@article{LueckerathLapaSpahmannetal.2013,
  author    = {L{\"u}ckerath, Katharina and Lapa, Constantin and Spahmann, Annika and J{\"o}rg, Gerhard and Samnick, Samuel and Rosenwald, Andreas and Einsele, Herrmann and Knop, Stefan and Buck, Andreas},
  title     = {Targeting Paraprotein Biosynthesis for Non-Invasive Characterization of Myeloma Biology},
  doi       = {10.1371/journal.pone.0084840},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111319},
  year      = {2013},
  abstract  = {Purpose Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity. Experimental Design To study the utility of 11C-MET, 18F-Fet and 18F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138+ plasma cells were characterized regarding uptake and biomedical features. Results Using myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of 11C-MET. Conclusion These data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.},
  language  = {en}
}
@article{LapaWernerBluemeletal.2014,
  author    = {Lapa, Constantin and Werner, Rudolf A. and Bluemel, Christina and Lueckerath, Katharina and Muegge, Dirk O. and Strate, Alexander and Haenscheid, Heribert and Schirbel, Andreas and Allen-Auerbach, Martin S. and Bundschuh, Ralph A. and Buck, Andreas K. and Herrmann, Ken},
  title     = {Prediction of clinically relevant hyperkalemia in patients treated with peptide receptor radionuclide therapy},
  series = {EJNMMI Research},
  volume    = {4},
  journal   = {EJNMMI Research},
  number    = {74},
  doi       = {10.1186/s13550-014-0074-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124963},
  year      = {2014},
  abstract  = {Background Peptide receptor radionuclide therapy (PRRT) is applied in patients with advanced neuroendocrine tumors. Co-infused amino acids (AA) should prevent nephrotoxicity. The aims of this study were to correlate the incidence of AA-induced hyperkalemia (HK) (≥5.0 mmol/l) and to identify predictors of AA-induced severe HK (>6.0). Methods In 38 patients, standard activity of \(^{177}Lu\)-labelled somatostatin analogs was administered. Pre-therapeutic kidney function was assessed by renal scintigraphy and laboratory tests. For kidney protection, AA was co-infused. Biochemical parameters (potassium, glomerular filtration rate, creatinine, blood urea nitrogen (BUN), sodium, phosphate, chloride, and lactate dehydrogenase (LDH)) were obtained prior to 4 and 24 h after the AA infusion. Incidence of HK (≥5.0) was correlated with pre-therapeutic kidney function and serum parameters. Formulas for the prediction of severe hyperkalemia (>6.0) were computed and prospectively validated. Results At 4 h, HK (≥5.0) was present in 94.7\% with severe HK (>6.0) in 36.1\%. Values normalized after 24 h in 84.2\%. Pre-therapeutic kidney function did not correlate with the incidence of severe HK. Increases in K+ were significantly correlated with decreases in phosphate (r = -0.444, p < 0.005) and increases in BUN (r = 0.313, p = 0.056). A baseline BUN of >28 mg/dl had a sensitivity of 84.6\% and a specificity of 60.0\% (AUC = 0.75) in predicting severe HK of >6.0 (phosphate, AUC = 0.37). Computing of five standard serum parameters (potassium, BUN, sodium, phosphate, LDH) resulted in a sensitivity of 88.9\% and a specificity of 79.3\% for the prediction of severe HK >6.0 (accuracy = 81.6\%). Conclusions A combination of serum parameters predicted prospectively the occurrence of relevant HK with an accuracy of 81.6\% underlining its potential utility for identifying 'high-risk' patients prone to PRRT.},
  language  = {en}
}
@article{BuderLapaKreissletal.2014,
  author    = {Buder, Kristina and Lapa, Constantin and Kreissl, Michael C. and Schirbel, Andreas and Herrmann, Ken and Schnack, Alexander and Br{\"o}cker, Eva-Bettina and Goebeler, Matthias and Buck, Andreas K. and Becker, J{\"u}rgen C.},
  title     = {"Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging"},
  doi       = {10.1186/1471-2407-14-268},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110326},
  year      = {2014},
  abstract  = {Background Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. Methods To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). Results SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73\% for nodal metastases, 100\% for bone, and 67\% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17\%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13\%). Conclusion SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.},
  language  = {en}
}
@article{WernerLapaBluemeletal.2014,
