@phdthesis{Schadt2022, author = {Schadt, Fabian}, title = {Entwicklung und erste Validierung eines innovativen Analysen-Tools f{\"u}r pr{\"a}klinische Bewertungen von PET-Radiopharmazeutika zur \(in\) \(vivo\) Untersuchungen neurologischer Erkrankungen}, doi = {10.25972/OPUS-24749}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-247499}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die pr{\"a}klinische Forschung stellt den ersten wichtigen Meilenstein in der Kl{\"a}rung und Untersuchung klinisch-relevanter Erkrankungen dar. Dar{\"u}ber hinaus unterst{\"u}tzt die pr{\"a}klinische 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 Komplexit{\"a}t der Krankheitsbilder, sowie der Etablierung neuer Radiotracer weiterhin eine große Herausforderung in der Medizin. Ziel dieser Doktorarbeit ist es daher, ein geeignetes, brauchbares Auswertungstool f{\"u}r 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 pr{\"a}klinischer Versuchs- bzw. Testreihen erprobt und etabliert. Bei den Datenreihen handelt es sich um µ-PET-Datens{\"a}tze 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 vollst{\"a}ndigen 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) k{\"o}nnen 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 M{\"o}glichkeit einer semiquantitativen Auswertung der PET-Bilddaten anhand von drei unterschiedlichen Parametern, der normalisierten Aktivit{\"a}t, dem Standardized Uptake Value und der Uptake Ratio. Durch die Matlab-integrierten Statistik-Algorithmen ist zus{\"a}tzlich eine M{\"o}glichkeit 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 erm{\"o}glicht und bereits erfolgreich f{\"u}r 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 hinzugef{\"u}gten Atlas' semi-automatisiert analysieren kann und potenziell f{\"u}r homogene und Target-spezifisch akkumulierende Radiotracer geeignet ist.}, subject = {PET}, language = {de} } @article{TolstikAliGuoetal.2022, author = {Tolstik, Elen and Ali, Nairveen and Guo, Shuxia and Ebersbach, Paul and M{\"o}llmann, Dorothe and Arias-Loza, Paula and Dierks, Johann and Schuler, Irina and Freier, Erik and Debus, J{\"o}rg and Baba, Hideo A. and Nordbeck, Peter and Bocklitz, Thomas and Lorenz, Kristina}, title = {CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {10}, issn = {1422-0067}, doi = {10.3390/ijms23105345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284427}, year = {2022}, abstract = {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.}, language = {en} } @article{ChenWernerKoshinoetal.2022, author = {Chen, Xinyu and Werner, Rudolf A. and Koshino, Kazuhiro and Nose, Naoko and M{\"u}hlig, Saskia and Rowe, Steven P. and Pomper, Martin G. and Lapa, Constantin and Decker, Michael and Higuchi, Takahiro}, title = {Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity - Introducing High NET Affinity PET Probe \(^{18}\)F-AF78}, series = {Theranostics}, volume = {12}, journal = {Theranostics}, number = {9}, doi = {10.7150/thno.63205}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300685}, pages = {4446 -- 4458}, year = {2022}, abstract = {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.}, language = {en} } @article{TamihardjaZehnerHartrampfetal.2022, author = {Tamihardja, J{\"o}rg and Zehner, Leonie and Hartrampf, Philipp E. and Cirsi, Sinan and Wegener, Sonja and Buck, Andreas K. and Flentje, Michael and Polat, B{\"u}lent}, title = {Dose-escalated salvage radiotherapy for macroscopic local recurrence of prostate cancer in the prostate-specific membrane antigen positron emission tomography era}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers14194956}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290302}, year = {2022}, abstract = {Simple Summary Prostate cancer often relapses after initial radical prostatectomy, and salvage radiotherapy offers a second chance of cure for relapsed patients. Modern imaging techniques, especially prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), enable radiation oncologists to target radiotherapy at the involved sites of disease. In a group of patients, PSMA PET/CT imaging can detect a macroscopic local recurrence with or without locoregional lymph node metastasis. In these cases, an escalation of the radiotherapy dose is often considered for controlling the visible tumor mass. As the evidence for dose-escalated salvage radiotherapy for macroscopic recurrent prostate cancer after PSMA PET/CT imaging is still limited, we address this topic in the current analysis. We found that the outcome of patients with dose-escalated salvage radiotherapy for macroscopic prostate cancer recurrence is encouragingly favorable, while the toxicity is very limited. Abstract Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2\%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3-72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1\% (95\% CI: 81.1-97.8\%) and the three-year metastasis-free survival rate reached 96.2\% (95\% CI: 91.2-100.0\%). The cumulative three-year late grade 3 GU toxicity rate was 3.4\%. No late grade 3 GI toxicity occurred. Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates.}, language = {en} } @article{LeubeGustafssonLassmannetal.2022, author = {Leube, Julian and Gustafsson, Johan and Lassmann, Michael and Salas-Ramirez, Maikol and Tran-Gia, Johannes}, title = {Analysis of a deep learning-based method for generation of SPECT projections based on a large Monte Carlo simulated dataset}, series = {EJNMMI Physics}, volume = {9}, journal = {EJNMMI Physics}, issn = {2197-7364}, doi = {10.1186/s40658-022-00476-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300697}, year = {2022}, abstract = {Background In recent years, a lot of effort has been put in the enhancement of medical imaging using artificial intelligence. However, limited patient data in combination with the unavailability of a ground truth often pose a challenge to a systematic validation of such methodologies. The goal of this work was to investigate a recently proposed method for an artificial intelligence-based generation of synthetic SPECT projections, for acceleration of the image acquisition process based on a large dataset of realistic SPECT simulations. Methods A database of 10,000 SPECT projection datasets of heterogeneous activity distributions of randomly placed random shapes was simulated for a clinical SPECT/CT system using the SIMIND Monte Carlo program. Synthetic projections at fixed angular increments from a set of input projections at evenly distributed angles were generated by different u-shaped convolutional neural networks (u-nets). These u-nets differed in noise realization used for the training data, number of input projections, projection angle increment, and number of training/validation datasets. Synthetic projections were generated for 500 test projection datasets for each u-net, and a quantitative analysis was performed using statistical hypothesis tests based on structural similarity index measure and normalized root-mean-squared error. Additional simulations with varying detector orbits were performed on a subset of the dataset to study the effect of the detector orbit on the performance of the methodology. For verification of the results, the u-nets were applied to Jaszczak and NEMA physical phantom data obtained on a clinical SPECT/CT system. Results No statistically significant differences were observed between u-nets trained with different noise realizations. In contrast, a statistically significant deterioration was found for training with a small subset (400 datasets) of the 10,000 simulated projection datasets in comparison with using a large subset (9500 datasets) for training. A good agreement between synthetic (i.e., u-net generated) and simulated projections before adding noise demonstrates a denoising effect. Finally, the physical phantom measurements show that our findings also apply for projections measured on a clinical SPECT/CT system. Conclusion Our study shows the large potential of u-nets for accelerating SPECT/CT imaging. In addition, our analysis numerically reveals a denoising effect when generating synthetic projections with a u-net. Clinically interesting, the methodology has proven robust against camera orbit deviations in a clinically realistic range. Lastly, we found that a small number of training samples (e.g., ~ 400 datasets) may not be sufficient for reliable generalization of the u-net.}, language = {en} } @article{LisowskiTroemelLutyjetal.2022, author = {Lisowski, Dominik and Tr{\"o}mel, Jannik and Lutyj, Paul and Lewitzki, Victor and Hartrampf, Philipp E. and Polat, B{\"u}lent and Flentje, Michael and Tamihardja, J{\"o}rg}, title = {Health-related quality of life and clinical outcome after radiotherapy of patients with intracranial meningioma}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, doi = {10.1038/s41598-022-24192-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301233}, year = {2022}, abstract = {This retrospective, single-institutional study investigated long-term outcome, toxicity and health-related quality of life (HRQoL) in meningioma patients after radiotherapy. We analyzed the data of 119 patients who received radiotherapy at our department from 1997 to 2014 for intracranial WHO grade I-III meningioma. Fractionated