@unpublished{WernerAndreeJavadietal.2018, author = {Werner, Rudolf A. and Andree, Christian and Javadi, Mehrbod S. and Lapa, Constantin and Buck, Andreas K. and Higuchi, Takahiro and Pomper, Martin G. and Gorin, Michael A. and Rowe, Steven P. and Pienta, Kenneth J.}, title = {A Voice From the Past: Re-Discovering the Virchow Node with PSMA-targeted \(^{18}\)F-DCFPyL PET Imaging}, series = {Urology - The Gold Journal}, journal = {Urology - The Gold Journal}, issn = {0090-4295}, doi = {10.1016/j.urology.2018.03.030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161103}, year = {2018}, abstract = {No abstract available.}, subject = {Virchow Node}, language = {en} } @article{WernerAndreeJavadietal.2018, author = {Werner, Rudolf A. and Andree, Christian and Javadi, Mehrbod S. and Lapa, Constantin and Buck, Andreas K. and Higuchi, Takahiro and Pomper, Martin G. and Gorin, Michael A. and Rowe, Steven P. and Pienta, Kenneth J.}, title = {A Voice From the Past: Re-Discovering the Virchow Node with PSMA-targeted \(^{18}\)F-DCFPyL PET Imaging}, series = {Urology - The Gold Journal}, volume = {117}, journal = {Urology - The Gold Journal}, issn = {0090-4295}, doi = {10.1016/j.urology.2018.03.030}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164632}, pages = {18-21}, year = {2018}, abstract = {No abstract available.}, language = {en} } @inproceedings{WernerHayakawaAriasLozaetal.2017, author = {Werner, Rudolf and Hayakawa, Nobuyuki and Arias-Loza, Paula-Anah and Wakabayashi, Hiroshi and Shinaji, Tetsuya and Lapa, Constantin and Pelzer, Theo and Higuchi, Takahiro}, title = {Bildgebung der fr{\"u}hen linksventrikul{\"a}ren Dysfunktion mit ECG-gated F-18-FDG PET in einem Diabetes-Ratten-Modell}, series = {Nuklearmedizin}, volume = {56}, booktitle = {Nuklearmedizin}, number = {2}, publisher = {Schattauer Verlag}, issn = {0029-5566}, doi = {10.3413/Nukmed-0880-17-02}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161396}, pages = {Abstract Nr.: V119}, year = {2017}, abstract = {Einleitung: Die linksventrikul{\"a}re diastolische Dysfunktion (LVDD) ist bei Diabetikern noch vor Entwicklung einer klinisch apparenten Herzinsuffizienz eines der ersten Anzeichen einer kardialen Beteiligung. Daher soll in dieser Studie untersucht werden, ob die LVDD mit ECG-gated F-18-FDG PET in einem Diabetes-Rattenmodell dargestellt werden kann. Methodik: Es wurden F-18-FDG PET Scans in einem Typ-2-Diabetes Rattenmodell (ZDF fa/fa, n=6) und in ZL Kontrollen (n=6) vorgenommen (Alter, jeweils 13 Wochen). Unter Hyperinsulinemic-Euglycemic Clamp-Technik wurden 37 MBq 18F-FDG {\"u}ber die Schwanzvene appliziert. 15-35 Minuten nach Tracergabe wurden mittels eines Kleintier-PET-Scanners sowie unter EKG-Ableitung PET Scans angefertigt (16 frames/cardiac cycle). Die linksventrikul{\"a}re Ejektionsfraktion (EF) und die Peak F{\"u}llrate (PFR) wurden mittels einer geeigneten Software (Heart Function View) gemessen, wobei die Software an die Gr{\"o}ße des Rattenherzes angepasst wurde. Ergebnisse: Im Alter von 13 Wochen entwickeln ZDF Diabetes-Ratten eine im Vergleich zu Kontrolltieren eine signifikante myokardiale Hypertrophie, best{\"a}tigt durch post-mortem Analyse des Herzgewichtes (994±78mg vs. 871±44mg in ZDF Diabetes-Ratten vs. ZL Kontrollen, p<0.01). ECG-gated PET zeigte eine signifikante Abnahme der LV diastolischen PFR (10.4±0.5 vs. 11.8±0.4 EDV/sec in ZDF Diabetes-Ratten vs. ZL Kontrollen, p<0.001), jedoch zeigte sich kein signifikanter Unterschied zwischen LVEF und der Herzfrequenz in den untersuchten ZDF Diabetes-Ratten und Kontrollen (LVEF: 60.0±4.5 vs. 63.7±4.1\%, n.s. und HR: 305±25 vs. 323±24 bpm, n.s.). Schlussfolgerung: Im Diabetes-Ratten-Modell kann unter Verwendung eines ECG-gated FDG-PET Protokolls die diastolische Dysfunktion als Parameter der fr{\"u}hen diabetischen Kardiomyopathie nachgewiesen werden.}, subject = {Positronen-Emissions-Tomografie}, language = {de} } @inproceedings{WernerMarcusSheikhbahaeietal.2018, author = {Werner, Rudolf A. and Marcus, Charles and Sheikhbahaei, Sara and Higuchi, Takahiro and Solnes, Lilja B. and Rowe, Steven P. and Buck, Andreas K. and Lapa, Constantin and Javadi, Mehrbod S.}, title = {Diagnostic Accuracy of Visual Assessment of an Initial DaT-Scan in Comparison to a Fully Automatic Semiquantitative Method}, series = {Journal of Nuclear Medicine}, volume = {59}, booktitle = {Journal of Nuclear Medicine}, number = {Supplement No. 1}, issn = {0161-5505}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-162208}, pages = {626}, year = {2018}, abstract = {No abstract available.