  author    = {Werner, Rudolf A. and Lapa, Constantin and Bluemel, Christina and L{\"u}ckerath, Katharina and Schirbel, Andreas and Strate, Alexander and Buck, Andreas K. and Herrmann, Ken},
  title     = {Influence of the amount of co-infused amino acids on post-therapeutic potassium levels in peptide receptor radionuclide therapy},
  doi       = {10.1186/s13550-014-0046-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110617},
  year      = {2014},
  abstract  = {Background Peptide receptor radionuclide therapy (PRRT) is routinely used for advanced or metastasized neuroendocrine tumours (NET). To prevent nephrotoxicity, positively charged amino acids (AA) are co-infused. The aim of this study was to correlate the risk for therapy-related hyperkalaemia with the total amount of AA infused. Methods Twenty-two patients undergoing PRRT with standard activities of 177Lu-DOTATATE/-TOC were monitored during two following treatment cycles with co-infusion of 75 and 50 g of AA (L-arginine and L-lysine), respectively. Mean serum levels of potassium and other parameters (glomerular filtration rate [GFR], creatinine, blood urea nitrogen [BUN], phosphate, chloride, lactate dehydrogenase) prior to, 4 h and 24 h after AA infusion were compared. Results Self-limiting hyperkalaemia (>5.0 mmol/l) resolving after 24 h occurred in 91\% (20/22) of patients in both protocols. Potassium levels, BUN, creatinine, GFR, phosphate, chloride and LDH showed a similar range at 4 h after co-infusion of 75 or 50 g of AA, respectively (p > 0.05). Only GFR and creatinine levels at 24 h varied significantly between the two co-infusion protocols (p < 0.05). Conclusions Hyperkalaemia is a frequent side effect of AA infusion in PRRT. Varying the dose of co-infused amino acids did not impact on the incidence and severity of hyperkalaemia.},
  language  = {en}
}
@article{LueckerathLapaAlbertetal.2015,
  author    = {L{\"u}ckerath, Katharina and Lapa, Constantin and Albert, Christa and Herrmann, Ken and J{\"o}rg, Gerhard and Samnick, Samuel and Einsele, Herrmann and Knop, Stefan and Buck, Andreas K.},
  title     = {\(^{11}\)C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma},
  series = {Oncotarget},
  volume    = {6},
  journal   = {Oncotarget},
  number    = {10},
  doi       = {10.18632/oncotarget.3053},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148688},
  pages     = {8418-8429},
  year      = {2015},
  abstract  = {Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers \(^{11}\)C-Methionine (paraprotein-biosynthesis) and \(^{18}\)F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138\(^{+}\) plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM. 1S tumors underwent MET- and FDG-\(\mu\)PET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79\% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET-but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.},
  language  = {en}
}
@article{LapaLinsenmannLueckerathetal.2015,
  author    = {Lapa, Constantin and Linsenmann, Thomas and L{\"u}ckerath, Katharina and Samnick, Samuel and Herrmann, Ken and Stoffer, Carolin and Ernestus, Ralf-Ingo and Buck, Andreas K. and L{\"o}hr, Mario and Monoranu, Camelia-Maria},
  title     = {Tumor-Associated Macrophages in Glioblastoma Multiforme—A Suitable Target for Somatostatin Receptor-Based Imaging and Therapy?},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {3},
  doi       = {10.1371/journal.pone.0122269},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125498},
  pages     = {e0122269},
  year      = {2015},
  abstract  = {Background Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM) have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN′,N″,N′″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A) which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM. Methods 15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68), proliferative activity (Ki67) as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET) imaging using \(^{68}Ga-DOTATATE\) was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry. Results The amount of microglia/macrophages ranged from <10\% to >50\% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns. Conclusion SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.},
  language  = {en}
}
@article{KlaesnerBuchmannGemptetal.2015,
  author    = {Kl{\"a}sner, Benjamin and Buchmann, Niels and Gempt, Jens and Ringel, Florian and Lapa, Constantin and Krause, Bernd Joachim},
  title     = {Early [\(^{18}\)F]FET-PET in Gliomas after Surgical Resection: Comparison with MRI and Histopathology},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {10},
