Azusa Kitao

Kanazawa University, Kanazawa, Ishikawa, Japan

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Publications (26)74.09 Total impact

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    ABSTRACT: The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here, we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in approximately 15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n = 70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n = 109). Conclusion: This non-invasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease. (Hepatology 2014;).
    Hepatology 02/2014; · 12.00 Impact Factor
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    ABSTRACT: To investigate the hemodynamics and progression of a hypervascular focus (HF) in a borderline lesion by dual-phase CT during hepatic arteriography (CTHA) and reveal the process of the transformation to hypervascular overt hepatocellular carcinoma (HCC). This study was performed with the approval of our institutional ethics committee, and informed consent for the retrospective usage of clinical materials was obtained from all the patients. The 121 nodules in 76 consecutive patients with liver cirrhosis and chronic hepatitis showing an HF in a borderline lesion on angiography-assisted CT were analyzed. Hemodynamic changes were observed in 24 patients who underwent repeated angiography-assisted CT. Histopathological analysis was conducted in eight nodules. HF was classifiable into type A (stain disappeared), B (stain prolonged), C (stain was washed out and corona-like drainage into the outer nodule was seen) and D (stain was washed out and corona-like drainage into the whole outer nodule was seen) on the late phase of CTHA and was seen to progress in this order on follow-up observation. Histopathologically, de-differentiated foci showed significantly higher expression of sinusoidal capillarization and unpaired arteries than background nodules and showed pseudocapsule, compressive and replacing growth at the border of the background nodule. HF showed multi-step progression and transformation to hypervascular overt HCC.
    Japanese journal of radiology 12/2013; · 0.73 Impact Factor
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    ABSTRACT: PURPOSE: We evaluated molecular features of hypervascular hepatocellular carcinoma (HCC) that shows iso- or hyperintensity (hyperintense HCC) in the hepatobiliary phase (HB phase) of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI). MATERIALS AND METHODS: We investigated 89 surgically resected cases. Patients were divided into two groups according to the signal intensity in the HB phase of EOB-MRI: hyperintense HCCs (n = 18) and hypointense HCCs (n = 71). We performed immunohistochemical staining for uptake transporter of gadoxetic acid: organic anion transporter polypeptides (OATP8); tumor markers: alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II); hepatic stem cell markers: epithelial cell adhesion molecule (EpCAM), cytokeratin 19 (CK19), and neural cell adhesion molecule (NCAM); biliary marker: CK7; hepatocyte marker: hepatocyte paraffin 1 (HepPar1); markers of HCC differentiation: glypican-3; signaling: beta-catenin, and the respective grade was semiquantitatively determined. RESULTS: Histopathologically, hyperintense HCCs showed significantly weaker expression of AFP (p < 0.05), PIVKA-II (p < 0.01), EpCAM (p < 0.005), glypican-3 (p < 0.005) relative to the hypointense HCCs, whereas OATP8 (p < 0.0001), HepPar1 (p < 0.05), and beta-catenin (p < 0.001) were overexpressed in hyperintense HCCs compared with hypointense HCCs. CONCLUSION: Hyperintense HCC expressed OATP8 and showed a feature of mature hepatocytes with a weak expression of stem cell characteristics immunohistochemically. In addition, this type of HCC demonstrated a weaker expression of the poorer prognosis markers including, AFP, PIVKA-II, EpCAM, CK19, and glypican-3.