}, subject = {Parkinson-Krankheit}, language = {en} } @inproceedings{WernerKobayashiWakabayashietal.2017, author = {Werner, Rudolf and Kobayashi, Ryohei and Wakabayashi, Hiroshi and Lapa, Constantin and Menke, Andreas and Higuchi, Takahiro}, title = {Effect of Antidepressants on Radiolabeled Metaiodobenzylguanidine (MIBG) Uptake}, series = {European Heart Journal - Cardiovascular Imaging}, volume = {18}, booktitle = {European Heart Journal - Cardiovascular Imaging}, number = {Supplement}, publisher = {Oxford University Press}, issn = {2047-2404}, doi = {10.1093/ehjci/jex080}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161116}, pages = {i52-53}, year = {2017}, abstract = {No abstract available.}, subject = {MIBG}, language = {en} } @unpublished{YinWernerHiguchietal.2018, author = {Yin, Yafu and Werner, Rudolf A. and Higuchi, Takahiro and Lapa, Constantin and Pienta, Kenneth J. and Pomper, Martin G. and Gorin, Michael A. and Rowe, Steven P.}, title = {Follow-Up of Lesions with Equivocal Radiotracer Uptake on PSMA-Targeted PET in Patients with Prostate Cancer: Predictive Values of the PSMA-RADS-3A and PSMARADS- 3B Categories}, series = {Journal of Nuclear Medicine}, journal = {Journal of Nuclear Medicine}, issn = {0161-5505}, doi = {10.2967/jnumed.118.217653}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167594}, year = {2018}, abstract = {Purpose: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has become commonly utilized in patients with prostate cancer (PCa). The PSMA reporting and data system version 1.0 (PSMA-RADS version 1.0) categorizes lesions on the basis of the likelihood of PCa involvement, with PSMA-RADS-3A (soft tissue) and PSMA-RADS-3B (bone) lesions being indeterminate for the presence of disease. We retrospectively reviewed the imaging follow-up of such lesions to determine the rate at which they underwent changes suggestive of underlying PCa. Methods: PET/CT imaging with \(^{18}\)F-DCFPyL was carried out in 110 patients with PCa and lesions were categorized according to PSMA-RADS Version 1.0. 56/110 (50.9\%) patients were determined to have indeterminate PSMA-RADS-3A or PSMA-RADS-3B lesions and 22/56 (39.3\%) patients had adequate follow-up to be included in the analysis. The maximum standardized uptake values (SUV\(_{max}\)) of the lesions were obtained and the ratios of SUV\(_{max}\) of the lesions to SUV\(_{mean}\) of blood pool (SUV\(_{max}\)-lesion/SUV\(_{mean}\)-bloodpool) were calculated. Pre-determined criteria were used to evaluate the PSMA-RADS-3A and PSMA-RADS-3B lesions on follow-up imaging to determine if they demonstrated evidence of underlying malignancy. Results: A total of 46 lesions in 22 patients were considered indeterminate for PCa (i.e. PSMA-RADS-3A (32 lesions) or PSMA-RADS-3B (14 lesions)) and were evaluable on follow-up imaging. 27/46 (58.7\%) lesions demonstrated changes on follow-up imaging consistent with the presence of underlying PCa at baseline. These lesions included 24/32 (75.0\%) PSMA-RADS-3A lesions and 3/14 (21.4\%) lesions categorized as PSMA-RADS-3B. The ranges of SUVmax and SUVmax-lesion/SUVmean-bloodpool overlapped between those lesions demonstrating changes consistent with malignancy on follow-up imaging and those lesions that remained unchanged on follow-up. Conclusion: PSMA-RADS-3A and PSMA-RADS-3B lesions are truly indeterminate in that proportions of findings in both categories demonstrate evidence of malignancy on follow-up imaging. Overall, PSMA-RADS-3A lesions are more likely than PSMA-RADS-3B lesions to represent sites of PCa and this information should be taken into when guiding patient therapy.}, subject = {Positronen-Emissions-Tomografie}, language = {en} } @article{WernerWakabyashiChenetal.2018, author = {Werner, Rudolf and Wakabyashi, Hiroshi and Chen, Xinyu and Hirano, Mitsuru and Shinaji, Tetsuya and Lapa, Constantin and Rowe, Steven and Javadi, Mehrbod and Higuchi, Takahiro}, title = {Functional renal imaging with \(^{18}\)F-FDS PET in rat models of renal disorders}, series = {Journal of Nuclear Medicine}, journal = {Journal of Nuclear Medicine}, issn = {0161-5505}, doi = {10.2967/jnumed.117.203828}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161279}, year = {2018}, abstract = {Background: Precise regional quantitative assessment of renal function is limited with conventional \(^{99m}\)Tc-labeled renal radiotracers. A recent study reported that the positron emission tomography (PET) radiotracer 2-deoxy-2-(\(^{18}\)F-fluorosorbitol (\(^{18}\)F-FDS) has ideal pharmacokinetics for functional renal imaging. Furthermore, (\(^{18}\)F-FDS is available via simple reduction from routinely used 2-deoxy-2-(\(^{18}\)F-fluoro-D-glucose ((\(^{18}\)F-FDG). We aimed to further investigate the potential of (\(^{18}\)F-FDS PET as a functional renal imaging agent using rat models of kidney diseases. Methods: Two different rat models of renal impairment were investigated: Glycerol induced acute renal failure (ARF) by intramuscular administration of glycerol in hind legs and unilateral ureteral obstruction (UUO) by ligation of the left ureter. 