TY - JOUR A1 - Kosmala, Aleksander A1 - Serfling, Sebastian E. A1 - Dreher, Niklas A1 - Lindner, Thomas A1 - Schirbel, Andreas A1 - Lapa, Constantin A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Weich, Alexander A1 - Werner, Rudolf A. T1 - Associations between normal organs and tumor burden in patients imaged with fibroblast activation protein inhibitor-directed positron emission tomography JF - Cancers N2 - (1) Background: We aimed to quantitatively investigate [\(^{68}\)Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [\(^{68}\)Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV\(_{mean}\)). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV\(_{mean}\) values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV\(_{max}\) (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV\(_{max}\) (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV\(_{max}\) (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [\(^{68}\)Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs. KW - PET KW - [\(^{68}\)Ga]Ga-FAPI KW - theranostics KW - radioligand therapy KW - fibroblast activation protein Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275154 SN - 2072-6694 VL - 14 IS - 11 ER - TY - JOUR A1 - Tolstik, Elen A1 - Ali, Nairveen A1 - Guo, Shuxia A1 - Ebersbach, Paul A1 - Möllmann, Dorothe A1 - Arias-Loza, Paula A1 - Dierks, Johann A1 - Schuler, Irina A1 - Freier, Erik A1 - Debus, Jörg A1 - Baba, Hideo A. A1 - Nordbeck, Peter A1 - Bocklitz, Thomas A1 - Lorenz, Kristina T1 - CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease JF - International Journal of Molecular Sciences N2 - Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient’s prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90–96%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD. KW - coherent anti-Stokes Raman scattering (CARS) microscopy KW - Raman micro-spectroscopy KW - cardiovascular diseases KW - Fabry Disease (FD) KW - Gb3 and lyso-Gb3 biomarkers KW - multivariate data analysis KW - immunohistochemistry Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284427 SN - 1422-0067 VL - 23 IS - 10 ER - TY - JOUR A1 - Hartrampf, Philipp E. A1 - Krebs, Markus A1 - Peter, Lea A1 - Heinrich, Marieke A1 - Ruffing, Julia A1 - Kalogirou, Charis A1 - Weinke, Maximilian A1 - Brumberg, Joachim A1 - Kübler, Hubert A1 - Buck, Andreas K. A1 - Werner, Rudolf A. A1 - Seitz, Anna Katharina T1 - Reduced segmentation of lesions is comparable to whole-body segmentation for response assessment by PSMA PET/CT: initial experience with the keyhole approach JF - Biology N2 - Simple Summary The calculation of PSMA-positive tumor volume (PSMA-TV) of the whole body from PSMA PET scans for response evaluation remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative tumor lesions. Changes in the whole-body PSMA-TV of 65 patients were comparable to the changes in PSMA-TV after including only the ten largest lesions. Moreover, changes in PSMA-TV correlated well with changes in PSA levels, as did the changes in PSMA-TV with the reduced number of lesions. We conclude that a response assessment using PSMA-TV with a reduced number of lesions is feasible and could lead to a simplified process for evaluating PSMA PET/CT. Abstract (1) Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-derived parameters, such as the commonly used standardized uptake value (SUV) and PSMA-positive tumor volume (PSMA-TV), have been proposed for response assessment in metastatic prostate cancer (PCa) patients. However, the calculation of whole-body PSMA-TV remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative lesions. (2) Methods: Sixty-five patients classified into different disease stages were assessed by PSMA PET/CT for staging and restaging after therapy. Whole-body PSMA-TV and whole-body SUV\(_{max}\) were calculated. We then repeated this calculation only including the five or ten hottest or largest lesions. The corresponding serum levels of prostate-specific antigen (PSA) were also determined. The derived delta between baseline and follow-up values provided the following parameters: ΔSUV\(_{maxall}\), ΔSUV\(_{max10}\), ΔSUV\(_{max5}\), ΔPSMA-TV\(_{all}\), ΔPSMA-TV\(_{10}\), ΔPSMA-TV\(_{5}\), ΔPSA. Finally, we compared the findings from our whole-body segmentation with the results from our keyhole approach (focusing on a limited number of lesions) and correlated all values with the biochemical response (ΔPSA). (3) Results: Among patients with metastatic hormone-sensitive PCa (mHSPC), none showed a relevant deviation for ΔSUV\(_{max10}\)/ΔSUV\(_{max5}\) or ΔPSMA-TV\(_{10}\)/ΔPSMA-TV\(_{5}\) compared to ΔSUV\(_{maxall}\) and ΔPSMA-TV\(_{all}\). For patients treated with taxanes, up to 6/21 (28.6%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only up to 2/21 (9.5%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). For patients treated with radioligand therapy (RLT), up to 5/28 (17.9%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only 1/28 (3.6%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). The highest correlations with ΔPSA were found for ΔPSMA-TV\(_{all}\) (r ≥ 0.59, p ≤ 0.01), followed by ΔPSMA-TV\(_{10}\) (r ≥ 0.57, p ≤ 0.01) and ΔPSMA-TV\(_{5}\) (r ≥ 0.53, p ≤ 0.02) in all cohorts. ΔPSA only correlated with ΔSUV\(_{maxall}\) (r = 0.60, p = 0.02) and with ΔSUV\(_{max10}\) (r = 0.53, p = 0.03) in the mHSPC cohort, as well as with ΔSUV\(_{maxall}\) (r = 0.51, p = 0.01) in the RLT cohort. (4) Conclusion: Response assessment using PSMA-TV with a reduced number of lesions is feasible, and may allow for a simplified evaluation process for PSMA PET/CT. KW - PET/CT KW - PSMA-TV KW - SUV KW - prostate cancer KW - taxane KW - radioligand therapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271191 SN - 2079-7737 VL - 11 IS - 5 ER - TY - JOUR A1 - Schadt, Fabian A1 - Israel, Ina A1 - Beez, Alexandra A1 - Alushi, Kastriot A1 - Weiland, Judith A1 - Ernestus, Ralf-Ingo A1 - Westermaier, Thomas A1 - Samnick, Samuel A1 - Lilla, Nadine T1 - Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage over 7 days JF - Scientific Reports N2 - Little is known about changes in brain metabolism following SAH, possibly leading towards secondary brain damage. Despite sustained progress in the last decade, analysis