Limits...
Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.

Territo PR, Maluccio M, Riley AA, McCarthy BP, Fletcher J, Tann M, Saxena R, Skill NJ - BMC Med Imaging (2015)

Bottom Line: This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα.In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. pterrito@iupui.edu.

ABSTRACT

Background: Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2(-/-) mice in order to facilitate therapeutic translational studies from bench to bedside.

Methods: 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2(-/-) mice (n = 3/tracer) with HCC and 12 m MDR2(-/+) control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2(-/-) (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list.

Results: Hepatic18F-FDG metabolism was not significantly increased in MDR2(-/-) mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2(-/-) mice when compared to MDR2(-/+) controls. Serum AFP and LPA levels increased in MDR2(-/-) mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.

Conclusions: Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2(-/-) mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.

Show MeSH

Related in: MedlinePlus

18F-FDG PET/CT imaging of MDR2−/−, MDR2−/+ and FVB wild type mice: PET/CT imaging was performed on 12 mo MDR2−/− and FVB control mice. a) Representative 18 F-FDG PET/CT parametric (%ID/g) images of MDR2−/− mouse. b) Representative 18 F-FDG PET/CT parametric (%ID/g) images of FVB control mouse (student’s t test p = 0.26, n = 3/group). c) Liver 18 F-FDG uptake was not significantly greater in MDR2 KO mouse when compared to controls. d) Heart 18 F-FDG uptake was significantly greater in MDR2 KO mouse when compared to controls (student’s t test p = 0.04, n = 3/group)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4493966&req=5

Fig3: 18F-FDG PET/CT imaging of MDR2−/−, MDR2−/+ and FVB wild type mice: PET/CT imaging was performed on 12 mo MDR2−/− and FVB control mice. a) Representative 18 F-FDG PET/CT parametric (%ID/g) images of MDR2−/− mouse. b) Representative 18 F-FDG PET/CT parametric (%ID/g) images of FVB control mouse (student’s t test p = 0.26, n = 3/group). c) Liver 18 F-FDG uptake was not significantly greater in MDR2 KO mouse when compared to controls. d) Heart 18 F-FDG uptake was significantly greater in MDR2 KO mouse when compared to controls (student’s t test p = 0.04, n = 3/group)

Mentions: Clinical monitoring of HCC disease for staging and determination of partial or complete liver transplants have been reported [37–40]. To evaluate the role of glycolytic metabolism in HCC, static 18 F-FDG PET/CT scans were conducted on MDR2−/− and control mice. There was no significant difference in 18 F-FDG uptake in the livers of MDR2−/− (3.61 ± 0.97 %ID/g) mice when compared to wild type controls (4.3 ± 0.6 %ID/g, p = 0.58, n = 3/group) (Fig. 3a-c). In contrast, cardiac 18 F-FDG uptake were significantly higher in MDR2−/− mice when compared to controls (14.9 ± 4.9 vs. 5 ± 0.7, p = 0.05, n = 3/group respectively) (Fig. 3a-b + d). The rationale behind an increase in cardiac 18 F-FDG is beyond the scope of this manuscript, but we include the data for dissemination purposes so that others may evaluate the relevance and importance.Fig. 3


Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.

Territo PR, Maluccio M, Riley AA, McCarthy BP, Fletcher J, Tann M, Saxena R, Skill NJ - BMC Med Imaging (2015)

18F-FDG PET/CT imaging of MDR2−/−, MDR2−/+ and FVB wild type mice: PET/CT imaging was performed on 12 mo MDR2−/− and FVB control mice. a) Representative 18 F-FDG PET/CT parametric (%ID/g) images of MDR2−/− mouse. b) Representative 18 F-FDG PET/CT parametric (%ID/g) images of FVB control mouse (student’s t test p = 0.26, n = 3/group). c) Liver 18 F-FDG uptake was not significantly greater in MDR2 KO mouse when compared to controls. d) Heart 18 F-FDG uptake was significantly greater in MDR2 KO mouse when compared to controls (student’s t test p = 0.04, n = 3/group)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4493966&req=5

Fig3: 18F-FDG PET/CT imaging of MDR2−/−, MDR2−/+ and FVB wild type mice: PET/CT imaging was performed on 12 mo MDR2−/− and FVB control mice. a) Representative 18 F-FDG PET/CT parametric (%ID/g) images of MDR2−/− mouse. b) Representative 18 F-FDG PET/CT parametric (%ID/g) images of FVB control mouse (student’s t test p = 0.26, n = 3/group). c) Liver 18 F-FDG uptake was not significantly greater in MDR2 KO mouse when compared to controls. d) Heart 18 F-FDG uptake was significantly greater in MDR2 KO mouse when compared to controls (student’s t test p = 0.04, n = 3/group)
Mentions: Clinical monitoring of HCC disease for staging and determination of partial or complete liver transplants have been reported [37–40]. To evaluate the role of glycolytic metabolism in HCC, static 18 F-FDG PET/CT scans were conducted on MDR2−/− and control mice. There was no significant difference in 18 F-FDG uptake in the livers of MDR2−/− (3.61 ± 0.97 %ID/g) mice when compared to wild type controls (4.3 ± 0.6 %ID/g, p = 0.58, n = 3/group) (Fig. 3a-c). In contrast, cardiac 18 F-FDG uptake were significantly higher in MDR2−/− mice when compared to controls (14.9 ± 4.9 vs. 5 ± 0.7, p = 0.05, n = 3/group respectively) (Fig. 3a-b + d). The rationale behind an increase in cardiac 18 F-FDG is beyond the scope of this manuscript, but we include the data for dissemination purposes so that others may evaluate the relevance and importance.Fig. 3

Bottom Line: This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα.In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. pterrito@iupui.edu.

ABSTRACT

Background: Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2(-/-) mice in order to facilitate therapeutic translational studies from bench to bedside.

Methods: 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2(-/-) mice (n = 3/tracer) with HCC and 12 m MDR2(-/+) control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2(-/-) (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list.

Results: Hepatic18F-FDG metabolism was not significantly increased in MDR2(-/-) mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2(-/-) mice when compared to MDR2(-/+) controls. Serum AFP and LPA levels increased in MDR2(-/-) mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.

Conclusions: Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2(-/-) mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.

Show MeSH
Related in: MedlinePlus