stereotactic radiotherapy (FSRT), intensity modulated radiotherapy (IMRT) or radiosurgery radiation was applied. The EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed for assessment of HRQoL. Overall survival (OS) for the entire study group was 89.6\% at 5 years and 75.9\% at 10 years. Local control (LC) at 5 and 10 years was 82.4\% and 73.4\%, respectively. Local recurrence was observed in 22 patients (18.5\%). Higher grade acute and chronic toxicities were observed in seven patients (5.9\%) and five patients (4.2\%), respectively. Global health status was rated with a mean of 59.9 points (SD 22.3) on QLQ-C30. In conclusion, radiotherapy resulted in very good long-term survival and tumor control rates with low rates of severe toxicities but with a deterioration of long-term HRQoL.}, language = {en} } @article{AsterRomanosWalitzaetal.2022, author = {Aster, Hans-Christoph and Romanos, Marcel and Walitza, Susanne and Gerlach, Manfred and M{\"u}hlberger, Andreas and Rizzo, Albert and Andreatta, Marta and Hasenauer, Natalie and Hartrampf, Philipp E. and Nerlich, Kai and Reiners, Christoph and Lorenz, Reinhard and Buck, Andreas K. and Deserno, Lorenz}, title = {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}, series = {Frontiers in Psychiatry}, volume = {13}, journal = {Frontiers in Psychiatry}, issn = {1664-0640}, doi = {10.3389/fpsyt.2022.804730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270862}, year = {2022}, abstract = {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.}, language = {en} } @article{WernerHiguchiNoseetal.2022, author = {Werner, Rudolf A. and Higuchi, Takahiro and Nose, Naoko and Toriumi, Fujio and Matsusaka, Yohji and Kuji, Ichiei and Kazuhiro, Koshino}, title = {Generative adversarial network-created brain SPECTs of cerebral ischemia are indistinguishable to scans from real patients}, series = {Scientific reports}, volume = {12}, journal = {Scientific reports}, doi = {10.1038/s41598-022-23325-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300757}, year = {2022}, abstract = {Deep convolutional generative adversarial networks (GAN) allow for creating images from existing databases. We applied a modified light-weight GAN (FastGAN) algorithm to cerebral blood flow SPECTs and aimed to evaluate whether this technology can generate created images close to real patients. Investigating three anatomical levels (cerebellum, CER; basal ganglia, BG; cortex, COR), 551 normal (248 CER, 174 BG, 129 COR) and 387 pathological brain SPECTs using N-isopropyl p-I-123-iodoamphetamine (123I-IMP) were included. For the latter scans, cerebral ischemic disease comprised 291 uni- (66 CER, 116 BG, 109 COR) and 96 bilateral defect patterns (44 BG, 52 COR). Our model was trained using a three-compartment anatomical input (dataset 'A'; including CER, BG, and COR), while for dataset 'B', only one anatomical region (COR) was included. Quantitative analyses provided mean counts (MC) and left/right (LR) hemisphere ratios, which were then compared to quantification from real images. For MC, 'B' was significantly different for normal and bilateral defect patterns (P < 0.0001, respectively), but not for unilateral ischemia (P = 0.77). Comparable results were recorded for LR, as normal and ischemia scans were significantly different relative to images acquired from real patients (P ≤ 0.01, respectively). Images provided by 'A', however, revealed comparable quantitative results when compared to real images, including normal (P = 0.8) and pathological scans (unilateral, P = 0.99; bilateral, P = 0.68) for MC. For LR, only uni- (P = 0.03), but not normal or bilateral defect scans (P ≥ 0.08) reached significance relative to images of real patients. With a minimum of only three anatomical compartments serving as stimuli, created cerebral SPECTs are indistinguishable to images from real patients. The applied FastGAN algorithm may allow to provide sufficient scan numbers in various clinical scenarios, e.g., for "data-hungry" deep learning technologies or in the context of orphan diseases.}, language = {en} } @article{WernerHabachaLuetjeetal.2022, author = {Werner, Rudolf A. and Habacha, Bil{\^e}l and L{\"u}tje, Susanne and Bundschuh, Lena and Higuchi, Takahiro and Hartrampf, Philipp and Serfling, Sebastian E. and Derlin, Thorsten and Lapa, Constantin and Buck, Andreas K. and Essler, Markus and Pienta, Kenneth J. and Eisenberger, Mario A. and Markowski, Mark C. and Shinehouse, Laura and AbdAllah, Rehab and Salavati, Ali and Lodge, Martin A. and Pomper, Martin G. and Gorin, Michael A. and Bundschuh, Ralph A. and Rowe, Steven P.