24h after these treatments, dynamic 30 min 18F-FDS PET data were acquired using a dedicated small animal PET system. Urine 18F-FDS radioactivity 30 min after radiotracer injection was measured together with co-injected \(^{99m}\)Tc-diethylenetriaminepentaacetic acid (\(^{99m}\)Tc-DTPA) urine activity. Results: Dynamic PET imaging demonstrated rapid (\(^{18}\)F-FDS accumulation in the renal cortex and rapid radiotracer excretion via kidneys in control healthy rats. On the other hand, significantly delayed renal radiotracer uptake (continuous slow uptake) was observed in ARF rats and UUO-treated kidneys. Measured urine radiotracer concentrations of (\(^{18}\)F-FDS and \(^{99m}\)Tc-DTPA were well correlated (R=0.84, P<0.05). Conclusions: (\(^{18}\)F-FDS PET demonstrated favorable kinetics for functional renal imaging in rat models of kidney diseases. Advantages of high spatiotemporal resolution of PET imaging and simple tracer production could potentially complement or replace conventional renal scintigraphy in select cases and significantly improve the diagnostic performance of renal functional imaging.}, subject = {Nierenfunktionsst{\"o}rung}, language = {en} } @article{KazuhinoWernerToriumietal.2018, author = {Kazuhino, Koshino and Werner, Rudolf A. and Toriumi, Fuijo and Javadi, Mehrbod S. and Pomper, Martin G. and Solnes, Lilja B. and Verde, Franco and Higuchi, Takahiro and Rowe, Steven P.}, title = {Generative Adversarial Networks for the Creation of Realistic Artificial Brain Magnetic Resonance Images}, series = {Tomography}, volume = {4}, journal = {Tomography}, number = {4}, doi = {10.18383/j.tom.2018.00042}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172185}, pages = {159-163}, year = {2018}, abstract = {Even as medical data sets become more publicly accessible, most are restricted to specific medical conditions. Thus, data collection for machine learning approaches remains challenging, and synthetic data augmentation, such as generative adversarial networks (GAN), may overcome this hurdle. In the present quality control study, deep convolutional GAN (DCGAN)-based human brain magnetic resonance (MR) images were validated by blinded radiologists. In total, 96 T1-weighted brain images from 30 healthy individuals and 33 patients with cerebrovascular accident were included. A training data set was generated from the T1-weighted images and DCGAN was applied to generate additional artificial brain images. The likelihood that images were DCGAN-created versus acquired was evaluated by 5 radiologists (2 neuroradiologists [NRs], vs 3 non-neuroradiologists [NNRs]) in a binary fashion to identify real vs created images. Images were selected randomly from the data set (variation of created images, 40\%-60\%). None of the investigated images was rated as unknown. Of the created images, the NRs rated 45\% and 71\% as real magnetic resonance imaging images (NNRs, 24\%, 40\%, and 44\%). In contradistinction, 44\% and 70\% of the real images were rated as generated images by NRs (NNRs, 10\%, 17\%, and 27\%). The accuracy for the NRs was 0.55 and 0.30 (NNRs, 0.83, 0.72, and 0.64). DCGAN-created brain MR images are similar enough to acquired MR images so as to be indistinguishable in some cases. Such an artificial intelligence algorithm may contribute to synthetic data augmentation for "data-hungry" technologies, such as supervised machine learning approaches, in various clinical applications.}, subject = {Magnetresonanztomografie}, language = {en} } @article{WernerWeichHiguchietal.2017, author = {Werner, Rudolf A. and Weich, Alexander and Higuchi, Takahiro and Schmid, Jan S. and Schirbel, Andreas and Lassmann, Michael and Wild, Vanessa and Rudelius, Martina and Kudlich, Theodor and Herrmann, Ken and Scheurlen, Michael and Buck, Andreas K. and Kropf, Saskia and Wester, Hans-J{\"u}rgen and Lapa, Constantin}, title = {Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {6}, doi = {10.7150/thno.18754}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158008}, pages = {1489-1498}, year = {2017}, abstract = {C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50\% of G2 and 80\% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.