Irina Heid1, Marija Trajkovic-Arsic2,3, Fabian Lohöfer4, Georgios Kaissis4,5,6, Felix N Harder4, Moritz Mayer4, Geoffrey J Topping7, Friderike Jungmann4, Barbara Crone8, Moritz Wildgruber9,10, Uwe Karst8, Lucia Liotta11, Hana Algül12, Hsi-Yu Yen13, Katja Steiger13, Wilko Weichert13,14, Jens T Siveke2,3, Marcus R Makowski4, Rickmer F Braren15,16. 1. School of Medicine, Institute of Diagnostic and Interventional Radiology, Technical University of Munich, Munich, Germany. Irina.Heid@tum.de. 2. Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. 3. Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany. 4. School of Medicine, Institute of Diagnostic and Interventional Radiology, Technical University of Munich, Munich, Germany. 5. Department of Computing, Imperial College London, London, SW7 2AZ, UK. 6. School of Medicine, Institute for Artificial Intelligence in Medicine and Healthcare, Technical University of Munich, Munich, Germany. 7. School of Medicine, Department of Nuclear Medicine, Technical University of Munich, Munich, Germany. 8. Institute of Inorganic and Analytical Chemistry, University of Muenster, Muenster, Germany. 9. Institute of Clinical Radiology, University Hospital Muenster, Muenster, Germany. 10. Department of Radiology, University Hospital, LMU Munich, Munich, Germany. 11. School of Medicine, Clinic and Policlinic of Internal Medicine II, Technical University of Munich, Munich, Germany. 12. Comprehensive Cancer Center Munich at the Klinikum rechts der Isar (CCCMTUM), Technical University of Munich, Munich, Germany. 13. School of Medicine, Institute of Pathology, Technical University of Munich, Munich, Germany. 14. German Cancer Consortium (DKTK, partner Site Munich), Munich, Germany. 15. School of Medicine, Institute of Diagnostic and Interventional Radiology, Technical University of Munich, Munich, Germany. rbraren@tum.de. 16. German Cancer Consortium (DKTK, partner Site Munich), Munich, Germany. rbraren@tum.de.
Abstract
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.
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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