@article{WernerOrdonezSanchezBautistaetal.2019, author = {Werner, Rudolf A. and Ordonez, Alvaro A. and Sanchez-Bautista, Julian and Marcus, Charles and Lapa, Constantin and Rowe, Steven P. and Pomper, Martin G. and Leal, Jeffrey P. and Lodge, Martin A. and Javadi, Mehrbod S. and Jain, Sanjay K. and Higuchi, Takahiro}, title = {Novel functional renal PET imaging with 18F-FDS in human subjects}, series = {Clinical Nuclear Medicine}, volume = {44}, journal = {Clinical Nuclear Medicine}, number = {5}, issn = {0363-9762}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174634}, pages = {410-411}, year = {2019}, abstract = {The novel PET probe 2-deoxy-2-18F-fluoro-D-sorbitol (18F-FDS) has demonstrated favorable renal kinetics in animals. We aimed to elucidate its imaging properties in two human volunteers. 18F-FDS was produced by a simple one-step reduction from 18F-FDG. On dynamic renal PET, the cortex was delineated and activity gradually transited in the parenchyma, followed by radiotracer excretion. No adverse effects were reported. Given the higher spatiotemporal resolution of PET relative to conventional scintigraphy, 18F-FDS PET offers a more thorough evaluation of human renal kinetics. Due to its simple production from 18F-FDG, 18F-FDS is virtually available at any PET facility with radiochemistry infrastructure.}, subject = {Positronen-Emissions-Tomografie}, 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{WernerWeichKircheretal.2018, author = {Werner, Rudolf A. and Weich, Alexander and Kircher, Malte and Solnes, Lilja B. and Javadi, Mehrbod S. and Higuchi, Takahiro and Buck, Andreas K. and Pomper, Martin G. and Rowe, Steven and Lapa, Constantin}, title = {The theranostic promise for neuroendocrine tumors in the late 2010s - Where do we stand, where do we go?}, series = {Theranostics}, volume = {8}, journal = {Theranostics}, number = {22}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170264}, pages = {6088-6100}, year = {2018}, abstract = {More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context.}, subject = {Positronen-Emissions-Tomografie}, 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} } @article{WernerBundschuhHiguchietal.2018, author = {Werner, Rudolf A. and Bundschuh, Ralph A. and Higuchi, Takahiro and Javadi, Mehrbod S. and Rowe, Steven P. and Zs{\´o}t{\´e}r, Norbert and Kroiss, Matthias and Fassnacht, Martin and Buck, Andreas K. and Kreissl, Michael C. and Lapa, Constantin}, title = {Volumetric and Texture Analysis of Pretherapeutic \(^{18}\)F-FDG PET can Predict Overall Survival in Medullary Thyroid Cancer Patients Treated with Vandetanib}, series = {Endocrine}, journal = {Endocrine}, issn = {1355-008X}, doi = {10.1007/s12020-018-1749-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167910}, year = {2018}, abstract = {Purpose: The metabolically most active lesion in 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) PET/CT can predict progression-free survival (PFS) in patients with medullary thyroid carcinoma (MTC) starting treatment with the tyrosine kinase inhibitor (TKI) vandetanib. However, this metric failed in overall survival (OS) prediction. In the present proof of concept study, we aimed to explore the prognostic value of intratumoral textural features (TF) as well as volumetric parameters (total lesion glycolysis, TLG) derived by pre-therapeutic \(^{18}\)F-FDG PET. Methods: Eighteen patients with progressive MTC underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after vandetanib initiation. By manual segmentation of the tumor burden at baseline and follow-up PET, intratumoral TF and TLG were computed. The ability of TLG, imaging-based TF, and clinical parameters (including age, tumor marker doubling times, prior therapies and RET (rearranged during transfection) mutational status) for prediction of both PFS and OS were evaluated. Results: The TF Complexity and the volumetric parameter TLG obtained at baseline prior to TKI initiation successfully differentiated between low- and high-risk patients. Complexity allocated 10/18 patients to the high-risk group with an OS of 3.3y (vs. low-risk group, OS=5.3y, 8/18, AUC=0.78, P=0.03). Baseline TLG designated 11/18 patients to the high-risk group (OS=3.5y vs. low-risk group, OS=5y, 7/18, AUC=0.83, P=0.005). The Hazard Ratio for cancer-related death was 6.1 for Complexity (TLG, 9.5). Among investigated clinical parameters, the age at initiation of TKI treatment reached significance for PFS prediction (P=0.02, OS, n.s.). Conclusions: The TF Complexity and the volumetric parameter TLG are both independent parameters for OS prediction.}, subject = {Positronen-Emissions-Tomografie}, 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} } @article{WernerIlhanLehneretal.2018, author = {Werner, Rudolf A. and Ilhan, Harun and Lehner, Sebastian and Papp, L{\´a}szl{\´o} and Zs{\´o}t{\´e}r, Norbert and Schatka, Imke and Muegge, Dirk O. and Javadi, Mehrbod S. and Higuchi, Takahiro and Buck, Andreas K. and Bartenstein, Peter and Bengel, Frank and Essler, Markus and Lapa, Constantin and Bundschuh, Ralph A.