of in vivo acquired data still remains challenging. The present interdisciplinary study uses a semi-automated data analysis tool analyzing imaging data independently from the administrated radiotracer. The uptake of 2-[18F]Fluoro-2-deoxy-glucose ([\(^{18}\)F]FDG) was evaluated in different brain regions in 14 male Sprague–Dawley rats, randomized into two groups: (1) SAH induced by the endovascular filament model and (2) sham operated controls. Serial [\(^{18}\)F]FDG-PET measurements were carried out. Quantitative image analysis was performed by uptake ratio using a self-developed MRI-template based data analysis tool. SAH animals showed significantly higher [\(^{18}\)F]FDG accumulation in gray matter, neocortex and olfactory system as compared to animals of the sham group, while white matter and basal forebrain region showed significant reduced tracer accumulation in SAH animals. All significant metabolic changes were visualized from 3 h, over 24 h (day 1), day 4 and day 7 following SAH/sham operation. This [\(^{18}\)F]FDG-PET study provides important insights into glucose metabolism alterations following SAH—for the first time in different brain regions and up to day 7 during course of disease. KW - SAH KW - metabolism KW - brain Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300725 VL - 13 IS - 1 ER - TY - THES A1 - Heider, Melanie T1 - Detektionsrate der \(^{68}\)Ga-PSMA-PET/CT bei Patienten mit Rezidiv eines Prostatakarzinoms und Androgendeprivationstherapie T1 - Detection Rate of \(^{68}\)Ga-PSMA Ligand PET/CT in Patients with Recurrent Prostate Cancer and Androgen Deprivation Therapy N2 - Die Detektion des Prostataspezifischen Membranantigens (PSMA) mittels kombinierter Positronenemissions- und Computertomographie (PET/CT) ist ein etabliertes diagnostisches Verfahren bei Patienten mit Prostatakarzinom. Hierbei ist bislang unklar, ob und wie eine bereits eingeleitete Androgendeprivationstherapie (ADT) die diagnostische Genauigkeit der PSMA-PET/CT beeinflusst. Ziel dieser Arbeit war es, die Detektionsrate der PSMA-PET/CT mit 68Ga-PSMA I&T unter ADT in Abhängigkeit des PSA-Wertes zu evaluieren und mit einer Kontrollgruppe ohne ADT zu vergleichen. In dieser retrospektiven Studie wurden Daten von Patienten mit biochemischem Rezidiv nach radikaler Prostatektomie analysiert, welche zwischen 2014 und 2018 eine PSMA-PET/CT am Universitätsklinikum Würzburg erhalten haben. Mittels Propensity Score Matching wurde für die Patienten mit ADT innerhalb der letzten 6 Monate vor Durchführung der PSMA-PET/CT eine Kontrollgruppe ohne ADT erstellt. Die Patienten mit ADT (n=62) wiesen eine signifikant höhere Detektionsrate auf als die Patienten ohne ADT (n=62). Die Traceranreicherung unterschied sich nicht signifikant in beiden Gruppen. Dagegen wiesen die Patienten mit ADT jedoch eine signifikant höhere Tumorlast auf und hatten häufiger Knochen- und Organmetastasen, sodass als Ursache für die höhere Detektionsrate der PSMA-PET/CT bei Patienten mit ADT ein fortgeschritteneres Tumorstadium angenommen wurde. Die Detektionsrate war bei den Patienten mit ADT auch bei niedrigen PSA-Werten hoch. Es scheint daher nicht erforderlich zu sein, eine bestehende ADT vor Durchführung der PSMA-PET/CT im biochemischen Rezidiv abzusetzen und damit das Risiko einer Krankheitsprogression einzugehen. Die Korrelation des PSA-Wertes mit der Tumorlast in der PSMA-PET/CT war bei Patienten mit ADT geringer ausgeprägt als bei Patienten ohne ADT. Patienten unter ADT könnten daher von einer regelmäßigen Durchführung der PSMA-PET/CT zur Überwachung der Krankheitsprogression profitieren. Hier bleibt allerdings eine Kosten-Nutzen-Analyse abzuwarten, da dies deutlich aufwendiger und teurer ist als die Bestimmung des PSA-Wertes. N2 - Detection of prostate specific membrane antigen (PSMA) by combined positron emission tomography and computed tomography (PET/CT) is an established diagnostic procedure in patients with prostate cancer. So far it is unclear whether an already initiated androgen deprivation therapy (ADT) influences the diagnostic accuracy of PSMA-PET/CT. The aim of this study was to evaluate the effect of ADT on the detection rate of PSMA-PET/CT with 68Ga-PSMA I&T. In this retrospective study, data from patients with biochemical recurrence after radical prostatectomy who received PSMA-PET/CT at the University Hospital of Würzburg between 2014 and 2018 were analyzed. Propensity score matching was used to create two balanced groups of 62 patients who either did or did not receive ADT within six months before imaging. The detection rate of PSMA-PET/CT was significantly higher in the group of patients with ADT than in the control group without ADT. Tracer accumulation was not significantly different in both groups. In contrast, patients with ADT had significantly higher tumor burden and more frequent bone and organ metastases, suggesting a more advanced disease stage as the reason for the higher detection rate of PSMA-PET/CT in patients with ADT. The detection rate was high in patients with ADT even at low PSA levels. Therefore, the withdrawal of ADT before PSMA-PET/CT in biochemical recurrence, thereby risking disease progression, cannot be recommended. The correlation of PSA level with tumor burden in PSMA-PET/CT is lower in patients with ADT than in patients without ADT. Patients with ADT may therefore benefit from routine performance of PSMA-PET/CT to monitor disease progression. However, a cost-benefit analysis remains to be performed, as this is significantly more time-consuming and expensive than the measuring of the PSA value. KW - Positronen-Emissions-Tomografie KW - Detektion KW - Computertomografie KW - Prostatakrebs KW - Rezidiv KW - Androgendeprivation KW - Prostataspezifisches Membranantigen Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306123 ER - TY - JOUR A1 - Matsusaka, Yohji A1 - Werner, Rudolf A. A1 - Arias-Loza, Paula A1 - Nose, Naoko A1 - Sasaki, Takanori A1 - Chen, Xinyu A1 - Lapa, Constantin A1 - Higuchi, Takahiro T1 - Performance Evaluation of a Preclinical SPECT Scanner with a Collimator Designed for Medium-Sized Animals JF - Molecular Imaging N2 - Background. Equipped with two stationary detectors, a large bore collimator for medium-sized animals has been