}, subject = {Positronen-Emissions-Tomografie}, language = {en} } @article{WernerKobayashiJavadietal.2018, author = {Werner, Rudolf A. and Kobayashi, Ryohei and Javadi, Mehrbod Som and K{\"o}ck, Zoe and Wakabayashi, Hiroshi and Unterecker, Stefan and Nakajima, Kenichi and Lapa, Constantin and Menke, Andreas and Higuchi, Takahiro}, title = {Impact of Novel Antidepressants on Cardiac Metaiodobenzylguanidine (mIBG) Uptake: Experimental Studies in SK-N-SH Cells and Healthy Rabbits}, series = {Journal of Nuclear Medicine}, journal = {Journal of Nuclear Medicine}, issn = {0161-5505}, doi = {10.2967/jnumed.117.206045}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161280}, year = {2018}, abstract = {Background: \(^{123}\)I-metaiodobenzylguanidine (mIBG) provides independent prognostic value for risk stratification among heart failure patients, but the use of concomitant medication should not impact its quantitative information. We aimed to evaluate the four most-prescribed antidepressants currently used as a first‑line treatment for patients with major depressive disorder (MDD) and their potential on altering mIBG imaging results. Methods: The inhibition effect of four different types of antidepressants (desipramine, escitalopram, venlafaxine and bupropion) for MDD treatment on \(^{131}\)I-mIBG uptake was assessed by in-vitro cell uptake assays using human neuroblastoma SK-N-SH cells. The half maximal inhibitory concentration (IC50) of tracer uptake was determined from dose-response curves. To evaluate the effects of IV pretreatment with desipramine (1.5 mg/kg) and escitalopram (2.5, 15 mg/kg) on mIBG cardiac uptake, in-vivo planar 123I-mIBG scans in healthy New Zealand White Rabbits were conducted. Results: The IC50 values of desipramine, escitalopram, venlafaxine and bupropion on \(^{131}\)I-mIBG cellular uptake were 11.9 nM, 7.5 μM, 4.92 μM, and 12.9 μM, respectively. At the maximum serum concentration (Cmax, as derived by previous clinical trials), the inhibition rates of 131I-mIBG uptake were 90.6 \% for desipramine, 25.5 \% for venlafaxine, 11.7 \% for bupropion and 0.72 \% for escitalopram. A low inhibition rate for escitalopram in the cell uptake study triggered investigation of an in-vivo rabbit model: with dosage considerably higher than clinical practice, the non-inhibitory effect of escitalopram was confirmed. Furthermore, pretreatment with desipramine led to a marked reduction of cardiac 123I-mIBG uptake. Conclusions: In the present in-vitro binding assay and in-vivo rabbit study, the selective-serotonin reuptake inhibitor escitalopram had no major impact on neuronal cardiac mIBG uptake within therapeutic dose ranges, while other types of first-line antidepressants for MDD treatment led to a significant decrease. These preliminary results warrant further confirmatory clinical trials regarding the reliability of cardiac mIBG imaging, in particular, if the patient's neuropsychiatric status would not tolerate withdrawal of a potentially norepinephrine interfering antidepressant.}, subject = {Antidepressants}, language = {en} } @article{WernerHaenscheidLealetal.2018, author = {Werner, Rudolf and H{\"a}nscheid, Heribert and Leal, Jeffrey P. and Javadi, Mehrbod S. and Higuchi, Takahiro and Lodge, Martin A. and Buck, Andreas K. and Pomper, Martin G. and Lapa, Constantin and Rowe, Steven P.}, title = {Impact of Tumor Burden on Quantitative [\(^{68}\)Ga]DOTATOC Biodistribution}, series = {Molecular Imaging and Biology}, journal = {Molecular Imaging and Biology}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170280}, pages = {1-9}, year = {2018}, abstract = {Purpose: As has been previously reported, the somatostatin receptor (SSTR) imaging agent [\(^{68}\)Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotate ([\(^{68}\)Ga]DOTATATE) demonstrates lower uptake in normal organs in patients with a high neuroendocrine tumor (NET) burden. Given the higher SSTR affinity of [\(^{68}\)Ga]DOTATATE, we aimed to quantitatively investigate the biodistribution of [\(^{68}\)Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ([68Ga]DOTATOC) to determine a potential correlation between uptake in normal organs and NET burden. Procedures: Of the 44 included patients, 36/44 (82\%) patients demonstrated suspicious radiotracer uptake on [\(^{68}\)Ga]DOTATOC positron emission tomography (PET)/x-ray computed tomography (CT). Volumes of Interest (VOIs) were defined for tumor lesions and normal organs (spleen, liver, kidneys, adrenals). Mean body weight corrected standardized uptake value (SUV\(_{mean}\)) for normal organs was assessed and was used to calculate the corresponding mean specific activity uptake (Upt: fraction of injected activity per kg of tissue). For the entire tumor burden, SUV\(_{mean}\), maximum standardized uptake value (SUV\(_{max}\)), and the total mass (TBM) was calculated and the decay corrected tumor fractional uptake (TBU) was assessed. A Spearman's rank correlation coefficient was used to determine the correlations between normal organ uptake and tumor burden. Results: The median SUV\(_{mean}\) was 18.7 for the spleen (kidneys, 9.2; adrenals, 6.8; liver, 5.6). For tumor burden, the median values were SUV\(_{mean}\) 6.9, SUV\(_{max}\) 35.5, TBM 42.6g, and TBU 1.2\%. With increasing volume of distribution, represented by lean body mass and body surface area (BSA), Upt decreased in kidneys, liver, and adrenal glands and SUV\(_{mean}\) increased in the spleen. Correlation improved only for both kidneys and adrenals when the influence of the tumor uptake on the activity available for organ uptake was taken into account by the factor 1/(1-TBU). TBU was neither predictive for SUV\(_{mean}\) nor for Upt in any of the organs. The distribution of organ Upt vs. BSA/(1-TBU) were not different for patients with minor TBU (<3\%) vs. higher TBU (>7\%), indicating that the correlations observed in the present study are explainable by the body size effect. High tumor mass and uptake mitigated against G1 NET. Conclusions: There is no significant impact on normal organ biodistribution with increasing tumor burden on [\(^{68}\)Ga]DOTATOC PET/CT. Potential implications include increased normal organ dose with [\(^{177}\)Lu-DOTA]\(^0\)-D-Phe\(^1\)-Tyr\(^3\)-Octreotide and decreased absolute lesion detection with [\(^{68}\)Ga]DOTATOC in high NET burden.}, subject = {Positronen-Emissions-Tomografie}, language = {en} } @unpublished{WernerBundschuhBundschuhetal.2018, author = {Werner, Rudolf A. and Bundschuh, Ralph A. and Bundschuh, Lena and Javadi, Mehrbod S. and Leal, Jeffrey P. and Higuchi, Takahiro and Pienta, Kenneth J. and Buck, Andreas K. and Pomper, Martin G. and Gorin, Michael A. and Lapa, Constantin and Rowe, Steven P.}, title = {Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on \(^{18}\)F-DCFPyL PET/CT Imaging}, series = {Journal of Nuclear Medicine}, journal = {Journal of Nuclear Medicine}, issn = {0161-5505}, doi = {10.2967/jnumed.118.217588}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167788}, year = {2018}, abstract = {Objectives: Recently, the standardized reporting and data system for prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging studies, termed PSMA-RADS version 1.0, was introduced. We aimed to determine the interobserver agreement for applying PSMA-RADS to imaging interpretation of 18F-DCFPyL PET examinations in a prospective setting mimicking the typical clinical work-flow at a prostate cancer referral center. Methods: Four readers (two experienced readers (ER, > 3 years of PSMA-targeted PET interpretation experience) and two inexperienced readers (IR, < 1 year of experience)), who had all read the initial publication on PSMA-RADS 1.0, assessed 50 18F-DCFPyL PET/computed tomography (CT) studies independently. Per scan, a maximum of 5 target lesions were selected by the observers and a PSMA-RADS score for every target lesion was recorded. No specific pre-existing conditions were placed on the selection of the target lesions, although PSMA-RADS 1.0 suggests that readers focus on the most highly avid or largest lesions. An overall scan impression based on PSMA-RADS was indicated and interobserver agreement rates on a target lesion-based, on an organ-based, and on an overall PSMA-RADS score-based level were computed. Results: The number of target lesions identified by each observer were as follows: ER 1, 123; ER 2, 134; IR 1, 123; and IR 2, 120. Among those selected target lesions, 125 were chosen by at least two individual observers (all four readers selected the same target lesion in 58/125 (46.4\%) instances, three readers in 40/125 (32\%) and two observers in 27/125 (21.6\%) instances). The interobserver agreement for PSMA-RADS scoring among identical target lesions was good (intraclass correlation coefficient (ICC) for four, three and two identical target lesions, ≥0.60, respectively). For lymph nodes, an excellent interobserver agreement was derived (ICC=0.79). The interobserver agreement for an overall scan impression based on PSMA-RADS was also excellent (ICC=0.84), with a significant difference for ER (ICC=0.97) vs. IR (ICC=0.74, P=0.005). Conclusions: PSMA-RADS demonstrates a high concordance rate in this study, even among readers with different levels of experience. This suggests that PSMA-RADS can be effectively used for communication with clinicians and can be implemented in the collection of data for large prospective trials.