing on potential incremental value compared to present diagnostic performance. (orig.)

[en] Position emission tomography imaging of angiogenesis may provide non-invasive insights into the corresponding molecular processes and may be applied for individualized treatment planning of antiangiogenic therapies. At the moment, most strategies are focusing on the development of radiolabelled proteins and antibody formats targeting VEGF and its receptor or the ED-B domain of a fibronectin isoform as well as radiolabelled matrix metalloproteinase inhibitors or α_vβ₃ integrin antagonists. Great efforts are being made to develop suitable tracers for different target structures. All of the major strategies focusing on the development of radiolabelled compounds for use with positron emission tomography are summarized in this review. However, because the most intensive work is concentrated on the development of radiolabelled RGD peptides for imaging α_vβ₃ expression, which has successfully made its way from bench to bedside, these developments are especially emphasized. (orig.)

[en] To evaluate the performance of conventional [¹¹C]choline PET/CT in comparison to that of simultaneous whole-body PET/MR. The study population comprised 32 patients with prostate cancer who underwent a single-injection dual-imaging protocol with PET/CT and subsequent PET/MR. PET/CT scans were performed applying standard clinical protocols (5 min after injection of 793 ± 69 MBq [¹¹C]choline, 3 min per bed position, intravenous contrast agent). Subsequently (52 ± 15 min after injection) PET/MR was performed (4 min per bed position). PET images were reconstructed iteratively (OSEM 3D), scatter and attenuation correction of emission data and regional allocation of [¹¹C]choline foci were performed using CT data for PET/CT and segmented Dixon MR, T1 and T2 sequences for PET/MR. Image quality of the respective PET scans and PET alignment with the respective morphological imaging modality were compared using a four point scale (0-3). Furthermore, number, location and conspicuity of the detected lesions were evaluated. SUVs for suspicious lesions, lung, liver, spleen, vertebral bone and muscle were compared. Overall 80 lesions were scored visually in 29 of the 32 patients. There was no significant difference between the two PET scans concerning number or conspicuity of the detected lesions (p not significant). PET/MR with T1 and T2 sequences performed better than PET/CT in anatomical allocation of lesions (2.87 ± 0.3 vs. 2.72 ± 0.5; p = 0.005). The quality of PET/CT images (2.97 ± 0.2) was better than that of the respective PET scan of the PET/MR (2.69 ± 0.5; p = 0.007). Overall the maximum and mean lesional SUVs exhibited high correlations between PET/CT and PET/MR (ρ = 0.87 and ρ = 0.86, respectively; both p < 0.001). Despite a substantially later imaging time-point, the performance of simultaneous PET/MR was comparable to that of PET/CT in detecting lesions with increased [¹¹C]choline uptake in patients with prostate cancer. Anatomical allocation of lesions was better with simultaneous PET/MR than with PET/CT, especially in the bone and pelvis. These promising findings suggest that [¹¹C]choline PET/MR might have a diagnostic benefit compared to PET/CT in patients with prostate cancer, and now needs to be further evaluated in prospective trials. (orig.)

[en] New technologies are needed to characterize the migration and survival of antigen-specific T cells in vivo. In this study, we developed a novel technique for the labeling of human cytotoxic T lymphocytes with superparamagnetic iron-oxide particles and the subsequent depiction with a conventional 1.5-T magnetic resonance scanner. Antigen-specific CD8⁺ T lymphocytes were labeled with ferucarbotran by lipofection. The uptake of ferucarbotran was confirmed by immunofluorescence microscopy using a dextran-specific antibody, and the intracellular enrichment of iron was measured by atomic absorption spectrometry. The imaging of T cells was performed by magnetic resonance on day 0, 2, 7 and 14 after the labeling procedure. On day 0 and 2 post labeling, a pronounced shortening of T2*-relaxation times was observed, which diminished after 7 days and was not detectable anymore after 14 days, probably due to the retained mitotic activity of the labeled T cells. Of importance, the antigen-specific cytolytic activity of the T cells was preserved following ferucarbotran labeling. Efficient ferucarbotran labeling of functionally active T lymphocytes and their detection by magnetic resonance imaging allows the in vivo monitoring of T cells and, subsequently, will impact the further development of T cell-based therapies. (orig.)

[en] In this study, the potential contribution of Dixon-based MR imaging with a rapid low-resolution breath-hold sequence, which is a technique used for MR-based attenuation correction (AC) for MR/positron emission tomography (PET), was evaluated for anatomical correlation of PET-positive lesions on a 3T clinical scanner compared to low-dose CT. This technique is also used in a recently installed fully integrated whole-body MR/PET system. Thirty-five patients routinely scheduled for oncological staging underwent ¹⁸F-fluorodeoxyglucose (FDG) PET/CT and a 2-point Dixon 3-D volumetric interpolated breath-hold examination (VIBE) T1-weighted MR sequence on the same day. Two PET data sets reconstructed using attenuation maps from low-dose CT (PET_ACCT) or simulated MR-based segmentation (PET_ACMR) were evaluated for focal PET-positive lesions. The certainty for the correlation with anatomical structures was judged in the low-dose CT and Dixon-based MRI on a 4-point scale (0-3). In addition, the standardized uptake values (SUVs) for PET_ACCT and PET_ACMR were compared. Statistically, no significant difference could be found concerning anatomical localization for all 81 PET-positive lesions in low-dose CT compared to Dixon-based MR (mean 2.51 ± 0.85 and 2.37 ± 0.87, respectively; p = 0.1909). CT tended to be superior for small lymph nodes, bone metastases and pulmonary nodules, while Dixon-based MR proved advantageous for soft tissue pathologies like head/neck tumours and liver metastases. For the PET_ACCT- and PET_ACMR-based SUVs (mean 6.36 ± 4.47 and 6.31 ± 4.52, respectively) a nearly complete concordance with a highly significant correlation was found (r = 0.9975, p < 0.0001). Dixon-based MR imaging for MR AC allows for anatomical allocation of PET-positive lesions similar to low-dose CT in conventional PET/CT. Thus, this approach appears to be useful for future MR/PET for body regions not fully covered by diagnostic MRI due to potential time constraints. (orig.)

[en] 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)acet amido)ethyl)carbamoyl)-3,5-dimethylphenoxy) propyl)amino)-6-oxohexyl)amino)-4-oxo butyl)-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 "6"8Ga-labelled α5β1 ligand in PET imaging. 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 "6"8Ga. 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. 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 "6"8Ga-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. Our results show that PET imaging of α5β1 expression with the "6"8Ga-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. (orig.)