Yttrium-90 Portal Vein Radioembolization in Sprague–Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver

Andrew C. Gordon; Sarah B. White; Vanessa L. Gates; Weiguo Li; Daniel Procissi; Zhuoli Zhang; Kathleen R. Harris; Dong Hyun Kim; Samdeep K. Mouli; Reed A. Omary; Riad Salem; Andrew C. Larson; Robert J. Lewandowski

doi:10.1007/s00270-020-02614-2

Yttrium-90 Portal Vein Radioembolization in Sprague–Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver

Andrew C. Gordon, Sarah B. White, Vanessa L. Gates, Weiguo Li, Daniel Procissi, Zhuoli Zhang, Kathleen R. Harris, Dong Hyun Kim, Samdeep K. Mouli, Reed A. Omary, Riad Salem, Andrew C. Larson, Robert J. Lewandowski^*

^*Corresponding author for this work

Radiology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Purpose: Portal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass ⁹⁰Y microspheres (Y90 PVE) in Sprague–Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy. Methods: Twenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. ⁹⁰Y PET/CT of ⁹⁰Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide). Results: Ex vivo measurements confirmed 91–97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was − 5.0% (95% CI − 17.0–6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6–29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 μm² for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively. Conclusion: Y90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8–12 weeks.

Original language	English (US)
Pages (from-to)	1925-1935
Number of pages	11
Journal	Cardiovascular and Interventional Radiology
Volume	43
Issue number	12
DOIs	https://doi.org/10.1007/s00270-020-02614-2
State	Published - Dec 1 2020

Funding

We are grateful for the generous funding that supported this work provided by the SIR Foundation Allied Scientist Grant (ACG) and the Department of Radiology of the Feinberg School of Medicine. ACG Medical Scientist Training Program (T32GM008152). Dose vials, administration kits, and additional funding was provided through an Investigator Initiated Study (IIS) grant from BTG. RS is supported in part by NIH grant CA126809. SBW receives salary support from NIH 5R25 CA132822-03. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 and the Robert H Lurie Comprehensive Cancer Center Pathology Core Facility (Bernice Frederick, Adriana Rosca, Demirkan Gürsel). Acknowledgements The authors thank Northwestern University Healthy Physics (Jose Macatangay, Joseph Princewill, Thomas E. Whittenhall Jr., Angelica E. Gheen). Survival studies were supported through dedicated housing and accommodation by the Center for Comparative Medicine (Dr. Stephen I. Levin, Giovanni Pompilio). Imaging for our studies was made possible by Northwestern University's Center for Translational Imaging (Sol Misener).

Keywords

Dosing
Fibrosis
Hepatic radioembolization
Magnetic resonance imaging
Portal vein embolization
Yttrium-90

ASJC Scopus subject areas

Radiology Nuclear Medicine and imaging
Cardiology and Cardiovascular Medicine

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10.1007/s00270-020-02614-2

Cite this

Gordon, A. C., White, S. B., Gates, V. L., Li, W., Procissi, D., Zhang, Z., Harris, K. R., Kim, D. H., Mouli, S. K., Omary, R. A., Salem, R., Larson, A. C., & Lewandowski, R. J. (2020). Yttrium-90 Portal Vein Radioembolization in Sprague–Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver. Cardiovascular and Interventional Radiology, 43(12), 1925-1935. https://doi.org/10.1007/s00270-020-02614-2

@article{7fd65d4de11f40dc8c9e12aa63145d97,

title = "Yttrium-90 Portal Vein Radioembolization in Sprague–Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver",

abstract = "Purpose: Portal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague–Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy. Methods: Twenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide). Results: Ex vivo measurements confirmed 91–97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was − 5.0% (95% CI − 17.0–6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6–29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 μm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively. Conclusion: Y90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8–12 weeks.",

keywords = "Dosing, Fibrosis, Hepatic radioembolization, Magnetic resonance imaging, Portal vein embolization, Yttrium-90",

author = "Gordon, {Andrew C.} and White, {Sarah B.} and Gates, {Vanessa L.} and Weiguo Li and Daniel Procissi and Zhuoli Zhang and Harris, {Kathleen R.} and Kim, {Dong Hyun} and Mouli, {Samdeep K.} and Omary, {Reed A.} and Riad Salem and Larson, {Andrew C.} and Lewandowski, {Robert J.}",

