@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{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{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{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{LapaHerrmannSchirbeletal.2017,
  author    = {Lapa, Constantin and Herrmann, Ken and Schirbel, Andreas and H{\"a}nscheid, Heribert and L{\"u}ckerath, Katharina and Schottelius, Margret and Kircher, Malte and Werner, Rudolf A. and Schreder, Martin and Samnick, Samuel and Kropf, Saskia and Knop, Stefan and Buck, Andreas K. and Einsele, Hermann and Wester, Hans-Juergen and Kort{\"u}m, K. Martin},
  title     = {CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma},
  series = {Theranostics},
  volume    = {7},
  journal   = {Theranostics},
  number    = {6},
  doi       = {10.7150/thno.19050},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172095},
  pages     = {1589-1597},
  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. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.},
  language  = {en}
}
@article{WernerSheikhbahaeiJonesetal.2017,
  author    = {Werner, Rudolf A. and Sheikhbahaei, Sara and Jones, Krystyna M. and Javadi, Mehrbod S. and Solnes, Lilja B. and Ross, Ashley E. and Allaf, Mohamad E. and Pienta, Kenneth J. and Lapa, Constantin and Buck, Andreas K. and Higuchi, Takahiro and Pomper, Martin G. and Gorin, Micheal A. and Rowe, Steven P.},
  title     = {Patterns of uptake of prostate-specific membrane antigen (PSMA)-targeted \(^{18}\)F-DCFPyL in peripheral ganglia},
  series = {Annals of Nuclear Medicine},
  volume    = {31},
  journal   = {Annals of Nuclear Medicine},
  number    = {9},
  issn      = {0914-7187},
  doi       = {10.1007/s12149-017-1201-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166971},
  pages     = {696-702},
  year      = {2017},
  abstract  = {Objective: Radiotracers targeting prostate-specific membrane antigen (PSMA) have increasingly been recognized as showing uptake in a number of normal structures, anatomic variants, and non-prostate-cancer pathologies. We aimed to explore the frequency and degree of uptake in peripheral ganglia in patients undergoing PET with the PSMA-targeted agent \(^{18}\)F-DCFPyL. Methods: A total of 98 patients who underwent \(^{18}\)F-DCFPyL PET/CT imaging were retrospectively analyzed. This included 76 men with prostate cancer (PCa) and 22 patients with renal cell carcinoma (RCC; 13 men, 9 women). Scans were evaluated for uptake in the cervical, stellate, celiac, lumbar and sacral ganglia. Maximum standardized uptake value corrected to body weight (SUV\(_{max}\)), and maximum standardized uptake value corrected to lean body mass (SUL\(_{max}\)) were recorded for all ganglia with visible uptake above background. Ganglia-to-background ratios were calculated by dividing the SUV\(_{max}\) and SUL\(_{max}\) values by the mean uptake in the ascending aorta (Aortamean) and the right gluteus muscle (Gluteusmean). Results: Overall, 95 of 98 (96.9\%) patients demonstrated uptake in at least one of the evaluated peripheral ganglia. With regard to the PCa cohort, the most frequent sites of radiotracer accumulation were lumbar ganglia (55/76, 72.4\%), followed by the cervical ganglia (51/76, 67.1\%). Bilateral uptake was found in the majority of cases [lumbar 44/55 (80\%) and cervical 30/51 (58.8\%)]. Additionally, discernible radiotracer uptake was recorded in 50/76 (65.8\%) of the analyzed stellate ganglia and in 45/76 (59.2\%) of the celiac ganglia, whereas only 5/76 (6.6\%) of the sacral ganglia demonstrated \(^{18}\)F-DCFPyL accumulation. Similar findings were observed for patients with RCC, with the most frequent locations of radiotracer uptake in both the lumbar (20/22, 90.9\%) and cervical ganglia (19/ 22, 86.4\%). No laterality preference was found in mean PSMA-ligand uptake for either the PCa or RCC cohorts. Conclusion: As PSMA-targeted agents become more widely disseminated, the patterns of uptake in structures that are not directly relevant to patients' cancers must be understood. This is the first systematic evaluation of the uptake of \(^{18}\)F-DCFPyL in ganglia demonstrating a general trend with a descending frequency of radiotracer accumulation in lumbar, cervical, stellate, celiac, and sacral ganglia. The underlying biology that leads to variability of PSMA-targeted radiotracers in peripheral ganglia is not currently understood, but may provide opportunities for future research.},
  subject      = {Positronen-Emissions-Tomografie},
  language  = {en}
}
@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{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     = {The Impact of Ageing on Dopamine Transporter Imaging},
  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-162213},
  pages     = {1646},
  year      = {2018},
  abstract  = {No abstract available.},
  subject      = {Parkinson-Krankheit},
  language  = {en}
}
@unpublished{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       = {https://doi.org/10.1007/s11307-018-1252-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164624},
  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}
}
@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}
}