}, title = {High SUVs Have More Robust Repeatability in Patients with Metastatic Prostate Cancer: Results from a Prospective Test-Retest Cohort Imaged with \(^{18}\)F-DCFPyL}, series = {Molecular Imaging}, volume = {2022}, journal = {Molecular Imaging}, doi = {10.1155/2022/7056983}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300748}, year = {2022}, abstract = {No abstract available.}, language = {en} } @article{WenzArndtSamnick2022, author = {Wenz, Jan and Arndt, Felix and Samnick, Samuel}, title = {A new concept for the production of \(^{11}\)C-labelled radiotracers}, series = {EJNMMI Radiopharmacy and Chemistry}, volume = {7}, journal = {EJNMMI Radiopharmacy and Chemistry}, doi = {10.1186/s41181-022-00159-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300731}, year = {2022}, abstract = {Background The GMP-compliant production of radiopharmaceuticals has been performed using disposable units (cassettes) with a dedicated synthesis module. To expand this "plug 'n' synthesize" principle to a broader scope of modules we developed a pressure controlled setup that offers an alternative to the usual stepper motor controlled rotary valves. The new concept was successfully applied to the synthesis of N-methyl-[\(^{11}\)C]choline, L-S-methyl-[\(^{11}\)C]methionine and [11C]acetate. Results The target gas purification of cyclotron produced [\(^{11}\)C]CO\(_2\) and subsequent conversion to [\(^{11}\)C]MeI was carried out on a TRACERlab Fx C Pro module. The labelling reactions were controlled with a TRACERlab Fx FE module. With the presented modular principle we were able to produce N-methyl-[\(^{11}\)C]choline and L-S-methyl-[\(^{11}\)C]methionine by loading a reaction loop with neat N,N'-dimethylaminoethanol (DMAE) or an ethanol/water mixture of NaOH and L-homocysteine (L-HC), respectively and a subsequent reaction with [\(^{11}\)C]MeI. After 18 min N-methyl-[\(^{11}\)C]choline was isolated with 52\% decay corrected yield and a radiochemical purity of > 99\%. For L-S-methyl-[\(^{11}\)C]methionine the total reaction time was 19 min reaction, yielding 25\% of pure product (> 97\%). The reactor design was used as an exemplary model for the technically challenging [\(^{11}\)C]acetate synthesis. The disposable unit was filled with 1 mL MeMgCl (0.75 M) in tetrahydrofuran (THF) bevore [\(^{11}\)C]CO\(_2\) was passed through. After complete release of [\(^{11}\)C]CO\(_2\) the reaction mixture was quenched with water and guided through a series of ion exchangers (H\(^+\), Ag\(^+\) and OH\(^-\)). The product was retained on a strong anion exchanger, washed with water and finally extracted with saline. The product mixture was acidified and degassed to separate excess [\(^{11}\)C]CO\(_2\) before dispensing. Under these conditions the total reaction time was 18 ± 2 min and pure [\(^{11}\)C]acetate (n = 10) was isolated with a decay corrected yield of 51 ± 5\%. Conclusion Herein, we described a novel single use unit for the synthesis of carbon-11 labelled tracers for preclinical and clinical applications of N-methyl-[\(^{11}\)C]choline, L-S-methyl-[\(^{11}\)C]methionine and [11C]acetate.}, language = {en} } @article{PrietoGarciaHartmannReisslandetal.2022, author = {Prieto-Garcia, Cristian and Hartmann, Oliver and Reissland, Michaela and Braun, Fabian and Bozkurt, S{\"u}leyman and Pahor, Nikolett and Fuss, Carmina and Schirbel, Andreas and Sch{\"u}lein-V{\"o}lk, Christina and Buchberger, Alexander and Calzado Canale, Marco A. and Rosenfeldt, Mathias and Dikic, Ivan and M{\"u}nch, Christian and Diefenbacher, Markus E.}, title = {USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K}, series = {Molecular Oncology}, volume = {16}, journal = {Molecular Oncology}, number = {17}, doi = {10.1002/1878-0261.13217}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312777}, pages = {3082-3106}, year = {2022}, abstract = {Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a 'premalignant' state, and its inhibition synergizes with clinically established compounds used to target EGFR\(^{L858R}\)-, BRAF\(^{V600E}\)- or PI3K\(^{H1047R}\)-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.}, language = {en} } @article{MatsusakaWernerAriasLozaetal.2022, author = {Matsusaka, Yohji and Werner, Rudolf A. and Arias-Loza, Paula and Nose, Naoko and Sasaki, Takanori and Chen, Xinyu and Lapa, Constantin and Higuchi, Takahiro}, title = {Performance Evaluation of a Preclinical SPECT Scanner with a Collimator Designed for Medium-Sized Animals}, series = {Molecular Imaging}, volume = {2022}, journal = {Molecular Imaging}, doi = {10.1155/2022/9810097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300713}, year = {2022}, abstract = {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.