  doi       = {10.1371/journal.pone.0141153},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139549},
  pages     = {e0141153},
  year      = {2015},
  abstract  = {Background The precise definition of the post-operative resection status in high-grade gliomas (HGG) is crucial for further management. We aimed to assess the feasibility of assessment of the resection status with early post-operative positron emission tomography (PET) using [\(^{18}\)F]O-(2-[\(^{18}\)F]-fluoroethyl)-L-tyrosine ([\(^{18}\)F]FET). Methods 25 patients with the suspicion of primary HGG were enrolled. All patients underwent preoperative [\(^{18}\)F]FET-PET and magnetic resonance imaging (MRI). Intra-operatively, resection status was assessed using 5-aminolevulinic acid (5-ALA). Imaging was repeated within 72h after neurosurgery. Post-operative [\(^{18}\)F]FET-PET was compared with MRI, intra-operative assessment and clinical follow-up. Results [\(^{18}\)F]FET-PET, MRI and intra-operative assessment consistently revealed complete resection in 12/25 (48\%) patients and incomplete resection in 6/25 cases (24\%). In 7 patients, PET revealed discordant findings. One patient was re-resected. 3/7 experienced tumor recurrence, 3/7 died shortly after brain surgery. Conclusion Early assessment of the resection status in HGG with [\(^{18}\)F]FET-PET seems to be feasible.},
  language  = {en}
}
@article{ChenWernerJavadietal.2015,
  author    = {Chen, Xinyu and Werner, Rudolf A. and Javadi, Mehrbod S. and Maya, Yoshifumi and Decker, Michael and Lapa, Constantin and Herrmann, Ken and Higuchi, Takahiro},
  title     = {Radionuclide imaging of neurohormonal system of the heart},
  series = {Theranostics},
  volume    = {5},
  journal   = {Theranostics},
  number    = {6},
  doi       = {10.7150/thno.10900},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149205},
  pages     = {545-558},
  year      = {2015},
  abstract  = {Heart failure is one of the growing causes of death especially in developed countries due to longer life expectancy. Although many pharmacological and instrumental therapeutic approaches have been introduced for prevention and treatment of heart failure, there are still limitations and challenges. Nuclear cardiology has experienced rapid growth in the last few decades, in particular the application of single photon emission computed tomography (SPECT) and positron emission tomography (PET), which allow non-invasive functional assessment of cardiac condition including neurohormonal systems involved in heart failure; its application has dramatically improved the capacity for fundamental research and clinical diagnosis. In this article, we review the current status of applying radionuclide technology in non-invasive imaging of neurohormonal system in the heart, especially focusing on the tracers that are currently available. A short discussion about disadvantages and perspectives is also included.},
  language  = {en}
}
@article{PhilippAbbrederisHerrmannKnopetal.2015,
  author    = {Philipp-Abbrederis, Kathrin and Herrmann, Ken and Knop, Stefan and Schottelius, Margret and Eiber, Matthias and L{\"u}ckerath, Katharina and Pietschmann, Elke and Habringer, Stefan and Gerngroß, Carlos and Franke, Katharina and Rudelius, Martina and Schirbel, Andreas and Lapa, Constantin and Schwamborn, Kristina and Steidle, Sabine and Hartmann, Elena and Rosenwald, Andreas and Kropf, Saskia and Beer, Ambros J and Peschel, Christian and Einsele, Hermann and Buck, Andreas K and Schwaiger, Markus and G{\"o}tze, Katharina and Wester, Hans-J{\"u}rgen and Keller, Ulrich},
  title     = {In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma},
  series = {EMBO Molecular Medicine},
  volume    = {7},
  journal   = {EMBO Molecular Medicine},
  number    = {4},
  doi       = {10.15252/emmm.201404698},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148738},
  pages     = {477-487},
  year      = {2015},
  abstract  = {CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination andpoor prognosis. We evaluated the novel CXCR4 probe [\(^{68}\)Ga]Pentixafor for invivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [\(^{68}\)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [\(^{68}\)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [\(^{18}\)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34\(^{+}\) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [\(^{68}\)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases.},