note = "Funding Information: We are grateful for the generous funding that supported this work provided by the SIR Foundation Allied Scientist Grant (ACG) and the Department of Radiology of the Feinberg School of Medicine. ACG Medical Scientist Training Program (T32GM008152). Dose vials, administration kits, and additional funding was provided through an Investigator Initiated Study (IIS) grant from BTG. RS is supported in part by NIH grant CA126809. SBW receives salary support from NIH 5R25 CA132822-03. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 and the Robert H Lurie Comprehensive Cancer Center Pathology Core Facility (Bernice Frederick, Adriana Rosca, Demirkan G{\"u}rsel). Acknowledgements Funding Information: The authors thank Northwestern University Healthy Physics (Jose Macatangay, Joseph Princewill, Thomas E. Whittenhall Jr., Angelica E. Gheen). Survival studies were supported through dedicated housing and accommodation by the Center for Comparative Medicine (Dr. Stephen I. Levin, Giovanni Pompilio). Imaging for our studies was made possible by Northwestern University's Center for Translational Imaging (Sol Misener). Publisher Copyright: {\textcopyright} 2020, Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).",

year = "2020",

month = dec,

day = "1",

doi = "10.1007/s00270-020-02614-2",

language = "English (US)",

volume = "43",

pages = "1925--1935",

journal = "Cardiovascular and Interventional Radiology",

issn = "0174-1551",

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number = "12",

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Gordon, AC, White, SB, Gates, VL, Li, W, Procissi, D, Zhang, Z, Harris, KR, Kim, DH , Mouli, SK, Omary, RA, Salem, R, Larson, AC & Lewandowski, RJ 2020, 'Yttrium-90 Portal Vein Radioembolization in Sprague–Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver', Cardiovascular and Interventional Radiology, vol. 43, no. 12, pp. 1925-1935. https://doi.org/10.1007/s00270-020-02614-2

TY - JOUR

T1 - Yttrium-90 Portal Vein Radioembolization in Sprague–Dawley Rats

T2 - Dose-Dependent Imaging and Pathological Changes in Normal Liver

AU - Gordon, Andrew C.

AU - White, Sarah B.

AU - Gates, Vanessa L.

AU - Li, Weiguo

AU - Procissi, Daniel

AU - Zhang, Zhuoli

AU - Harris, Kathleen R.

AU - Kim, Dong Hyun

AU - Mouli, Samdeep K.

AU - Omary, Reed A.

AU - Salem, Riad

AU - Larson, Andrew C.

AU - Lewandowski, Robert J.

N1 - Funding Information: We are grateful for the generous funding that supported this work provided by the SIR Foundation Allied Scientist Grant (ACG) and the Department of Radiology of the Feinberg School of Medicine. ACG Medical Scientist Training Program (T32GM008152). Dose vials, administration kits, and additional funding was provided through an Investigator Initiated Study (IIS) grant from BTG. RS is supported in part by NIH grant CA126809. SBW receives salary support from NIH 5R25 CA132822-03. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 and the Robert H Lurie Comprehensive Cancer Center Pathology Core Facility (Bernice Frederick, Adriana Rosca, Demirkan Gürsel). Acknowledgements Funding Information: The authors thank Northwestern University Healthy Physics (Jose Macatangay, Joseph Princewill, Thomas E. Whittenhall Jr., Angelica E. Gheen). Survival studies were supported through dedicated housing and accommodation by the Center for Comparative Medicine (Dr. Stephen I. Levin, Giovanni Pompilio). Imaging for our studies was made possible by Northwestern University's Center for Translational Imaging (Sol Misener). Publisher Copyright: © 2020, Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Purpose: Portal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague–Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy. Methods: Twenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide). Results: Ex vivo measurements confirmed 91–97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was − 5.0% (95% CI − 17.0–6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6–29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 μm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively. Conclusion: Y90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8–12 weeks.

AB - Purpose: Portal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague–Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy. Methods: Twenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide). Results: Ex vivo measurements confirmed 91–97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was − 5.0% (95% CI − 17.0–6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6–29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 μm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively. Conclusion: Y90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8–12 weeks.

KW - Dosing

KW - Fibrosis

KW - Hepatic radioembolization

KW - Magnetic resonance imaging

KW - Portal vein embolization

KW - Yttrium-90

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Yttrium-90 Portal Vein Radioembolization in Sprague–Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver

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