    Japanese journal of radiology 06/2013; · 0.73 Impact Factor
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    ABSTRACT: OBJECTIVES: To clarify radiological findings and hemodynamic characteristics of hepatic pseudolymphoma, as compared with the histopathological findings. METHODS: Radiological findings of ten histopathologically confirmed hepatic pseudolymphomas in seven patients were examined using US, CT, and MRI. Six patients also underwent angiography-assisted CT, including CT during arterial portography (CTAP) and CT during hepatic arteriography (CTHA) to analyze hemodynamics. RESULTS: The nodules were depicted as hypoechoic on US, hypodense on precontrast CT, hypointense on T1-weighted images, and hyperintense on T2-weighted images. On contrast-enhanced CT/MRI, they showed various degrees of enhancement, and sometimes, perinodular enhancement was observed at the arterial dominant and/or equilibrium phase. On CTAP, the nodules showed portal perfusion defects, including some in the perinodular liver parenchyma. On CTHA, irregular bordered enhancement was observed in perinodular liver parenchyma on early phase, and continued until delayed phase. Some nodules had preserved intra-tumoral portal tracts. Histopathologically, the nodules consisted of marked lymphoid cells. In perinodular liver parenchyma, stenosis or disappearance of portal venules, caused by lymphoid cell infiltration in the portal tracts, was observed. CONCLUSIONS: Hepatic pseudolymphoma showed some characteristic radiological findings including hemodynamics on CT, MRI, and angiography-assisted CT. These findings are useful in the differentiation from hepatocellular carcinoma and other tumors.
    Abdominal Imaging 06/2013; · 1.91 Impact Factor
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    ABSTRACT: We summarize here the consensus reached at the Symposium of the 48th Annual Meeting of the Liver Cancer Study Group of Japan held in Kanazawa on July 20th and 21st, 2012, on the role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) in the management of hepatocellular carcinoma (HCC). Currently, dynamic CT is the first choice of imaging modality when HCC is suspected. EOB-MRI is useful for differentiation and definitive diagnosis of HCC when dynamic CT/MRI does not show conclusive findings for HCC. In addition, contrast- enhanced ultrasound with Sonazoid is useful for making a decision on whether or not to treat a hypovascular lesion <1 cm when the nodules are shown with low intensity in the hepatocyte phase of EOB-MRI. Furthermore, EOB-MRI should be performed in selected cases of HCC ultrahigh-risk groups every 3-4 months, or EOB-MRI should be performed at least once at the first visit in all HCC ultrahigh-risk groups.
    Oncology 01/2013; 84 Suppl 1:21-7. · 2.17 Impact Factor
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    ABSTRACT: Purpose: To analyze the correlation among biologic features, tumor marker production, and signal intensity at gadoxetic acid-enhanced MR imaging in hepatocellular carcinomas (HCCs). Materials and Methods: Institutional ethics committee approval and informed consent were obtained for this retrospective study. From April 2008 to September 2011, 180 surgically resected HCCs in 180 patients (age, 65.0 years ± 10.3 [range, 34-83 years]; 138 men, 42 women) were classified as either hypointense (n = 158) or hyperintense (n = 22) compared with the signal intensity of the background liver on hepatobiliary phase gadoxetic acid-enhanced MR images. Pathologic features were analyzed and a fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) production were compared by means of serum analysis and immunohistochemical staining. Recurrence and survival rates were also evaluated. The Mann-Whitney and Pearson correlation tests were used for statistical analysis. Results: The grade of differentiation was higher (P = .028) and portal vein invasion was less frequent in hyperintense HCCs (13.6%) than in hypointense HCCs (36.7%) (P = .039). The serum levels of AFP, Lens culinaris agglutinin reactive fraction of AFP, and PIVKA-II were lower in hyperintense than in hypointense HCCs (P = .003, .004, and .026, respectively). Immunohistochemical AFP and PIVKA-II expression were lower in hyperintense than in hypointense HCCs (both P < .001). The recurrence rate was lower in hyperintense than in hypointense HCCs (P = .039). Conclusion: The results suggest that hyperintense HCCs on gadoxetic acid-enhanced MR images are less aggressive than hypointense HCCs. © RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120226/-/DC1.
