TY - JOUR A1 - Werner, Rudolf A. A1 - Kircher, Stefan A1 - Higuchi, Takahiro A1 - Kircher, Malte A1 - Schirbel, Andreas A1 - Wester, Hans-Jürgen A1 - Buck, Andreas K. A1 - Pomper, Martin G. A1 - Rowe, Steven P. A1 - Lapa, Constantin T1 - CXCR4-directed imaging in solid tumors JF - Frontiers in Oncology N2 - Despite histological evidence in various solid tumor entities, available experience with CXCR4-directed diagnostics and endoradiotherapy mainly focuses on hematologic diseases. With the goal of expanding the application of CXCR4 theranostics to solid tumors, we aimed to elucidate the feasibility of CXCR4-targeted imaging in a variety of such neoplasms. Methods: Nineteen patients with newly diagnosed, treatment-naïve solid tumors including pancreatic adenocarcinoma or neuroendocrine tumor, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, and prostate cancer underwent [\(^{68}\)Ga]Pentixafor PET/CT. CXCR4-mediated uptake was assessed both visually and semi-quantitatively by evaluation of maximum standardized uptake values (SUV\(_{max}\)) of both primary tumors and metastases. With physiologic liver uptake as reference, tumor-to-background ratios (TBR) were calculated. [\(^{68}\)Ga]Pentixafor findings were further compared to immunohistochemistry and [\(^{18}\)F]FDG PET/CT. Results: On [\(^{68}\)Ga]Pentixafor PET/CT, 10/19 (52.6%) primary tumors were visually detectable with a median SUVmax of 5.4 (range, 1.7–16.0) and a median TBR of 2.6 (range, 0.8–7.4), respectively. The highest level of radiotracer uptake was identified in a patient with cholangiocarcinoma (SUVmax, 16.0; TBR, 7.4). The relatively low uptake on [\(^{68}\)Ga]Pentixafor was also noted in metastases, exhibiting a median SUVmax of 4.5 (range, 2.3–8.8; TBR, 1.7; range, 1.0–4.1). A good correlation between uptake on [\(^{68}\)Ga]Pentixafor and histological derived CXCR4 expression was noted (R = 0.62, P < 0.05). In the 3 patients in whom [\(^{18}\)F]FDG PET/CT was available, [\(^{68}\)Ga]Pentixafor exhibited lower uptake in all lesions. Conclusions: In this cohort of newly diagnosed, treatment-naïve patients with solid malignancies, CXCR4 expression as detected by [\(^{68}\)Ga]Pentixafor-PET/CT and immunohistochemistry was rather moderate. Thus, CXCR4-directed imaging may not play a major role in the management of solid tumors in the majority of patients. KW - CXCR4 KW - [68Ga]Pentixafor KW - theranostics KW - solid tumors KW - chemokine receptor Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195678 SN - 2234-943X VL - 9 IS - 770 ER - TY - JOUR A1 - Morales-Lozano, Maria I. A1 - Viering, Oliver A1 - Samnick, Samuel A1 - Rodriguez-Otero, Paula A1 - Buck, Andreas K. A1 - Marcos-Jubilar, Maria A1 - Rasche, Leo A1 - Prieto, Elena A1 - Kortüm, K. Martin A1 - San-Miguel, Jesus A1 - Garcia-Velloso, Maria J. A1 - Lapa, Constantin T1 - \(^{18}\)F-FDG and \(^{11}\)C-methionine PET/CT in newly diagnosed multiple myeloma patients: comparison of volume-based PET biomarkers JF - Cancers N2 - \(^{11}\)C-methionine (\(^{11}\)C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of \(^{11}\)C-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to \(^{18}\)F-FDG. Twenty-two patients with newly diagnosed, treatment-naïve symptomatic MM who had undergone \(^{11}\)C-MET and \(^{18}\)F-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion \(^{11}\)C-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), \(^{11}\)C-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in \(^{11}\)C-MET than in \(^{18}\)F-FDG (p < 0.05, respectively). \(^{11}\)C-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that \(^{11}\)C-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than \(^{18}\)F-FDG. Its implications for prognosis evaluation need further investigation. KW - multiple myeloma KW - methionine KW - total lesion glycolysis (TLG) KW - metabolic tumor volume (MTV) KW - total lesion methionine uptake (TLMU) Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203686 SN - 2072-6694 VL - 12 IS - 4 ER - TY - JOUR A1 - Breun, Maria A1 - Monoranu, Camelia M. A1 - Kessler, Almuth F. A1 - Matthies, Cordula A1 - Löhr, Mario A1 - Hagemann, Carsten A1 - Schirbel, Andreas A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Buck, Andreas K. A1 - Wester, Hans-Jürgen A1 - Ernestus, Ralf-Ingo A1 - Lapa, Constantin T1 - [\(^{68}\)Ga]-Pentixafor PET/CT for CXCR4-mediated imaging of vestibular schwannomas JF - Frontiers in Oncology N2 - We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor. Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients. Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors. Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression. KW - vestibular schwannoma KW - CXCR4 KW - PET/CT KW - molecular imaging KW - Pentixafor Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201863 VL - 9 IS - 503 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Derlin, Thorsten A1 - Lapa, Constantin A1 - Sheikbahaei, Sara A1 - Higuchi, Takahiro A1 - Giesel, Frederik L. A1 - Behr, Spencer A1 - Drzezga, Alexander A1 - Kimura, Hiroyuki A1 - Buck, Andreas K. A1 - Bengel, Frank M. A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Rowe, Steven P. T1 - \(^{18}\)F-labeled, PSMA-targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging JF - Theranostics N2 - Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with \(^{68}\)Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from \(^{68}\)Ga- to \(^{18}\)F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite \(^{68}\)Ge/\(^{68}\)Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, \(^{18}\)F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, \(^{18}\)F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging \(^{18}\)F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available \(^{18}\)F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios. KW - Radiofluorine KW - prostate-specific membrane antigen KW - prostate cancer KW - \(^{18}\)F KW - PSMA KW - \(^{68}\)Ga KW - theranostics KW - radioligand therapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202559 SN - 1838-7640 VL - 10 IS - 1 ER - TY - JOUR A1 - Nose, Naoko A1 - Nogami, Suguru A1 - Koshino, Kazuhiro A1 - Chen, Xinyu A1 - Werner, Rudolf A. A1 - Kashima, Soki A1 - Rowe, Steven P. A1 - Lapa, Constantin A1 - Fukuchi, Kazuki A1 - Higuchi, Takahiro T1 - [18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species JF - Scientific Reports N2 - Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n=1), rats (n=4), rabbits (n=4) and non-human primates (n=3), via carotid artery in rats (n=4) and non-human primates (n=3), and via intra-myocardial injection in rats (n=5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research. KW - biomarkers KW - molecular medicine KW - stem-cell research KW - stem cells Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260590 VL - 11 IS - 1 ER - TY - JOUR A1 - Lapa, Constantin A1 - Garcia-Velloso, Maria J. A1 - Lückerath, Katharina A1 - Samnick, Samuel A1 - Schreder, Martin A1 - Otero, Paula Rodriguez A1 - Schmid, Jan-Stefan A1 - Herrmann, Ken A1 - Knop, Stefan A1 - Buck, Andreas K. A1 - Einsele, Hermann A1 - San-Miguel, Jesus A1 - Kortüm, Klaus Martin T1 - \(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions JF - Theranostics N2 - \(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM. KW - medicine KW - PET/CT KW - \(^{11}\)C-methionine KW - multiple myeloma KW - FDG Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172038 VL - 7 IS - 11 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Marcus, Charles A1 - Sheikhbahaei, Sara A1 - Solnes, Lilja B. A1 - Leal, Jeffrey P. A1 - Du, Yong A1 - Rowe, Steven P. A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. T1 - Visual and Semiquantitative Accuracy in Clinical Baseline 123I-Ioflupane SPECT/CT Imaging JF - Clinical Nuclear Medicine N2 - PURPOSE: We aimed to (a) elucidate the concordance of visual assessment of an initial I-ioflupane scan by a human interpreter with comparison to results using a fully automatic semiquantitative method and (b) to assess the accuracy compared to follow-up (f/u) diagnosis established by movement disorder specialists. METHODS: An initial I-ioflupane scan was performed in 382 patients with clinically uncertain Parkinsonian syndrome. An experienced reader performed a visual evaluation of all scans independently. The findings of the visual read were compared with semiquantitative evaluation. In addition, available f/u clinical diagnosis (serving as a reference standard) was compared with results of the human read and the software. RESULTS: When comparing the semiquantitative method with the visual assessment, discordance could be found in 25 (6.5%) of 382 of the cases for the experienced reader (ĸ = 0.868). The human observer indicated region of interest misalignment as the main reason for