  language  = {en}
}
@article{WernerBeykanHiguchietal.2016,
  author    = {Werner, Rudolf A. and Beykan, Seval and Higuchi, Takahiro and L{\"u}ckerath, Katharina and Weich, Alexander and Scheurlen, Michael and Bluemel, Christina and Herrmann, Ken and Buck, Andreas K. and Lassmann, Michael and Lapa, Constantin and H{\"a}nscheid, Heribert},
  title     = {The impact of \(^{177}\)Lu-octreotide therapy on \(^{99m}\)Tc-MAG3 clearance is not predictive for late nephropathy},
  series = {Oncotarget},
  volume    = {7},
  journal   = {Oncotarget},
  number    = {27},
  doi       = {10.18632/oncotarget.9775},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177318},
  pages     = {41233-41241},
  year      = {2016},
  abstract  = {Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3\%, range: -27\% to +19\%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3­clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.},
  language  = {en}
}
@article{LapaReiterKircheretal.2016,
  author    = {Lapa, Constantin and Reiter, Theresa and Kircher, Malte and Schirbel, Andreas and Werner, Rudolf A. and Pelzer, Theo and Pizarro, Carmen and Skowasch, Dirk and Thomas, Lena and Schlesinger-Irsch, Ulrike and Thomas, Daniel and Bundschuh, Ralph A. and Bauer, Wolfgang R. and Gartner, Florian C.},
  title     = {Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI},
  series = {Oncotarget},
  volume    = {7},
  journal   = {Oncotarget},
  number    = {47},
  doi       = {10.18632/oncotarget.12799},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175423},
  pages     = {77807-77814},
  year      = {2016},
  abstract  = {Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with \(^{18}\)F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR-PET/CT for detecting cardiac sarcoidosis in comparison to CMR. 15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUV\(_{mean}\)) and maximum standardized uptake values (SUV\(_{max}\)) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity. SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25\% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up. In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1\% (245/255 segments analyzed). SUV\(_{mean}\) and SUV\(_{max}\) in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUV\(_{mean}\) and 2.0±0.3 and 1.7±0.3 for SUV\(_{max}\), respectively. Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series.},
  language  = {en}
}
@article{LapaLueckerathKleinleinetal.2016,
  author    = {Lapa, Constantin and L{\"u}ckerath, Katharina and Kleinlein, Irene and Monoranu, Camelia Maria and Linsenmann, Thomas and Kessler, Almuth F. and Rudelius, Martina and Kropf, Saskia and Buck, Andreas K. and Ernestus, Ralf-Ingo and Wester, Hans-J{\"u}rgen and L{\"o}hr, Mario and Herrmann, Ken},
  title     = {\(^{68}\)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma},
  series = {Theranostics},
  volume    = {6},
  journal   = {Theranostics},
  number    = {3},
  doi       = {10.7150/thno.13986},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168174},
  pages     = {428-434},
  year      = {2016},
  abstract  = {Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand \(^{68}\)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent \(^{68}\)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-\(^{18}\)F-fluoroethyl)-L-tyrosine (\(^{18}\)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUV\(_{max}\), SUV\(_{mean}\)). Tumor-to-background ratios (TBR) were calculated for both PET probes. \(^{68}\)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. \(^{68}\)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high \(^{68}\)Ga-Pentixafor uptake; regions of the same tumor without apparent \(^{68}\)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, \(^{68}\)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, \(^{68}\)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.},
  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}
}
@article{LapaAriasLozaHayakawaetal.2017,
  author    = {Lapa, Constantin and Arias-Loza, Paula and Hayakawa, Nobuyuki and Wakabayashi, Hiroshi and Werner, Rudolf A. and Chen, Xinyu and Shinaji, Tetsuya and Herrmann, Ken and Pelzer, Theo and Higuchi, Takahiro},
  title     = {Whitening and impaired glucose utilization of brown adipose tissue in a rat model of type 2 diabetes mellitus},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-017-17148-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159066},
  pages     = {16795},
  year      = {2017},