}, language = {en} } @article{HartrampfWeinzierlSerflingetal.2022, author = {Hartrampf, Philipp E. and Weinzierl, Franz-Xaver and Serfling, Sebastian E. and Pomper, Martin G. and Rowe, Steven P. and Higuchi, Takahiro and Seitz, Anna Katharina and K{\"u}bler, Hubert and Buck, Andreas K. and Werner, Rudolf A.}, title = {Hematotoxicity and nephrotoxicity in prostate cancer patients undergoing radioligand therapy with [\(^{177}\)Lu]Lu-PSMA I\&T}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers14030647}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254825}, year = {2022}, abstract = {(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [\(^{177}\)Lu]Lu-PSMA I\&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [\(^{177}\)Lu]Lu-PSMA I\&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [\(^{99m}\)Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22\%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67\%) according to eGFR. Only 5/42 (13\%) showed reduced TER, defined as <70\% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2\% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1\%; GFR, 1/49 (2\%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2\%); G3a to G3b, 2/49 (4.1\%)). After three cycles, follow-up eGFR correlated negatively with age (r = -0.40, p = 0.005) and the eGFR change with Gleason score (r = -0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2\%) (CTCAE I, 20/49 (41\%)) and CTCAE I thrombocytopenia in 7/49 (14\%), with an absolute decrease of 15.2\% and 16.6\% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20\%) (CTCAE I, 36/49 (73\%)) with a decrease in hemoglobin of 4.7\%. (4) Conclusions: After PSMA-targeted therapy using [\(^{177}\)Lu]Lu-PSMA I\&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.}, language = {en} } @article{TamihardjaZehnerHartrampfetal.2022, author = {Tamihardja, J{\"o}rg and Zehner, Leonie and Hartrampf, Philipp and Lisowski, Dominik and Kneitz, Susanne and Cirsi, Sinan and Razinskas, Gary and Flentje, Michael and Polat, B{\"u}lent}, title = {Salvage nodal radiotherapy as metastasis-directed therapy for oligorecurrent prostate cancer detected by positron emission tomography shows favorable outcome in long-term follow-up}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {15}, issn = {2072-6694}, doi = {10.3390/cancers14153766}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286064}, year = {2022}, abstract = {Simple Summary Patients, who suffer from oligorecurrent prostate cancer with limited nodal involvement, may be offered positron emission tomography (PET)-directed salvage nodal radiotherapy to delay disease progression. This current analysis aimed to access salvage radiotherapy for nodal oligorecurrent prostate cancer with simultaneous integrated boost to PET-involved lymph nodes as metastasis-directed therapy. A long-term oncological outcome was favorable after salvage nodal radiotherapy and severe toxicity rates were low. Androgen deprivation therapy plays a major role in recurrent prostate cancer management and demonstrates a positive influence on the rate of biochemical progression in patients receiving salvage nodal radiotherapy. The present long-term analysis may help clinicians identify patients who would benefit from salvage nodal radiotherapy and androgen deprivation therapy, as a multimodal treatment strategy for oligorecurrent prostate cancer. Abstract Background: The study aimed to access the long-term outcome of salvage nodal radiotherapy (SNRT) in oligorecurrent prostate cancer. Methods: A total of 95 consecutive patients received SNRT for pelvic and/or extrapelvic nodal recurrence after prostate-specific membrane antigen (PSMA) or choline PET from 2010 to 2021. SNRT was applied as external beam radiotherapy with simultaneous integrated boost up to a median total dose of 62.9 Gy (EQD2\(_{1.5Gy}\)) to the recurrent lymph node metastases. The outcome was analyzed by cumulative incidence functions with death as the competing risk. Fine-Gray regression analyses were performed to estimate the relative hazards of the outcome parameters. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (v5.0). The results are as follows: the median follow-up was 47.1 months. The five-year biochemical progression rate (95\% CI) was 50.1\% (35.7-62.9\%). Concomitant androgen deprivation therapy (ADT) was adminstered in 60.0\% of the patients. The five-year biochemical progression rate was 75.0\% (42.0-90.9\%) without ADT versus 35.3\% (19.6-51.4\%) with ADT (p = 0.003). The cumulative five-year late grade 3 GU toxicity rate was 2.1\%. No late grade 3 GI toxicity occured. Conclusions: Metastasis-directed therapy through SNRT for PET-staged oligorecurrent prostate cancer demonstrated a favorable long-term oncologic outcome. Omittance of ADT led to an increased biochemical progression.