recently introduced for dedicated preclinical single-photon emission computed tomography (SPECT) imaging. We aimed to evaluate the basic performance of the system using phantoms and healthy rabbits. Methods. A general-purpose medium-sized animal (GP-MSA) collimator with 135 mm bore diameter and thirty-three holes of 2.5 mm diameter was installed on an ultrahigh-resolution scanner equipped with two large stationary detectors (U-SPECT5-E/CT). The sensitivity and uniformity were investigated using a point source and a cylinder phantom containing 99mTc-pertechnetate, respectively. Uniformity (in %) was derived using volumes of interest (VOIs) on images of the cylinder phantom and calculated as , with lower values of % indicating superior performance. The spatial resolution and contrast-to-noise ratios (CNRs) were evaluated with images of a hot-rod Derenzo phantom using different activity concentrations. Feasibility of in vivo SPECT imaging was finally confirmed by rabbit imaging with the most commonly used clinical myocardial perfusion SPECT agent [99mTc]Tc-sestamibi (dynamic acquisition with a scan time of 5 min). Results. In the performance evaluation, a sensitivity of 790 cps/MBq, a spatial resolution with the hot-rod phantom of 2.5 mm, and a uniformity of 39.2% were achieved. The CNRs of the rod size 2.5 mm were 1.37, 1.24, 1.20, and 0.85 for activity concentration of 29.2, 1.0, 0.5, and 0.1 MBq/mL, respectively. Dynamic SPECT imaging in rabbits allowed to visualize most of the thorax and to generate time-activity curves of the left myocardial wall and ventricular cavity. Conclusion. Preclinical U-SPECT5-E/CT equipped with a large bore collimator demonstrated adequate sensitivity and resolution for in vivo rabbit imaging. Along with its unique features of SPECT molecular functional imaging is a superior collimator technology that is applicable to medium-sized animal models and thus may promote translational research for diagnostic purposes and development of novel therapeutics. KW - SPECT Scanner KW - medium-sized animals KW - performance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300713 VL - 2022 ER - TY - JOUR A1 - Matsusaka, Yohji A1 - Chen, Xinyu A1 - Arias-Loza, Paula A1 - Werner, Rudolf A. A1 - Nose, Naoko A1 - Sasaki, Takanori A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Lapa, Constantin A1 - Higuchi, Takahiro T1 - In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using [\(^{18}\)F]Me4FDG PET in Rats JF - Molecular Imaging N2 - Background. Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[\(^{18}\)F]fluoro-D-glucopyranoside ([\(^{18}\)F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport. Methods. We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[\(^{18}\)F]fluoro-D-glucose ([\(^{18}\)F]FDG), or the SGLT-targeting agent, [\(^{18}\)F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [18F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV). Results. Serving as reference, intestinal administration of [\(^{18}\)F]FDG led to slow absorption with retention of % of administered radioactivity at 15 min. [\(^{18}\)F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of % (). Intraintestinal phlorizin led to marked increase of [\(^{18}\)F]Me4FDG uptake (15 min, %; vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [\(^{18}\)F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (%ID/g at 60 min, vs. untreated controls, ; ). Conclusion. As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [\(^{18}\)F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [\(^{18}\)F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies. KW - Sodium-Glucose Cotransporters (SGLTs) KW - diabetes KW - rats Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300708 VL - 2022 ER - TY - JOUR A1 - Gram, Maximilian A1 - Gensler, Daniel A1 - Albertova, Petra A1 - Gutjahr, Fabian Tobias A1 - Lau, Kolja A1 - Arias-Loza, Paula-Anahi A1 - Jakob, Peter Michael A1 - Nordbeck, Peter T1 - Quantification correction for free-breathing myocardial T1ρ mapping in mice using a recursively derived description of a T\(_{1p}\)\(^{*}\) relaxation pathway JF - Journal of Cardiovascular Magnetic Resonance N2 - Background Fast and accurate T1ρ mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T\(_{1p}\) relaxation pathway. In this study, we present an improved quantification method for T\(_{1p}\) using a newly derived formalism of a T\(_{1p}\)\(^{*}\) relaxation pathway. Methods The new signal equation was derived by solving a recursion problem for spin-lock prepared fast gradient echo readouts. Based on Bloch simulations, we compared quantification errors using the common monoexponential model and our corrected model. The method was validated in phantom experiments and tested in vivo for myocardial T\(_{1p}\) mapping in mice. Here, the impact of the breath dependent spin recovery time T\(_{rec}\) on the quantification results was examined in detail. Results Simulations indicate that a correction is necessary, since systematically underestimated values are measured under in vivo conditions. In the phantom study, the mean quantification error could be reduced from − 7.4% to − 0.97%. In vivo, a correlation of uncorrected T\(_{1p}\) with the respiratory cycle was observed. Using the newly derived correction method, this correlation was significantly reduced from r = 0.708 (p < 0.001) to r = 0.204 and the standard deviation of left ventricular T\(_{1p}\) values in different animals was reduced by at least 39%. Conclusion The suggested quantification formalism enables fast and precise myocardial T\(_{1p}\) quantification for small animals during free breathing and can improve the comparability of study results. Our new technique offers a reasonable tool for assessing myocardial diseases, since pathologies that cause a change in heart or breathing rates do not lead to systematic misinterpretations. Besides, the derived signal equation can be used for sequence optimization or for subsequent correction of prior study results. KW - T1rho KW - radial KW - cardiac KW - correction KW - quantitative MRI KW - mapping KW - spin-lock KW - T1ρ Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300491 VL - 24 IS - 1 ER - TY - JOUR A1 - Chen, Xinyu A1 - Werner, Rudolf A. A1 - Koshino, Kazuhiro A1 - Nose, Naoko A1 - Mühlig, Saskia A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Lapa, Constantin A1 - Decker, Michael A1 - Higuchi, Takahiro T1 - Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity - Introducing High NET Affinity PET Probe \(^{18}\)F-AF78 JF - Theranostics N2 - Background: Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events. We aimed to fully characterize the kinetic profile of the novel \(^{18}\)F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species. Methods: \(^{18}\)F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing in vitro cell assays, followed by an in vivo PET imaging approach with healthy rats, rabbits and nonhuman primates (NHPs). Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS. Results: Relative to other SNS radiotracers, 18F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC\(^{50}\) 0.42 ± 0.14 µM), almost identical to that of NE (IC\(^{50}\), 0.50 ± 0.16 µM, n.s.). In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition. Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that \(^{18}\)F-AF78 is stored and can be released via the synaptic vesicular turnover process. Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of \(^{18}\)F-AF78. Conclusion: \(^{18}\)F-AF78 demonstrated high in vitro NET affinity and advantageous in vivo radiotracer kinetics across various species, indicating that \(^{18}\)F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine. KW - norepinephrine transporter KW - T-shaped π-π stacking KW - nonhuman primates KW - radiotracer kinetics KW - cardiac innervation imaging KW - sympathetic nervous system Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300685 VL - 12 IS - 9 SP - 4446 EP - 4458 ER - TY - JOUR A1 - Aster, Hans-Christoph A1 - Romanos, Marcel A1 - Walitza, Susanne A1 - Gerlach, Manfred A1 - Mühlberger, Andreas A1 - Rizzo, Albert A1 - Andreatta, Marta A1 - Hasenauer, Natalie A1 - Hartrampf, Philipp E. A1 - Nerlich, Kai A1 - Reiners, Christoph A1 - Lorenz, Reinhard A1 - Buck, Andreas K. A1 - Deserno, Lorenz T1 - Responsivity of the striatal dopamine system to methylphenidate — A within-subject I-123-β-CIT-SPECT study in male children and adolescents with attention-deficit/hyperactivity disorder JF - Frontiers in Psychiatry N2 - Background: Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods Thirteen adolescent male patients (9–16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-β-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results On-MPH status was associated with a highly significant change (−29.9%) of striatal DAT BP as compared to off-MPH (t = −4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04). Conclusion Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity. KW - methylphenidate KW - attention deficit/hyperactivity disorder (ADHD) KW - striatum KW - single photon emission computed tomography (SPECT) KW - responsivity KW - caudate nucleus KW - dopamine transporter (DAT) Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270862 SN - 1664-0640 VL - 13 ER - TY - THES A1 - Page, Lukas T1 - Entwicklung und präklinische Evaluation immunologischer und nuklearmedizinischer diagnostischer Tests für Schimmelpilz-assoziierte Hypersensitivität und invasive Mykosen T1 - Development and preclinical evaluation of immunological and nuclear medical diagnostic assays for mould-associated hypersensitivity and invasive mycoses N2 - Schimmelpilze können in Abhängigkeit des Immunstatus und der Vorerkrankungen betroffener Patienten unterschiedliche Krankheitsbilder wie Hypersensitivitäts-erkrankungen oder lebensbedrohliche invasive Infektionen hervorrufen. Da die Diagnosestellung dieser Erkrankungen mitunter komplex und insensitiv ist, sollten im Rahmen dieser Arbeit unterschiedliche Ansätze neuer diagnostischer Assays untersucht werden. In den letzten Jahren wurden Assays entwickelt, die auf Basis durchflusszytometrisch quantifizierter Pilz-spezifischer T-Zellen aus peripherem Blut einen supportiven Biomarker zur Diagnostik invasiver Mykosen liefern könnten. Da die hierfür isolierten T-Zellen anfällig gegenüber präanalytischer Lagerzeiten und immunsuppressiver Medikation sind, wurden hier Protokolloptimierungen vorgenommen, um anhand eines Vollblut-basierten Assays mit zusätzlicher CD49d-Kostimulation diesen Limitationen entgegen zu wirken. In einer Studie an gesunden Probanden konnte dabei gezeigt werden, dass die Kombination der Durchflusszytometrie mit ausgewählten Zytokin-Messungen (IL-5, IL-10 und IL-17) zu einer verbesserten Erkennung vermehrt Schimmelpilz-exponierter Personen beitragen könnte. Neben Infektionen könnten dabei im umwelt- und arbeitsmedizinischen Kontext Polarisationen der T-Zell-Populationen detektiert werden, welche mit Sensibilisierungen und Hypersensitivität assoziiert werden. Zusätzlich wurde ein in vitro Transwell® Alveolarmodell zur Simulation pulmonaler Pilzinfektionen für Erreger der Ordnung Mucorales adaptiert, durch Reproduktion wichtiger Merkmale der Pathogenese von Mucormykosen validiert, und für Untersuchungen der Immunpathologie und Erreger-Invasion verwendet. Das Modell wurde anschließend zur in vitro Evaluation von radioaktiv markiertem Amphotericin B mit 99mTc oder 68Ga als nuklearmedizinischen Tracer verwendet. Die untersuchten Schimmelpilze zeigten dabei eine zeit- und dosis-abhängige Aufnahme der Tracer, während bakteriell infizierte Proben nicht detektiert wurden. Die erhobenen Daten dokumentieren ein vielversprechendes Potenzial von Amphotericin B-basierten Tracer, das in zukünftigen in vivo Studien weiter evaluiert werden sollte. N2 - Depending on the immune constitution and predisposing illnesses, moulds can cause a variety of diseases ranging from hypersensitivity syndromes to life-threatening invasive infections. As the diagnosis of mould-associated diseases remains challenging, this work aimed to refine immunological assays and to develop molecular imaging protocols for pulmonary mould infections. Recently, a flow cytometric assay for mould specific T cell quantification has been proposed as a novel supportive biomarker to diagnose invasive mycoses. As these assays are susceptible to pre-analytic delays and immunosuppressive drugs, a whole blood-based protocol with enhanced CD28 