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Heid, I.* ; Trajkovic-Arsic, M.* ; Lohöfer, F.* ; Kaissis, G.* ; Harder, F.N.* ; Mayer, M.* ; Topping, G.J.* ; Jungmann, F.* ; Crone, B.* ; Wildgruber, M.* ; Karst, U.* ; Liotta, L.A.* ; Algül, H.* ; Yen, H.Y.* ; Steiger, K.* ; Weichert, W.* ; Siveke, J.T.* ; Makowski, M.R.* ; Braren, R.F.*

Functional biomarkers derived from computed tomography and magnetic resonance imaging differentiate PDAC subgroups and reveal gemcitabine-induced hypo-vascularization.

Eur. J. Nucl. Med. Mol. Imaging, DOI: 10.1007/s00259-022-05930-6 (2022)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a molecularly heterogeneous tumor entity with no clinically established imaging biomarkers. We hypothesize that tumor morphology and physiology, including vascularity and perfusion, show variations that can be detected by differences in contrast agent (CA) accumulation measured non-invasively. This work seeks to establish imaging biomarkers for tumor stratification and therapy response monitoring in PDAC, based on this hypothesis. METHODS AND MATERIALS: Regional CA accumulation in PDAC was correlated with tumor vascularization, stroma content, and tumor cellularity in murine and human subjects. Changes in CA distribution in response to gemcitabine (GEM) were monitored longitudinally with computed tomography (CT) Hounsfield Units ratio (HUr) of tumor to the aorta or with magnetic resonance imaging (MRI) ΔR1 area under the curve at 60 s tumor-to-muscle ratio (AUC60r). Tissue analyses were performed on co-registered samples, including endothelial cell proliferation and cisplatin tissue deposition as a surrogate of chemotherapy delivery. RESULTS: Tumor cell poor, stroma-rich regions exhibited high CA accumulation both in human (meanHUr 0.64 vs. 0.34, p < 0.001) and mouse PDAC (meanAUC60r 2.0 vs. 1.1, p < 0.001). Compared to the baseline, in vivo CA accumulation decreased specifically in response to GEM treatment in a subset of human (HUr -18%) and mouse (AUC60r -36%) tumors. Ex vivo analyses of mPDAC showed reduced cisplatin delivery (GEM: 0.92 ± 0.5 mg/g, vs. vehicle: 3.1 ± 1.5 mg/g, p = 0.004) and diminished endothelial cell proliferation (GEM: 22.3% vs. vehicle: 30.9%, p = 0.002) upon GEM administration. CONCLUSION: In PDAC, CA accumulation, which is related to tumor vascularization and perfusion, inversely correlates with tumor cellularity. The standard of care GEM treatment results in decreased CA accumulation, which impedes drug delivery. Further investigation is warranted into potentially detrimental effects of GEM in combinatorial therapy regimens.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Ca Accumulation ; Ct ; Dce-mri ; Gemcitabine ; Pdac
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 1619-7070
e-ISSN 1432-105X
Zeitschrift European Journal of Nuclear Medicine and Molecular Imaging
Verlag Springer
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Artifical Intelligence Cooperation Unit (HAICU)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-530014-001
DOI 10.1007/s00259-022-05930-6
PubMed ID 36074156
Erfassungsdatum 2022-09-13
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