}, subject = {Positronen-Emissions-Tomografie}, language = {en} } @inproceedings{WernerChenLapaetal.2017, author = {Werner, Rudolf and Chen, Xinyu and Lapa, Constantin and Robinson, Simon and Higuchi, Takahiro}, title = {Intracellular behavior of the novel sympathetic nerve agent \(^{18}\)F-LMI1195}, series = {Journal of Nuclear Cardiology}, volume = {24}, booktitle = {Journal of Nuclear Cardiology}, number = {4 Supplement (2017) Aug}, issn = {1071-3581}, doi = {10.1007/s12350-017-0984-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161137}, pages = {1461-1496}, year = {2017}, abstract = {No abstract available.}, subject = {Herz}, language = {en} } @article{WernerEisslerHayakawaetal.2018, author = {Werner, Rudolf A. and Eissler, Christoph and Hayakawa, Nobuyuki and Arias-Loza, Paula and Wakabayashi, Hiroshi and Javadi, Mehrbod S. and Chen, Xinyu and Shinaji, Tetsuya and Lapa, Constantin and Pelzer, Theo and Higuchi, Takahiro}, title = {Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated \(^{18}\)F-FDG PET}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, number = {17631}, doi = {10.1038/s41598-018-35986-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171765}, year = {2018}, abstract = {In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated \(^{18}\)F-fluorodeoxyglucose positron emission tomography (\(^{18}\)F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated \(^{18}\)F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n=6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, \(^{18}\)F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5±4.2 vs. 59.4±4.5\%; HR: 331±35 vs. 309±24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1±0.8 vs. 10.2±1 Enddiastolic Volume/sec, P<0.01). Investigating a diabetic rat model, ECG-gated \(^{18}\)F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.}, language = {en} } @article{WernerWakabayashiBaueretal.2018, author = {Werner, Rudolf and Wakabayashi, Hiroshi and Bauer, Jochen and Sch{\"u}tz, Claudia and Zechmeister, Christina and Hayakawa, Nobuyuki and Javadi, Mehrbod S. and Lapa, Constantin and Jahns, Roland and Erg{\"u}n, S{\"u}leyman and Jahns, Valerie and Higuchi, Takahiro}, title = {Longitudinal \(^{18}\)F-FDG PET imaging in a Rat Model of Autoimmune Myocarditis}, series = {European Heart Journal Cardiovascular Imaging}, journal = {European Heart Journal Cardiovascular Imaging}, issn = {2047-2404}, doi = {10.1093/ehjci/jey119}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165601}, pages = {1-8}, year = {2018}, abstract = {Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-\(^{18}\)F-fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis. Methods and results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund's adjuvant. Time course of disease was assessed by longitudinal \(^{18}\)F-FDG PET imaging. A correlative analysis between in- and ex vivo \(^{18}\)F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal \(^{18}\)F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo \(^{18}\)F-FDG PET signalling (R\(^2\) = 0.92) as well as with ex vivo 18F-FDG autoradiography (R\(^2\) = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at \(^{18}\)F-FDG decrease). Conclusion: \(^{18}\)F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.