plus CD49d co-stimulation was developed and was shown to be less prone to these limitations. In addition, a study on healthy volunteers demonstrated the applicability of flow cytometric antigen-reactive T cell quantification as a surrogate of environmental mould exposure, especially when combined with T-cellular cytokine measurements (specifically, IL-5, IL-10, and IL-17). Therefore, these assays could potentially be used to detect polarizations of T-cell populations associated with sensitization and hypersensitivity, e. g. in allergology and occupational medicine. Moreover, an in vitro Transwell® alveolar model of invasive pulmonary mould infections has been adapted to study mucormycoses, validated by recapitulation of known pathogenicity factors, and used to characterize the immunopathology and epithelial invasion of Mucorales. The Transwell® model was subsequently used to evaluate radioactively labelled Amphotericin B with either 99mTc or 68Ga as a potential nuclear medical tracer. Time- and dose-dependent enrichment of the tracers was found in both Aspergillus and Mucorales, whereas samples infected with bacteria showed negligible uptake. These in vitro data document a promising potential of radiolabeled amphotericin B for molecular imaging of invasive mycoses and encourage further evaluation in animal models. KW - Schimmelpilze KW - Diagnostik KW - Biomarker KW - Tracer KW - Zellkultur KW - Antimykotika KW - Mucorales KW - Aspergillus KW - T-Zellen KW - Immunsuppressiva KW - Antifungal KW - Mucormycosis KW - Aspergillosis KW - T cells KW - Immunosuppressant Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252459 ER - TY - JOUR A1 - Angheloiu, George O. A1 - Hänscheid, Heribert A1 - Wen, Xiaoyan A1 - Capponi, Vincent A1 - Anderson, William D. A1 - Kellum, John A. T1 - Experimental first-pass method for testing and comparing sorbent polymers used in the clearance of iodine contrast materials JF - Blood Purification N2 - Background: Sorbents have been shown to adsorb iodinated radiocontrast media. Objective: In this study we describe a simple method to compare various sorbents in terms of capacity to adsorb radiocontrast media. Methods: Iodixanol solution was injected into columns filled with three types of sorbent at filtration velocities of increasing magnitude. Two variables of interest – contrast removal rate and matched iodine retention (MIR) – were calculated to measure the adsorption efficiency and the mass of contrast iodine adsorbed versus sorbent used, respectively. Results: The highest contrast removal and MIR for Porapak Q, CST 401 and Amberlite XAD4 were 41, 38 and 16% (p = 0.22 and 0.0005 for comparisons between Porapak Q-CST 401 and CST 401-Amberlite XAD4) and 0.060, 0.055 and 0.024, respectively (p = 0.18 and 0.0008). Extrapolation to a clinical scenario may suggest that removal of 8 ml iodixanol could be achieved by masses of sorbents of 43, 47 and 107 g, respectively. Conclusion: In this study we set a benchmark for comparing the radiocontrast-adsorbing efficiency of polymer sorbents during first-pass experiments, using a readily available methodology. KW - adsorption KW - acute renal failure KW - sorbents KW - iodine contrast Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199118 SN - 0253-5068 SN - 1421-9735 N1 - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich. VL - 34 IS - 1 ER - TY - JOUR A1 - Mihatsch, Patrick W. A1 - Beissert, Matthias A1 - Pomper, Martin G. A1 - Bley, Thorsten A. A1 - Seitz, Anna K. A1 - Kübler, Hubert A1 - Buck, Andreas K. A1 - Rowe, Steven P. A1 - Serfling, Sebastian E. A1 - Hartrampf, Philipp E. A1 - Werner, Rudolf A. T1 - Changing threshold-based segmentation has no relevant impact on semi-quantification in the context of structured reporting for PSMA-PET/CT JF - Cancers N2 - Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with \(^{18}\)F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUV\(_{max}\), SUV\(_{peak}\), SUV\(_{mean}\)) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50%). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories (p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUV\(_{max}\) and SUV\(_{peak}\) compared to the entire PSMA-RADS-4 or -5 cohort (p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort (p < 0.0001), but not to the PSMA-RADS-4 cohort (SUV\(_{max}\), p = 0.07; SUV\(_{peak}\), p = 0.08). SUV\(_{mean}\) (p = 0.30) and TL-PSMA (p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50% MIT (p = 0.0066), which was driven by lymph nodes (p = 0.0239), but not bone lesions (p = 0.15). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in \(^{18}\)F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUV\(_{mean}\) and TL-PSMA in contrast to PSMA-TV. KW - \(^{18}\)F-PSMA-1007 KW - PET/CT KW - staging KW - prostate cancer KW - standardized reporting system KW - PSMA-RADS Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254782 SN - 2072-6694 VL - 14 IS - 2 ER - TY - THES A1 - Schadt, Fabian T1 - Entwicklung und erste Validierung eines innovativen Analysen-Tools für präklinische Bewertungen von PET-Radiopharmazeutika zur \(in\) \(vivo\) Untersuchungen neurologischer Erkrankungen T1 - Development and initial validation of an innovative analytical tool for preclinical evaluations of PET radiopharmaceuticals for \(in\) \(vivo\) investigations of neurological disease N2 - Die präklinische Forschung stellt den ersten wichtigen Meilenstein in der Klärung und Untersuchung klinisch-relevanter Erkrankungen dar. Darüber hinaus unterstützt die präklinische Forschung erheblich die Entwicklung von Therapien. Die Kleintier-Positronenemissionstomographie (µ-PET) spielt dabei eine wichtige Rolle, da sie in der Lage ist, funktionelle, physiologische und biochemische Prozesse in vivo darzustellen und zu quantifizieren. Trotz diverser etablierter PET-Datenauswertungs-Programme bleibt die Analyse von in vivo akquirierten Bilddaten aufgrund der Vielzahl an medizinischen Fragestellungen, der Komplexität der Krankheitsbilder, sowie der Etablierung neuer Radiotracer weiterhin eine große Herausforderung in der Medizin. Ziel dieser Doktorarbeit ist es daher, ein geeignetes, brauchbares Auswertungstool für eine einfache und effiziente Analyse von akquirierten µ-PET-Daten zu