  abstract  = {Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by \(^{18}\)F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic \(^{18}\)F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. \(^{18}\)F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased \(^{18}\)F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.},
  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}
}
@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}
}
@inproceedings{WernerHiguchiMueggeetal.2017,
  author    = {Werner, Rudolf and Higuchi, Takahiro and Muegge, Dirk and Javadi, Mehrbod S. and M{\"a}rkl, Bruno and Aulmann, Christoph and Buck, Andreas K. and Fassnacht, Martin and Lapa, Constantin and Kreissl, Michael C.},
  title     = {Predictive value of FDG-PET in patients with advanced medullary thyroid cancer undergoing vandetanib treatment},
  series = {Journal of Nuclear Medicine},
  volume    = {58},
  booktitle = {Journal of Nuclear Medicine},
  number    = {no. supplement 1},
  issn      = {0161-5505},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161147},
  pages     = {169},
  year      = {2017},
  abstract  = {Introduction: The prognosis of medullary thyroid carcinoma (MTC) is poor using common chemotherapeutic approaches. However, during the last years encouraging results of recently introduced tyrosine kinase inhibitors (TKI) such as vandetanib have been published. In this study we aimed to correlate the results of \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG) positron emission tomography (PET) imaging with treatment outcome. Methods: Eighteen patients after thyroidectomy with recurrent/advanced MTC lesions receiving vandetanib (300 mg orally/day) could be analysed. A baseline \(^{18}\)F-FDG PET prior to and a follow-up \(^{18}\)F-FDG PET 3 months after TKI initiation were performed. During follow-up, tumor progression was assessed every 3 months including computed tomography according to RECIST. Progression-free survival (PFS) was correlated with the maximum standardized uptake value of \(^{18}\)F-FDG in lymph nodes (SUV(LN)max) or visceral metastases (SUV(MTS)max) as well as with clinical parameters using ROC analysis. Results: Within median 3.6 years of follow-up, 9 patients showed disease progression at median 8.5 months after TKI initiation. An elevated glucose consumption assessed by baseline \(^{18}\)F-FDG PET (SUV(LN)max > 7.25) could predict a shorter PFS (2 y) with an accuracy of 76.5\% (SUV(LN)max <7.25, 4.3 y; p=0.03). Accordingly, preserved tumor metabolism in the follow-up PET (SUV(MTS)max >2.7) also demonstrated an unfavorable prognosis (accuracy, 85.7\%). On the other hand, none of the clinical parameters reached significance in response prediction. Conclusions: In patients with advanced and progressive MTC, tumors with higher metabolic activity at baseline are more aggressive and more prone to progression as reflected by a shorter PFS; they should be monitored more closely. Preserved glucose consumption 3 months after treatment initiation was also related to poorer prognosis.},
  language  = {en}
}
@inproceedings{WernerLapaBucketal.2017,
  author    = {Werner, Rudolf and Lapa, Constantin and Buck, Andreas and Lassmann, Michael and H{\"a}nscheid, Heribert},
  title     = {Less is sometimes more - Accurate Dose Mapping after Endoradiotherapy with \(^{177}\)Lu-DOTATATE/-TOC by One-Single Measurement after 96 h},
  series = {Journal of Nuclear Medicine},
  volume    = {58},
  booktitle = {Journal of Nuclear Medicine},
  number    = {No. Supplement 1},
  publisher = {Society of Nuclear Medicine and Molecular Imaging},
  issn      = {0161-5505},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161168},
  pages     = {247},
  year      = {2017},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{LapaKircherSchirbeletal.2017,
  author    = {Lapa, Constantin and Kircher, Stefan and Schirbel, Andreas and Rosenwald, Andreas and Kropf, Saskia and Pelzer, Theo and Walles, Thorsten and Buck, Andreas K. and Weber, Wolfgang A. and Wester, Hans-Juergen and Herrmann, Ken and L{\"u}ckerath, Katharina},
  title     = {Targeting CXCR4 with [\(^{68}\)Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma?},
  series = {Oncotarget},
  volume    = {8},
  journal   = {Oncotarget},
  number    = {57},
  doi       = {10.18632/oncotarget.18235},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169989},
  pages     = {96732-96737},
  year      = {2017},
  abstract  = {C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.},
  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}
}