}, subject = {Myokarditis}, language = {en} } @unpublished{NoseWernerUedaetal.2018, author = {Nose, Naoko and Werner, Rudolf A. and Ueda, Yuichiro and G{\"u}nther, Katharina and Lapa, Constantin and Javadi, Mehrbod S. and Fukushima, Kazuhito and Edenhofer, Frank and Higuchi, Takahiro}, title = {Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: Functional assessment using in vitro radionuclide uptake assay}, series = {International Journal of Cardiology}, journal = {International Journal of Cardiology}, issn = {0167-5273}, doi = {10.1016/j.ijcard.2018.06.089}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-163320}, year = {2018}, abstract = {Background: Recent developments in cellular reprogramming technology enable the production of virtually unlimited numbers of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Although hiPSC-CM share various characteristic hallmarks with endogenous cardiomyocytes, it remains a question as to what extent metabolic characteristics are equivalent to mature mammalian cardiomyocytes. Here we set out to functionally characterize the metabolic status of hiPSC-CM in vitro by employing a radionuclide tracer uptake assay. Material and Methods: Cardiac differentiation of hiPSC was induced using a combination of well-orchestrated extrinsic stimuli such as WNT activation (by CHIR99021) and BMP signalling followed by WNT inhibition and lactate based cardiomyocyte enrichment. For characterization of metabolic substrates, dual tracer uptake studies were performed with \(^{18}\)F-2-fluoro-2-deoxy-D-glucose (\(^{18}\)F-FDG) and \(^{125}\)I-β-methyl-iodophenyl-pentadecanoic acid (\(^{125}\)I-BMIPP) as transport markers of glucose and fatty acids, respectively. Results: After cardiac differentiation of hiPSC, in vitro tracer uptake assays confirmed metabolic substrate shift from glucose to fatty acids that was comparable to those observed in native isolated human cardiomyocytes. Immunostaining further confirmed expression of fatty acid transport and binding proteins on hiPSC-CM. Conclusions: During in vitro cardiac maturation, we observed a metabolic shift to fatty acids, which are known as a main energy source of mammalian hearts, suggesting hi-PSC-CM as a potential functional phenotype to investigate alteration of cardiac metabolism in cardiac diseases. Results also highlight the use of available clinical nuclear medicine tracers as functional assays in stem cell research for improved generation of autologous differentiated cells for numerous biomedical applications.}, subject = {Stammzelle}, language = {en} } @article{NoseWernerUedaetal.2018, author = {Nose, Naoko and Werner, Rudolf A. and Ueda, Yuichiro and G{\"u}nther, Katharina and Lapa, Constantin and Javadi, Mehrbod S. and Fukushima, Kazuhito and Edenhofer, Frank and Higuchi, Takahiro}, title = {Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: Functional assessment using in vitro radionuclide uptake assay}, series = {International Journal of Cardiology}, volume = {269}, journal = {International Journal of Cardiology}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170699}, pages = {229-234}, year = {2018}, abstract = {BACKGROUND: Recent developments in cellular reprogramming technology enable the production of virtually unlimited numbers of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Although hiPSC-CM share various characteristic hallmarks with endogenous cardiomyocytes, it remains a question as to what extent metabolic characteristics are equivalent to mature mammalian cardiomyocytes. Here we set out to functionally characterize the metabolic status of hiPSC-CM in vitro by employing a radionuclide tracer uptake assay. MATERIAL AND METHODS: Cardiac differentiation of hiPSC was induced using a combination of well-orchestrated extrinsic stimuli such as WNT activation (by CHIR99021) and BMP signalling followed by WNT inhibition and lactate based cardiomyocyte enrichment. For characterization of metabolic substrates, dual tracer uptake studies were performed with \(^{18}\)F‑2‑fluoro‑2‑deoxy‑d‑glucose (\(^{18}\)F-FDG) and \(^{125}\)I‑β‑methyl‑iodophenyl‑pentadecanoic acid (\(^{125}\)I-BMIPP) as transport markers of glucose and fatty acids, respectively. RESULTS: After cardiac differentiation of hiPSCs, in vitro tracer uptake assays confirmed metabolic substrate shift from glucose to fatty acids that was comparable to those observed in native isolated human cardiomyocytes. Immunostaining further confirmed expression of fatty acid transport and binding proteins on hiPSC-CM. CONCLUSIONS: During in vitro cardiac maturation, we observed a metabolic shift to fatty acids, which are known as a main energy source of mammalian hearts, suggesting hi-PSC-CM as a potential functional phenotype to investigate alteration of cardiac metabolism in cardiac diseases. Results also highlight the use of available clinical nuclear medicine tracers as functional assays in stem cell research for improved generation of autologous differentiated cells for numerous biomedical applications.