entwickeln und zu etablieren, welches das Spektrum bereits vorhandener Programme erweitert. Das entwickelte nuklearmedizinische Datenverarbeitungs-Analyseprogramm (engl. nuclear medicine data processing analysis tool, NU_DPA) wurde in Matlab implementiert und anhand dreier präklinischer Versuchs- bzw. Testreihen erprobt und etabliert. Bei den Datenreihen handelt es sich um µ-PET-Datensätze verschiedener Schlaganfall-Rattenhirnmodelle unter Verwendung folgender Radiotracer. Zum einen die im Gehirn homogen akkumulierende 2-[18F]Fluor-2-desoxy-glukose ([18F]FDG) zum anderen das spezifisch an P-Selektin anreichernde [68Ga]Fucoidan. Das NU_DPA umfasst die automatische Selektion des Zielvolumens (volume-of-interest, VOI) aus dem vollständigen PET-Bild und die anschließende Ausrichtung des VOI mit Hilfe eines PET-Templates (gemittelter PET-Datensatz). Dieses PET Template wird aus den eigenen akquirierten PET-Daten erstellt. Durch das Einbinden eines geeigneten anatomischen MRT-Atlas‘ (anpassbar) können die ausgerichteten PET-Daten einzelnen, Atlas-spezifischen Teilregionen zugeordnet werden. Eine solche Subklassifikation des VOI erlaubt eine genauere Betrachtung und Auswertung der Radiotracer-Akkumulation. Des Weiteren bietet NU_DPA die Möglichkeit einer semiquantitativen Auswertung der PET-Bilddaten anhand von drei unterschiedlichen Parametern, der normalisierten Aktivität, dem Standardized Uptake Value und der Uptake Ratio. Durch die Matlab-integrierten Statistik-Algorithmen ist zusätzlich eine Möglichkeit der statistischen Auswertung der zuvor berechneten Parameter gegeben. Das NU_DPA-Programm stellt somit ein semi-automatisiertes Datenauswertungs-Programm dar, das sowohl die Registrierung als auch die semiquantitative Auswertung von PET-Bilddaten innerhalb einer Versuchsreihe ermöglicht und bereits erfolgreich für die Radiotracer [18F]FDG und [68Ga]Fucoidan in Tiermodellen getestet wurde. Nach derzeitigem Kenntnisstand ist kein Datenauswertungs-Programm bekannt, das PET-Bilddaten unter Verwendung des hinzugefügten Atlas‘ semi-automatisiert analysieren kann und potenziell für homogene und Target-spezifisch akkumulierende Radiotracer geeignet ist. N2 - Preclinical research represents the first important milestone in the clarification and investigation of clinically relevant diseases. In addition, preclinical research significantly supports the development of therapies. Small animal positron emission tomography (µ-PET) plays an important role in this context, as it is able to image and quantify functional, physiological and biochemical processes in vivo. Despite various established µ-PET data analysis programs, the analysis of in vivo acquired image data remains a major challenge in medicine due to the multitude of medical questions, the complexity of disease patterns, and the establishment of new radiotracers. Therefore, the aim of this PhD thesis is to develop and establish a suitable, usable evaluation tool for a simple and efficient analysis of acquired µ-PET data, which extends the spectrum of already existing programs. The developed nuclear medicine data processing analysis tool (NU_DPA) was implemented in Matlab and tested and established on the basis of three preclinical experimental or test series. The data series are µ-PET datasets of different stroke rat brain models using the following radiotracers: 2-[18F]fluoro-2-deoxy-glucose ([18F]FDG), which accumulates homogeneously in the brain and [68Ga]fucoidan, which specifically accumulates at p-selectin. The NU_DPA involves automatic segmentation of a volume-of-interest (VOI) from the full PET image and the subsequent alignment of the VOI using a PET template (averaged PET dataset). This PET template is created from the own acquired PET data. By embedding a suitable anatomical MR atlas (customizable), the aligned PET data can be assigned to individual atlas-specific sub-regions. Such a sub-classification of the VOI allows a more detailed analysis and evaluation of the radiotracer accumulation. Furthermore, NU_DPA offers the possibility of a semi-quantitative evaluation of the PET image data based on three different parameters, the normalized activity, the standardized uptake value and the uptake ratio. The Matlab-integrated statistical algorithms provide an additional option for statistical evaluation of the previously calculated semi-quantitative parameters. The NU_DPA program thus represents a semi-automatic data evaluation program that enables both the registration and the semi-quantitative evaluation of PET image data within a series of experiments and it has already been successfully tested for the radiotracers [18F]FDG and [68Ga]fucoidan in animal models. To the best of our current knowledge, there is no known data analysis program that can semi-automatically analyze PET image data using the added atlas and is potentially suitable for homogeneous and target-specific accumulating radiotracers. KW - PET KW - Präklinische Bildgebung Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-247499 ER - TY - JOUR A1 - Hänscheid, Heribert A1 - Hartrampf, Philipp E. A1 - Schirbel, Andreas A1 - Buck, Andreas K. A1 - Lapa, Constantin T1 - Intraindividual comparison of [\(^{177}\)Lu]Lu-DOTA-EB-TATE and [\(^{177}\)Lu]Lu-DOTA-TOC JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Purpose The radiolabelled somatostatin analogue [\(^{177}\)Lu]Lu-DOTA-EB-TATE binds to albumin via Evans blue, thereby increasing the residence time in the blood and potentially allowing more therapeutic agent to be absorbed into the target tissue during peptide receptor radionuclide therapy. It was tested in selected patients whether the substance is superior to [\(^{177}\)Lu]Lu-DOTA-TOC. Methods Activity kinetics in organs and tumours after [\(^{177}\)Lu]Lu-DOTA-EB-TATE and [\(^{177}\)Lu]Lu-DOTA-TOC were compared intraindividually in five patients with progressive somatostatin receptor-positive disease scheduled for radionuclide therapy. Resuluts In comparison to [\(^{177}\)Lu]Lu-DOTA-TOC, tumour doses per administered activity were higher for [\(^{177}\)Lu]Lu-DOTA-EB-TATE in 4 of 5 patients (median ratio: 1.7; range: 0.9 to 3.9), kidney doses (median ratio: 3.2; range: 1.6 to 9.8) as well as spleen doses (median ratio: 4.7; range 1.2 to 