12065
2014
eng
4050-59
12
5
article
1
2015-10-21
--
--
Week one FLT-PET response predicts complete remission to R-CHOP and survival in DLBCL
Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure.
Oncotarget
1949-2553
urn:nbn:de:bvb:20-opus-120659
Oncotarget, Vol. 5, No. 12, 4050-59
Ken Herrmann
Andreas K. Buck
Tibor Schuster
Kathrin Abbrederis
Christina Blümel
Ivan Santi
Martina Rudelius
Hans-Jürgen Wester
Christian Peschel
Markus Schwaiger
Tobias Dechow
Ulrich Keller
eng
uncontrolled
[18F]Fluorodeoxythymidine
eng
uncontrolled
FLT-PET
eng
uncontrolled
positron emission tomography
eng
uncontrolled
DLBCL
eng
uncontrolled
lymphoma
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Pathologisches Institut
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12065/111_Hermann_Oncotarget.pdf
11791
2014
eng
789-798
7
article
1
2015-08-14
--
--
Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma
Background: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[F-18] fluorothymidine (FLT).
Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects.
Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue.
Conclusion: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.
Oncotargets and Therapy
10.2147/OTT.S59314
24920919
urn:nbn:de:bvb:20-opus-117915
OncoTargets and Therapy 2014:7 789–798
Nicolas Graf
Zhoulei Li
Ken Herrmann
Daniel Weh
Michaela Aichler
Jolanta Slawska
Axel Walch
Christian Peschel
Markus Schwaiger
Andreas K. Buck
Tobias Dechow
Ulrich Keller
eng
uncontrolled
mammalian target of rapamycin
eng
uncontrolled
phosphatidylinositol-3-kinase
eng
uncontrolled
lymphoma
eng
uncontrolled
early response
eng
uncontrolled
NVP-BGT226
eng
uncontrolled
non-hodgkins-lymphoma
eng
uncontrolled
signaling pathway
eng
uncontrolled
FDG-PET
eng
uncontrolled
in-vivo
eng
uncontrolled
target
eng
uncontrolled
tumor
eng
uncontrolled
imaging proliferation
eng
uncontrolled
inhibition
eng
uncontrolled
positron emission tomography
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11791/149_Graf_ONCOTARGETS_AND_THERAPY.pdf
14453
2015
eng
618-630
6
5
article
1
2017-02-16
--
--
Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging
Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [\(^{68}\)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [\(^{68}\)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [\(^{68}\)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [\(^{68}\)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.
Theranostics
10.7150/thno.11251
urn:nbn:de:bvb:20-opus-144537
Theranostics 2015; 5(6): 618-630. DOI: 10.7150/thno.11251
CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell 4.0 International
Hans Jürgen Wester
Ulrich Keller
Margret Schottelius
Ambros Beer
Kathrin Philipp-Abbrederis
Frauke Hoffmann
Jakub Šimeček
Carlos Gerngross
Michael Lassmann
Ken Herrmann
Natalia Pellegata
Martina Rudelius
Horst Kessler
Markus Schwaiger
eng
uncontrolled
acute myeloid leukemia
eng
uncontrolled
prognostic value
eng
uncontrolled
therapeutic target
eng
uncontrolled
chemokine receptor
eng
uncontrolled
CXCR4
eng
uncontrolled
lymphoma
eng
uncontrolled
in vivo imaging
eng
uncontrolled
positron emission tomography
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Pathologisches Institut
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14453/073_Wester_Theranostics.pdf
14873
2015
eng
477-487
4
7
article
1
2017-05-17
--
--
In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma
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.
EMBO Molecular Medicine
10.15252/emmm.201404698
urn:nbn:de:bvb:20-opus-148738
EMBO Molecular Medicine 7(4), 477-487 (2015). DOI: 10.15252/emmm.201404698
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Kathrin Philipp-Abbrederis
Ken Herrmann
Stefan Knop
Margret Schottelius
Matthias Eiber
Katharina Lückerath
Elke Pietschmann
Stefan Habringer
Carlos Gerngroß
Katharina Franke
Martina Rudelius
Andreas Schirbel
Constantin Lapa
Kristina Schwamborn
Sabine Steidle
Elena Hartmann
Andreas Rosenwald
Saskia Kropf
Ambros J Beer
Christian Peschel
Hermann Einsele
Andreas K Buck
Markus Schwaiger
Katharina Götze
Hans-Jürgen Wester
Ulrich Keller
eng
uncontrolled
FDG PET/CT
eng
uncontrolled
cells
eng
uncontrolled
CXCR4/SDF-1
eng
uncontrolled
CXCR4
eng
uncontrolled
multiple myeloma
eng
uncontrolled
positron emission tomography
eng
uncontrolled
chemokine receptor
eng
uncontrolled
in vivo imaging
eng
uncontrolled
malignancies
eng
uncontrolled
involvement
eng
uncontrolled
microenvironment
eng
uncontrolled
survival
eng
uncontrolled
cancer
eng
uncontrolled
autologous transplantation
eng
uncontrolled
bone disease
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Pathologisches Institut
Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14873/043_Philipp-Abbrederis_EMBO_Molecular_Medicine.pdf