@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{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{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{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{LapaGarciaVellosoLueckerathetal.2017,
  author    = {Lapa, Constantin and Garcia-Velloso, Maria J. and L{\"u}ckerath, Katharina and Samnick, Samuel and Schreder, Martin and Otero, Paula Rodriguez and Schmid, Jan-Stefan and Herrmann, Ken and Knop, Stefan and Buck, Andreas K. and Einsele, Hermann and San-Miguel, Jesus and Kort{\"u}m, Klaus Martin},
  title     = {\(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions},
  series = {Theranostics},
  volume    = {7},
  journal   = {Theranostics},
  number    = {11},
  doi       = {10.7150/thno.20491},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172038},
  pages     = {2956-2964},
  year      = {2017},
  abstract  = {\(^{11}\)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 W{\"u}rzburg, 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.},
  language  = {en}
}
@article{LapaSchrederSchirbeletal.2017,
  author    = {Lapa, Constantin and Schreder, Martin and Schirbel, Andreas and Samnick, Samuel and Kort{\"u}m, Klaus Martin and Herrmann, Ken and Kropf, Saskia and Einsele, Herrmann and Buck, Andreas K. and Wester, Hans-J{\"u}rgen and Knop, Stefan and L{\"u}ckerath, Katharina},
  title     = {[\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values},
  series = {Theranostics},
  volume    = {7},
  journal   = {Theranostics},
  number    = {1},
  doi       = {10.7150/thno.16576},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172106},
  pages     = {205-212},
  year      = {2017},
  abstract  = {Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66\%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21\%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37\%). In the remaining 8/19 (42\%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018). [\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.},
  language  = {en}
}
@article{LueckerathLapaMalzahnetal.2014,
  author    = {L{\"u}ckerath, Katharina and Lapa, Constantin and Malzahn, Uwe and Samnick, Samuel and Einsele, Herrmann and Buck, Andreas K. and Herrmann, Ken and Knop, Stefan},
  title     = {18FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113107},
  year      = {2014},
  abstract  = {The aim of this study was to investigate the prognostic value of 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pre-treated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed. Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p<0.01). Presence of >10 focal lesions correlated with both TTP (p<0.01) and OS (p<0.05). Interestingly, presence of >10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p<0.01, respectively). PET resulted in a change of management in 30\% of patients. Our data underline the prognostic value of 18F-FDG-PET/CT in MM patients also in the setting of post-SCT relapse. PET/CT has a significant impact on patient management.},
  language  = {en}
}