6.2) in all patients, and liver doses in 3 of 4 evaluable patients (median ratio: 4.0; range: 0.7 to 4.9). The tumour to critical organs absorbed dose ratios were higher after [\(^{177}\)Lu]Lu-DOTA-TOC in 4 of 5 patients. Conclusions Prior to a treatment with [\(^{177}\)Lu]Lu-DOTA-EB-TATE, it should be assessed individually whether the compound is superior to established substances. KW - intraindividual comparison KW - DOTA-EB-TATE KW - somatostatin receptor KW - evans blue KW - biokinetics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265470 SN - 1619-7089 VL - 48 IS - 8 ER - TY - JOUR A1 - Schumann, S. A1 - Eberlein, U. A1 - Lapa, C. A1 - Müller, J. A1 - Serfling, S. A1 - Lassmann, M. A1 - Scherthan, H. T1 - α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [\(^{223}\)Ra]RaCl\(_{2}\)-treated prostate cancer patients JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Purpose One therapy option for prostate cancer patients with bone metastases is the use of [\(^{223}\)Ra]RaCl\(_{2}\). The α-emitter \(^{223}\)Ra creates DNA damage tracks along α-particle trajectories (α-tracks) in exposed cells that can be revealed by immunofluorescent staining of γ-H2AX+53BP1 DNA double-strand break markers. We investigated the time- and absorbed dose-dependency of the number of α-tracks in peripheral blood mononuclear cells (PBMCs) of patients undergoing their first therapy with [\(^{223}\)Ra]RaCl\(_{2}\). Methods Multiple blood samples from nine prostate cancer patients were collected before and after administration of [\(^{223}\)Ra]RaCl\(_{2}\), up to 4 weeks after treatment. γ-H2AX- and 53BP1-positive α-tracks were microscopically quantified in isolated and immuno-stained PBMCs. Results The absorbed doses to the blood were less than 6 mGy up to 4 h after administration and maximally 16 mGy in total. Up to 4 h after administration, the α-track frequency was significantly increased relative to baseline and correlated with the absorbed dose to the blood in the dose range < 3 mGy. In most of the late samples (24 h - 4 weeks after administration), the α-track frequency remained elevated. Conclusion The γ-H2AX+53BP1 assay is a potent method for detection of α-particle-induced DNA damages during treatment with or after accidental incorporation of radionuclides even at low absorbed doses. It may serve as a biomarker discriminating α- from β-emitters based on damage geometry. KW - γ-H2AX KW - DNA damage KW - nuclear medicine KW - dosimetry KW - α-Emitter KW - biokinetics KW - prostate cancer KW - [\(^{223}\)Ra]RaCl\(_{2}\) KW - 53BP1 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265462 SN - 1619-7089 VL - 48 IS - 9 ER - TY - THES A1 - Messerschmidt, Konstantin Felix T1 - Einfluss der PSMA-Expression auf die Docetaxel-Sensitivität sowie systemischer Medikamente auf die Expression von PSMA, CXCR4 und SSTR2 T1 - Influence of PSMA expression on docetaxel sensitivity and of systemic drugs on PSMA, CXCR4 and SSTR2 expression N2 - Für das klinische Management des Prostatakarzinoms werden nuklearmedizinische Verfahren zunehmend relevant. Bildgebung und Therapie, welche gegen das Prostataspezifische Membranantigen (PSMA) gerichtet sind, werden bereits im klinischen Alltag angewendet. Weitere potenzielle Biomarker des Prostatakarzinoms, wie beispielsweise der CXC-Motiv-Chemokinrezeptor 4 (CXCR4) und der Somatostatinrezeptor Typ 2 (SSTR2), werden zudem als nuklearmedizinische Zielstrukturen diskutiert. Vorangegangene Arbeiten legten einen Zusammenhang zwischen dem Ausmaß der PSMA-Expression und der Sensitivität gegenüber Docetaxel in Prostatakarzinomzellen nahe. Ein Ziel der vorliegenden Arbeit war, diesen Mechanismus genauer zu untersuchen. Dabei wurden die Aktivität onkogener Signalwege, die Proliferation und die CXCR4- sowie die Androgenrezeptor (AR)- Expression in Prostatakarzinomzelllinien mit unterschiedlicher PSMA-Expression durchflusszytometrisch quantifiziert. Im zweiten Projektteil sollte der Einfluss von Metformin und verschiedener, bereits in der Prostatakarzinomtherapie angewandter Medikamente (Docetaxel, Dexamethason, Abirateron und Enzalutamid), auf die Expression von PSMA, CXCR4 und SSTR2 untersucht werden. Die Quantifizierung der Expression erfolgte mittels Durchflusszytometrie. Ein kausaler Mechanismus für den Zusammenhang zwischen PSMA-Expression und Docetaxel-Sensitivität konnte in dieser Arbeit schließlich nicht hergestellt werden. Es zeigten sich jedoch vor allem Expressionsmodulationen von PSMA und CXCR4. Mittels Docetaxel konnte z.B. bei C4-2 Zellen eine Verdopplung der PSMA-Expression und eine Verdreifachung der CXCR4-Expression erreicht werden. Darüber hinaus zeigte die Behandlung mit Abirateron eine deutliche Heraufregulation der PSMA- Expression bei LNCaP und C4-2 Zellen, sowie eine Zunahme der CXCR4- Expression bei allen untersuchten Zelllinien. Sollte sich der Einfluss der medikamentösen Behandlung auf die Expression von PSMA und CXCR4 bestätigen, kann dies zukünftig zur verbesserten und individualisierten Diagnostik und Therapie von Prostatakarzinompatienten beitragen. N2 - Nuclear medicine methods are becoming increasingly relevant for the clinical management of prostate carcinoma. Imaging and therapy directed against the prostate specific membrane antigen (PSMA) are already used in clinical practice. Other potential biomarkers of prostate cancer, such as CXC motif chemokine receptor 4 (CXCR4) and somatostatin receptor type 2 (SSTR2), are also being discussed as nuclear medicine targets. Previous work suggested a relationship between the level of PSMA expression and sensitivity to docetaxel in prostate cancer cells. One aim of the present work was to further investigate this mechanism. The activity of oncogenic signalling pathways, proliferation and CXCR4 expression as well as androgen receptor (AR) expression in prostate carcinoma cell lines with different PSMA expression were quantified by flow cytometry. In the second part of the study, the influence of metformin and various drugs already used in prostate carcinoma therapy (docetaxel, dexamethasone, abiraterone and enzalutamide) on the expression of PSMA, CXCR4 and SSTR2 was assessed. Expression was quantified by flow cytometry analysis. A causal mechanism for the connection between PSMA