discordance. With neurology f/u serving as reference, the results of the reader revealed a slightly higher accuracy rate (87.7%, ĸ = 0.75) compared to semiquantification (86.2%, ĸ = 0.719, P < 0.001, respectively). No significant difference in the diagnostic performance of the visual read versus software-based assessment was found. CONCLUSIONS: In comparison with a fully automatic semiquantitative method in I-ioflupane interpretation, human assessment obtained an almost perfect agreement rate. However, compared to clinical established diagnosis serving as a reference, visual read seemed to be slightly more accurate as a solely software-based quantitative assessment. KW - Single-Photon-Emissions-Computertomographie KW - SPECT KW - Parkinson’s disease KW - Parkinsonism KW - DaTscan KW - 123I-Ioflupane KW - SPECT KW - SPECT/CT Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168181 SN - 1536-0229 VL - 44 IS - 1 ER - TY - JOUR A1 - Zhou, Xiang A1 - Dierks, Alexander A1 - Kertels, Olivia A1 - Samnick, Samuel A1 - Kircher, Malte A1 - Buck, Andreas K. A1 - Haertle, Larissa A1 - Knorz, Sebastian A1 - Böckle, David A1 - Scheller, Lukas A1 - Messerschmidt, Janin A1 - Barakat, Mohammad A1 - Truger, Marietta A1 - Haferlach, Claudia A1 - Einsele, Hermann A1 - Rasche, Leo A1 - Kortüm, K. Martin A1 - Lapa, Constantin T1 - The link between cytogenetics/genomics and imaging patterns of relapse and progression in patients with relapsed/refractory multiple myeloma: a pilot study utilizing 18F-FDG PET/CT JF - Cancers N2 - Utilizing 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT), we performed this pilot study to evaluate the link between cytogenetic/genomic markers and imaging patterns in relapsed/refractory (RR) multiple myeloma (MM). We retrospectively analyzed data of 24 patients with RRMM who were treated at our institution between November 2018 and February 2020. At the last relapse/progression, patients had been treated with a median of three (range 1–10) lines of therapy. Six (25%) patients showed FDG avid extramedullary disease without adjacency to bone. We observed significantly higher maximum standardized uptake values (SUV\(_{max}\)) in patients harboring del(17p) compared with those without del(17p) (p = 0.025). Moreover, a high SUV\(_{max}\) of >15 indicated significantly shortened progression-free survival (PFS) (p = 0.01) and overall survival (OS) (p = 0.0002). One female patient exhibited biallelic TP53 alteration, i.e., deletion and mutation, in whom an extremely high SUV\(_{max}\) of 37.88 was observed. In summary, this pilot study suggested a link between del(17p)/TP53 alteration and high SUV\(_{max}\) on 18F-FDG PET/CT in RRMM patients. Further investigations are highly warranted at this point. KW - radiogenomics KW - 18F-FDG PET/CT KW - multiple myeloma KW - relapse KW - progression KW - pattern Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211157 SN - 2072-6694 VL - 12 IS - 9 ER - TY - JOUR A1 - Lapa, Constantin A1 - Kircher, Malte A1 - Hänscheid, Heribert A1 - Schirbel, Andreas A1 - Grigoleit, Götz Ulrich A1 - Klinker, Erdwine A1 - Böck, Markus A1 - Samnick, Samuel A1 - Pelzer, Theo A1 - Buck, Andreas K T1 - Peptide receptor radionuclide therapy as a new tool in treatment-refractory sarcoidosis - initial experience in two patients JF - Theranostics N2 - Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors. Methods: We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT. Results: PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively. Conclusion: Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted. KW - peptide receptor KW - PRRT KW - sarcoidosis KW - somatostatin receptors KW - radionuclide therapy Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158983 VL - 8 IS - 3 ER - TY - INPR A1 - Nose, Naoko A1 - Werner, Rudolf A. A1 - Ueda, Yuichiro A1 - Günther, Katharina A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. A1 - Fukushima, Kazuhito A1 - Edenhofer, Frank A1 - Higuchi, Takahiro T1 - Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: Functional assessment using in vitro radionuclide uptake assay T2 - International Journal of Cardiology N2 - 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. KW - tracer KW - Stammzelle KW - induced pluripotent stem cells KW - cardiomyocytes KW - fatty acid KW - stem cell therapy KW - hiPSC-CM Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163320 SN - 0167-5273 ER -