}, title = {Pre-therapy Somatostatin-Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy}, series = {Molecular Imaging and Biology}, journal = {Molecular Imaging and Biology}, issn = {1536-1632}, doi = {10.1007/s11307-018-1252-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167168}, year = {2018}, abstract = {Purpose: Early identification of aggressive disease could improve decision-support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-PET before PRRT was analyzed. Procedures: 31 patients with G1/G2 pNET were enrolled (G2, n=23/31). Prior to PRRT with [\(^{177}\)Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET/CT was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUV\(_{mean/max}\)), imaging-based TF as well as clinical parameters (Ki67, CgA) for prediction of both progression-free (PFS) and overall survival (OS) after PRRT was evaluated. Results: Within a median follow-up of 3.7y, tumor progression was detected in 21 patients (median, 1.5y) and 13/31 deceased (median, 1.9y). In ROC analysis, the TF Entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff=6.7, AUC=0.71, p=0.02). Of note, increasing Entropy could predict a longer survival (>6.7, OS=2.5y, 17/31), whereas less voxel-based derangement portended inferior outcome (<6.7, OS=1.9y, 14/31). These findings were supported in a G2 subanalysis (>6.9, OS=2.8y, 9/23 vs. <6.9, OS=1.9y, 14/23). Kaplan-Meier analysis revealed a significant distinction between high- and low-risk groups using Entropy (n=31, p<0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n=31, p=0.04). Ki67 was negatively associated with PFS (p=0.002); however, SUVmean/max failed in prognostication (n.s.). Conclusions: In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification.}, subject = {Positronen-Emissions-Tomografie}, 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{ChenWernerLapaetal.2018, author = {Chen, Xinyu and Werner, Rudolf A. and Lapa, Constantin and Nose, Naoko and Hirano, Mitsuru and Javadi, Mehrbod S. and Robinson, Simon and Higuchi, Takahiro}, title = {Subcellular storage and release mode of the novel \(^{18}\)F-labeled sympathetic nerve PET tracer LMI1195}, series = {EJNMMI Research}, volume = {8}, journal = {EJNMMI Research}, number = {12}, issn = {2191-219X}, doi = {10.1186/s13550-018-0365-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167081}, year = {2018}, abstract = {Background: \(^{18}\)F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine (\(^{18}\)F-LMI1195) is a new class of PET tracer designed for sympathetic nervous imaging of the heart. The favorable image quality with high and specific neural uptake has been previously demonstrated in animals and humans, but intracellular behavior is not yet fully understood. The aim of the present study is to verify whether it is taken up in storage vesicles and released in company with vesicle turnover. Results: Both vesicle-rich (PC12) and vesicle-poor (SK-N-SH) norepinephrine-expressing cell lines were used for in vitro tracer uptake studies. After 2 h of \(^{18}\)F-LMI1195 preloading into both cell lines, effects of stimulants for storage vesicle turnover (high concentration KCl (100 mM) or reserpine treatment) were measured at 10, 20, and 30 min. \(^{131}\)I-meta-iodobenzylguanidine (\(^{131}\)I-MIBG) served as a reference. Both high concentration KCl and reserpine enhanced \(^{18}\)F-LMI1195 washout from PC12 cells, while tracer retention remained stable in the SK-N-SH cells. After 30 min of treatment, 18F-LMI1195 releasing index (percentage of tracer released from cells) from vesicle-rich PC12 cells achieved significant differences compared to cells without treatment condition. In contrast, such effect could not be observed using vesicle-poor SK-N-SH cell lines. Similar tracer kinetics after KCl or reserpine treatment were also observed using 131I-MIBG. In case of KCl exposure, Ca\(^{2+}\)-free buffer with the calcium chelator, ethylenediaminetetracetic acid (EDTA), could suppress the tracer washout from PC12 cells. This finding is consistent with the tracer release being mediated by Ca\(^{2+}\) influx resulting from membrane depolarization. Conclusions: Analogous to \(^{131}\)I-MIBG, the current in vitro tracer uptake study confirmed that \(^{131}\)F-LMI1195 is also stored in vesicles in PC12 cells and released along with vesicle turnover. Understanding the basic kinetics of \(^{18}\)FLMI1195 at a subcellular level is important for the design of clinical imaging protocols and imaging interpretation.}, subject = {Positronen-Emissions-Tomografie}, 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} }