expression and docetaxel sensitivity could, eventually, not be established in this work. However, expression modulations were primarily found for PSMA and CXCR4. Using docetaxel, for instance, a doubling of PSMA expression and a tripling of CXCR4 expression could be achieved in C4-2 cells. In addition, treatment with abiraterone showed a significant upregulation of PSMA expression in LNCaP and C4-2 cells, as well as an increase in CXCR4 expression in all cell lines examined. If the influence of drug treatment on the expression of PSMA and CXCR4 is confirmed, this may contribute to improved and individualised diagnostics and therapy of prostate cancer patients. KW - Prostatakrebs KW - Docetaxel KW - Dexamethason KW - Metformin KW - Nuklearmedizin KW - PSMA KW - CXCR4 KW - SSTR2 KW - Akt KW - ERK1/2 KW - p38 KW - Abirateron KW - Enzalutamid KW - LNCaP KW - PC3 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283364 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Higuchi, Takahiro A1 - Pomper, Martin G. A1 - Rowe, Steven P. T1 - Theranostics in oncology — thriving, now more than ever JF - Diagnostics N2 - Tracing its roots back to the 1940s, theranostics in nuclear oncology has proved successful mainly due to the beneficial effects of image-guided therapeutic concepts for patients afflicted with a variety of different cancers. The majority of these treatments are not only characterized by substantial prolongation of progression-free and overall survival, but are also generally safe, rendering theranostic agents as an attractive treatment option in various clinical scenarios in oncology. In this Special Issue Novel Theranostic Agents, nine original articles from around the globe provide further evidence on the use of the theranostic concept for neuroendocrine neoplasm (NEN), prostate cancer (PC), meningioma, and neuroblastoma. The investigated diagnostic and therapeutic radiotracers target not only established structures, such as somatostatin receptor, prostate-specific membrane antigen or norepinephrine transporter, but also recently emerging targets such as the C-X-C motif chemokine receptor 4. Moreover, the presented original articles also combine the concept of theranostics with in-depth read-out techniques such as radiomics or novel reconstruction algorithms on pretherapeutic scans, e.g., for outcome prediction. Even 80 years after its initial clinical introduction, theranostics in oncology continues to thrive, now more than ever. KW - theranostics KW - somatostatin receptor (SSTR) KW - prostate-specific membrane antigen (PSMA) KW - prostate cancer KW - neuroendocrine neoplasms (NEN) KW - neuroendocrine tumors (NET) KW - meningioma KW - norepinephrine transporter KW - neuroblastoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236662 SN - 2075-4418 VL - 11 IS - 5 ER - TY - JOUR A1 - Khatri, Wajahat A1 - Chung, Hyun Woo A1 - Werner, Rudolf A. A1 - Leal, Jeffrey P. A1 - Pienta, Kenneth J. A1 - Lodge, Martin A. A1 - Gorin, Michael A. A1 - Pomper, Martin G. A1 - Rowe, Steven P. T1 - Effect of point-spread function reconstruction for indeterminate PSMA-RADS-3A lesions on PSMA-targeted PET imaging of men with prostate cancer JF - Diagnostics N2 - Purpose: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is emerging as an important modality for imaging patients with prostate cancer (PCa). As with any imaging modality, indeterminate findings will arise. The PSMA reporting and data system (PSMA-RADS) version 1.0 codifies indeterminate soft tissue findings with the PSMA-RADS-3A moniker. We investigated the role of point-spread function (PSF) reconstructions on categorization of PSMA-RADS-3A lesions. Methods: This was a post hoc analysis of an institutional review board approved prospective trial. Around 60 min after the administration of 333 MBq (9 mCi) of PSMA-targeted \(^{18}\)F-DCFPyL, patients underwent PET/computed tomography (CT) acquisitions from the mid-thighs to the skull vertex. The PET data were reconstructed with and without PSF. Scans were categorized according to PSMA-RADS version 1.0, and all PSMA-RADS-3A lesions on non-PSF images were re-evaluated to determine if any could be re-categorized as PSMA-RADS-4. The maximum standardized uptake values (SUVs) of the lesions, mean SUVs of blood pool, and the ratios of those values were determined. Results: A total of 171 PSMA-RADS-3A lesions were identified in 30 patients for whom both PSF reconstructions and cross-sectional imaging follow-up were available. A total of 13/171 (7.6%) were re-categorized as PSMA-RADS-4 lesions with PSF reconstructions. A total of 112/171 (65.5%) were found on follow-up to be true positive for PCa, with all 13 of the re-categorized lesions being true positive on follow-up. The lesions that were re-categorized trended towards having higher SUV\(_{max}\)-lesion and SUV\(_{max}\)-lesion/SUV\(_{mean}\)-blood-pool metrics, although these relationships were not statistically significant. Conclusions: The use of PSF reconstructions for \(^{18}\)F-DCFPyL PET can allow the appropriate re-categorization of a small number of indeterminate PSMA-RADS-3A soft tissue lesions as more definitive PSMA-RADS-4 lesions. The routine use of PSF reconstructions for PSMA-targeted PET may be of value at those sites that utilize this technology. KW - prostate-specific membrane antigen KW - reporting and data system KW - positron emission tomography Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236528 SN - 2075-4418 VL - 11 IS - 4 ER - TY - JOUR A1 - Weich, Alexander A1 - Rogoll, Dorothee A1 - Gawlas, Sophia A1 - Mayer, Lars A1 - Weich, Wolfgang A1 - Pongracz, Judit A1 - Kudlich, Theodor A1 - Meining, Alexander A1 - Scheurlen, Michael T1 - Wnt/β-catenin signaling regulates CXCR4 expression and [\(^{68}\)Ga] Pentixafor internalization in neuroendocrine tumor cells JF - Diagnostics N2 - Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [\(^{68}\)Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [\(^{68}\)Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified. KW - neuroendocrine tumor KW - NET KW - Wnt KW - β-catenin KW - CXCR4 KW - [\(^{68}\)Ga] Pentixafor KW - BON-1 KW - QGP-1 KW - MS-18 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228914 SN - 2075-4418 VL - 11 IS - 2 ER -