}, language = {en} } @article{GargWernerChungetal.2022, author = {Garg, Tushar and Werner, Rudolf A. and Chung, Hyun Woo and Khatri, Wajahat and Pienta, Kenneth J. and Pomper, Martin G. and Gorin, Michael A. and Saad, Elie and Rowe, Steven P.}, title = {Association of true positivity with serum prostate-specific antigen levels and other clinical factors in indeterminate PSMA-RADS-3A lesions identified on \(^{18}\)F-DCFPyL PET/CT scans}, series = {Tomography}, volume = {8}, journal = {Tomography}, number = {6}, issn = {2379-139X}, doi = {10.3390/tomography8060220}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290510}, pages = {2639 -- 2647}, year = {2022}, abstract = {The use of prostate-specific membrane antigen targeted PET imaging for the evaluation of prostate cancer has increased significantly in the last couple of decades. When evaluating these imaging findings based on the PSMA reporting and data system version 1.0, which categorize lesions based on their likelihood of prostate cancer involvement, PSMA-RADS-3A lesions are commonly seen, which are indeterminate for the presence of disease. A total of 28 patients with 171 PSMA-RADS-3A lesions on \(^{18}\)F-DCFPyL PET/CT scans from June 2016 to May 2017 who had follow-up cross-sectional imaging over time were included in this study. The PSA levels of patients with PSMA-RADS-3A lesions were categorized into four groups, 0-0.2, 0.2-1, 1-2, and >2 ng/mL. The pre-operative Gleason score of these patients was categorized into two groups, Gleason score < 7 or ≥7. The median age for these patients was 72.5 years (range 59-81). The median PSA value for patients with positive lesions was significantly higher than those with negative lesions (5.8 ng/mL vs. 0.2 ng/mL, p < 0.0001). The lesion positivity rate was significantly higher in patients with PSA > 1 ng/mL (18.2\% vs. 81.9\%, p < 0.001). On ROC analysis, the highest classification accuracy was seen at PSA ≥ 0.6 ng/mL of 80.12\% (95\% CI = 73.69-86.16\%), and the area under the curve was 71.32\% (95\% CI = 61.9-80.7\%, p < 0.0001). A total of 96.4\% (108/112) of patients with positive lesions and 86.4\% (51/59) of patients with negative lesions had a PSMA-RADS-4/5 lymph node on the initial \(^{18}\)F-DCFPyL PET/CT scan (p = 0.02). In patients with a Gleason score ≥ 7, the presence of positive PSMA-RADS-3A lesions was higher, compared to negative PSMA-RADS-3A lesions (p = 0.049). Higher PSA levels in patients with PSMA-RADS-3A lesions can point towards the presence of true positivity. PSA levels may be considered in deciding whether to call an indeterminate lesion on PSMA PET.}, language = {en} } @article{LenschowWennmannHendricksetal.2022, author = {Lenschow, Christina and Wennmann, Andreas and Hendricks, Anne and Germer, Christoph-Thomas and Fassnacht, Martin and Buck, Andreas and Werner, Rudolf A. and Plassmeier, Lars and Schlegel, Nicolas}, title = {Questionable value of [\(^{99m}\)Tc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {8}, doi = {10.1007/s00423-022-02648-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323926}, pages = {3661-3669}, year = {2022}, abstract = {Purpose A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures. Methods A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels. Results From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13-93) years and 71\% were female. Neck ultrasound was carried out in 91.7\% and localized a PA in 76.6\%. In 23.4\% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4\% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4\% of patients (OR 13.23; 95\% CI 5.24-33.56). Conclusion [\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.}, language = {en} } @article{SerflingLapaDreheretal.2022, author = {Serfling, Sebastian E. and Lapa, Constantin and Dreher, Niklas and Hartrampf, Philipp E. and Rowe, Steven P. and Higuchi, Takahiro and Schirbel, Andreas and Weich, Alexander and Hahner, Stefanie and Fassnacht, Martin and Buck, Andreas K. and Werner, Rudolf A.