}, subject = {Stammzelle}, language = {en} } @article{WernerBundschuhBundschuhetal.2018, author = {Werner, Rudolf A. and Bundschuh, Ralph A. and Bundschuh, Lena and Javadi, Mehrbod S. and Higuchi, Takahiro and Weich, Alexander and Sheikhbahaei, Sara and Pienta, Kenneth J. and Buck, Andreas K. and Pomper, Martin G. and Gorin, Michael A. and Lapa, Constantin and Rowe, Steven P.}, title = {MI-RADS: Molecular Imaging Reporting and Data Systems - A Generalizable Framework for Targeted Radiotracers with Theranostic Implications}, series = {Annals of Nuclear Medicine}, journal = {Annals of Nuclear Medicine}, issn = {0914-7187}, doi = {10.1007/s12149-018-1291-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166995}, year = {2018}, abstract = {Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET) imaging agents for staging and restaging of prostate carcinoma or neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Both framework systems may contribute to increase the level of a reader's confidence and to navigate the imaging interpreter through indeterminate lesions, so that appropriate workup for equivocal findings can be pursued. Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e. if the reader is familiar with one system, the other system can readily be applied as well. In the present review we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a future role of the umbrella framework MI-RADS compared to other harmonization systems.}, subject = {Positronen-Emissions-Tomografie}, language = {en} } @article{WernerChenRoweetal.2018, author = {Werner, Rudolf A. and Chen, Xinyu and Rowe, Steven P. and Lapa, Constantin and Javadi, Mehrbod S. and Higuchi, Takahiro}, title = {Moving into the Next Era of PET Myocardial Perfusion Imaging - Introduction of Novel \(^{18}\)F-labeled Tracers}, series = {The International Journal of Cardiovascular Imaging}, journal = {The International Journal of Cardiovascular Imaging}, issn = {1569-5794}, doi = {10.1007/s10554-018-1469-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169134}, year = {2018}, abstract = {The heart failure (HF) epidemic continues to rise with coronary artery disease (CAD) as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 sec), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18F-labeled perfusion radiotracers will be discussed.}, subject = {Positronenemissionstomografie}, language = {en} } @article{ChenHiranoWerneretal.2018, author = {Chen, Xinyu and Hirano, Mitsuru and Werner, Rudolf A. and Decker, Michael and Higuchi, Takahiro}, title = {Novel \(^{18}\)F-labeled PET Imaging Agent FV45 targeting the Renin-Angiotensin System}, series = {ACS Omega}, volume = {3}, journal = {ACS Omega}, number = {9}, issn = {2470-1343}, doi = {10.1021/acsomega.8b01885}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167144}, pages = {10460-10470}, year = {2018}, abstract = {Renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure and hormonal balance. Using positron emission tomography (PET) technology, it is possible to monitor the physiological and pathological distribution of angiotensin II type 1 receptors (AT\(_1\)), which reflects the functionality of RAS. A new \(^{18}\)F-labeled PET tracer derived from the clinically used AT\(_1\) antagonist valsartan showing the least possible chemical alteration from the valsartan structure has been designed and synthesized with several strategies, which can be applied for the syntheses of further derivatives. Radioligand binding study showed that the cold reference FV45 (K\(_i\) 14.6 nM) has almost equivalent binding affinity as its lead valsartan (K\(_i\) 11.8 nM) and angiotensin II (K\(_i\) 1.7 nM). Successful radiolabeling of FV45 in a one-pot radiofluorination followed by the deprotection procedure with 21.8 ± 8.5\% radiochemical yield and >99\% radiochemical purity (n = 5) enabled a distribution study in rats and opened a path to straightforward large-scale production. A fast and clear kidney uptake could be observed, and this renal uptake could be selectively blocked by pretreatment with AT\(_1\)-selective antagonist valsartan. Overall, as the first \(^{18}\)F-labeled PET tracer based on a derivation from clinically used drug valsartan with almost identical chemical structure, [\(^{18}\)F]FV45 will be a new tool for assessing the RAS function by visualizing AT\(_i\) receptor distributions and providing further information regarding cardiovascular system malfunction as well as possible applications in inflammation research and cancer diagnosis.}, subject = {Positronen-Emissions-Tomografie}, language = {en} }