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Molecular Imaging and Biology

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11.05.2023 | Research Article

Impact of Arterial Input Function and Pharmacokinetic Models on DCE-MRI Biomarkers for Detection of Vascular Effect Induced by Stroma-Directed Drug in an Orthotopic Mouse Model of Pancreatic Cancer

verfasst von: Jianbo Cao, Stephen Pickup, Mark Rosen, Rong Zhou

Erschienen in: Molecular Imaging and Biology | Ausgabe 4/2023

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Abstract

Purpose

We demonstrated earlier in mouse models of pancreatic ductal adenocarcinoma (PDA) that K^trans derived from dynamic contrast-enhanced (DCE) MRI detected microvascular effect induced by PEGPH20, a hyaluronidase which removes stromal hyaluronan, leading to reduced interstitial fluid pressure in the tumor (Clinical Cancer Res (2019) 25: 2314–2322). How the choice of pharmacokinetic (PK) model and arterial input function (AIF) may impact DCE-derived markers for detecting such an effect is not known.

Procedures

Retrospective analyses of the DCE-MRI of the orthotopic PDA model are performed to examine the impact of individual versus group AIF combined with Tofts model (TM), extended-Tofts model (ETM), or shutter-speed model (SSM) on the ability to detect the microvascular changes induced by PEGPH20 treatment.

Results

Individual AIF exhibit a marked difference in peak gadolinium concentration. However, across all three PK models, k_ep values show a significant correlation between individual versus group-AIF (p < 0.01). Regardless individual or group AIF, when k_ep is obtained from fitting the DCE-MRI data using the SSM, k_ep shows a significant increase after PEGPH20 treatment (p < 0.05 compared to the baseline); %change of k_ep from baseline to post-treatment is also significantly different between PEGPH20 versus vehicle group (p < 0.05). In comparison, when k_ep is derived from the TM, only the use of individual AIF leads to a significant increase of k_ep after PEGPH20 treatment, whereas the %change of k_ep is not different between PEGPH20 versus vehicle group. Group AIF but not individual AIF allows detection of a significant increase of V_p (derived from the ETM) in PEGPH20 versus vehicle group (p < 0.05). Increase of V_p is consistent with a large increase of mean capillary lumen area estimated from immunostaining.

Conclusion

Our results suggest that k_ep derived from SSM and V_p from ETM, both using group AIF, are optimal for the detection of microvascular changes induced by stroma-directed drug PEGPH20. These analyses provide insights in the choice of PK model and AIF for optimal DCE protocol design in mouse pancreatic cancer models.

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Titel: Impact of Arterial Input Function and Pharmacokinetic Models on DCE-MRI Biomarkers for Detection of Vascular Effect Induced by Stroma-Directed Drug in an Orthotopic Mouse Model of Pancreatic Cancer
verfasst von: Jianbo Cao
Stephen Pickup
Mark Rosen
Rong Zhou
Publikationsdatum: 11.05.2023
Verlag: Springer International Publishing
Erschienen in: Molecular Imaging and Biology / Ausgabe 4/2023
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-023-01824-7

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Impact of Arterial Input Function and Pharmacokinetic Models on DCE-MRI Biomarkers for Detection of Vascular Effect Induced by Stroma-Directed Drug in an Orthotopic Mouse Model of Pancreatic Cancer

Abstract

Purpose

Procedures

Results

Conclusion

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