}, title = {Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT}, series = {Molecular Imaging and Biology}, volume = {24}, journal = {Molecular Imaging and Biology}, number = {4}, doi = {10.1007/s11307-022-01717-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324622}, pages = {659-665}, year = {2022}, abstract = {Background CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. Methods Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. Results Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 - 10.55), 3.27 for the kidneys (range, 1.52 - 17.4), followed by bone marrow (1.76, range, 0.84 - 3.98), heart (1.66, range, 0.88 - 2.89), and liver (1.28, range, 0.73 - 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. Conclusions In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.}, language = {en} } @article{WeichHiguchiBundschuhetal.2022, author = {Weich, Alexander and Higuchi, Takahiro and Bundschuh, Ralph A. and Lapa, Constantin and Serfling, Sebastian E. and Rowe, Steven P. and Pomper, Martin G. and Herrmann, Ken and Buck, Andreas K. and Derlin, Thorsten and Werner, Rudolf A.}, title = {Training on reporting and data system (RADS) for somatostatin-receptor targeted molecular imaging can reduce the test anxiety of inexperienced readers}, series = {Molecular Imaging and Biology}, volume = {24}, journal = {Molecular Imaging and Biology}, number = {4}, doi = {10.1007/s11307-022-01712-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324645}, pages = {631-640}, year = {2022}, abstract = {Purpose For somatostatin receptor (SSTR)-positron emission tomography/computed tomography (PET/CT), a standardized framework termed SSTR-reporting and data system (RADS) has been proposed. We aimed to elucidate the impact of a RADS-focused training on reader's anxiety to report on SSTR-PET/CT, the motivational beliefs in learning such a system, whether it increases reader's confidence, and its implementation in clinical routine. Procedures A 3-day training course focusing on SSTR-RADS was conducted. Self-report questionnaires were handed out prior to the course (Pre) and thereafter (Post). The impact of the training on the following categories was evaluated: (1) test anxiety to report on SSTR-PET/CT, (2) motivational beliefs, (3) increase in reader's confidence, and (4) clinical implementation. To assess the effect size of the course, Cohen's d was calculated (small, d = 0.20; large effect, d = 0.80). Results Of 22 participants, Pre and Post were returned by 21/22 (95.5\%). In total, 14/21 (66.7\%) were considered inexperienced (IR, < 1 year experience in reading SSTR-PET/CTs) and 7/21 (33.3\%) as experienced readers (ER, > 1 year). Applying SSTR-RADS, a large decrease in anxiety to report on SSTR-PET/CT was noted for IR (d =  - 0.74, P = 0.02), but not for ER (d = 0.11, P = 0.78). For the other three categories motivational beliefs, reader's confidence, and clinical implementation, agreement rates were already high prior to the training and persisted throughout the course (P ≥ 0.21). Conclusions A framework-focused reader training can reduce anxiety to report on SSTR-PET/CTs, in particular for inexperienced readers. This may allow for a more widespread adoption of this system, e.g., in multicenter trials for better intra- and interindividual comparison of scan results.}, language = {en} } @article{LambertiniHartrampfHiguchietal.2022, author = {Lambertini, Alessandro and Hartrampf, Philipp E. and Higuchi, Takahiro and Serfling, Sebastian E. and Meybohm, Patrick and Schirbel, Andreas and Buck, Andreas K. and Werner, Rudolf A.}, title = {CXCR4-targeted molecular imaging after severe SARS-Cov-2 infection}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {50}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {1}, doi = {10.1007/s00259-022-05932-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324619}, pages = {228-229}, year = {2022}, abstract = {No abstract available.}, language = {en} } @article{GoeringSchumannMuelleretal.2022, author = {G{\"o}ring, Lukas and Schumann, Sarah and M{\"u}ller, Jessica and Buck, Andreas K. and Port, Matthias and Lassmann, Michael and Scherthan, Harry and Eberlein, Uta}, title = {Repair of a-particle-induced DNA damage in peripheral blood mononuclear cells after internal ex vivo irradiation with \(^{223}\)Ra}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05860-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324557}, pages = {3981-3988}, year = {2022}, abstract = {Purpose As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [\(^{223}\)Ra]RaCl2. Methods Blood samples of ten volunteers were irradiated by adding [\(^{223}\)Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. Results For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h-1 for 25 mGy, (0.16 ± 0.04) h-1 for 50 mGy and (0.13 ± 0.02) h-1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. Conclusion The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.}, language = {en} }