    Radiology 12/2012; 265(3):780-9. · 6.34 Impact Factor
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    ABSTRACT: PURPOSE To analyze the hemodynamic features of bile ductular carcinoma (BDC; pure type of cholangiolocellular carcinoma without internal hepatocellular and cholangiocellular carcinoma; CCC) with special references to hemodynamics evaluated by angiography-assisted CT with histopathologic correlation. METHOD AND MATERIALS Total of 8 BDC and 7 mixed BDC (consisted of both pure BDC components and ordinary cholangiocellular carcinoma components). Dynamic CT was obtained all patients and angiography-assisted CT was obtained thirteen of 15 patients. Enhancement pattern of the tumor and peritumoral area, and interface pathology with special attention to tumor growth pattern and tumoral capillaries communication were assessed. RESULTS Seven of 8 BDCs showed inhomogeneous stain and remaining one showed homogeneous stain on early phase. Six of 7 mixed BDCs showed rim-like and the remaining one inhomogeneous stain in early phase. Peritumoral staining on early phase was evident in seven of 8 BDCs and six of 7 mixed BDCs. Penetrating or terminal branches of portal tracts were seen in all BDCs and mixed BDCs, though all 13 nodules which were underwent CT during arterio-portography showed portal defect. Histopathologically, BDC showed nest of carcinoma cells with fibrous stroma which was denser in central portion than in peripheral portion. On the other hand mixed BDC showed BDC components in peripheral potion and CCC components in central portion with various proportions. Seven of 8 BDCs and six of 7 mixed BDCs showed replacing infiltration growth and remained BDC and mixed BDC showed compressive growth. The tumor cells directly connected to surrounding hepatocytes. There were the continuities between the tumor blood sinusoids and peritumoral hepatic sinusoids. The immunohistochemical staining showed there were many tumor blood sinusoids which continued to intra-tumoral intermingled portal veins. CONCLUSION Peritumoral early enhancement may reflect possible early drainage of contrast medium from the tumor blood sinusoids through the abundant communications between surrounding hepatic sinusoids and intermingled portal venules due to replacing growth manner of BDCs. CLINICAL RELEVANCE/APPLICATION Though peritumoral early enhancement is not specific but we believe this is one of BDC’s characteristic findings different from HCC.
    Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
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    ABSTRACT: PURPOSE To elucidate the signal intensity patterns of borderline lesions of HCC on hepatobiliary phase Gd-EOB-DTPA (EOB) enhanced MRI and clarify the natural histories of these lesions. METHOD AND MATERIALS Total 99 borderline lesions of HCC were identified by angiography-assisted CT in 63 patients. EOB-enhanced MRI was performed within 1 month before or after angiography-assisted CT, and the signal intensity of borderline lesions on hepatobiliary phase were analyzed. Progress rate from borderline lesions to hypervascular HCC were calculated with the Kaplan-Meier method among each signal intensity groups. Log-rank method was applied for comparison of progress rate from borderline lesions to HCC. A two-sided P value of less than 0.05 was considered statistically significant. RESULTS On hepatoboliary phase of EOB enhanced MRI, 41.4% of the borderline lesions showed hypo-, 42.4% showed iso-, and 16.2% showed hyperintense, compared to the background liver parenchyma. Within them, 78 were followed using multiphasic contrast-enhanced CT and/or MRI (follow up period range, 14 to 1240 days). Overall progress rate from borderline lesions to hypervascular HCC were 10% in 1 year, 14% in 2 year and 20% in 3 year follow up period. Eight of 32 hypointense borderline lesions and 2 of 35 isointense borderline lesions progressed to hypervascular HCC over a follow-up period of 134 to 985 days. Progress rates to HCC in hypointense borderline lesions were 17% in 1 year, 28% in 2 year and 41% in 3 year follow up period, and in isointense borderline lesions were 7% in 1 year, 7% in 2 year and 7% in 3 year follow up period. No hyperintense borderline lesions progressed to HCC in the follow up period. There are significant differences in progress rate from borderline lesions to HCC in both between “isointense and hypointense” and “hyperintense and hypointense” borderline lesions (P=.032 and P=0.037, respectively). CONCLUSION Although borderline lesions of HCC may show hypo-, iso- and hyperintensity on hepatobiliary phase of EOB-enhanced MRI, hypointense borderline lesions are high risk to progress overt HCC. CLINICAL RELEVANCE/APPLICATION Although borderline lesions of HCC may show hypo-, iso- and hyperintensity on hepatobiliary phase of EOB-enhanced MRI, hypointense borderline lesions are high risk to progress overt HCC.
    Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
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    ABSTRACT: PURPOSE: To evaluate the usefulness of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MR imaging (EOB-MRI) in differentiating between simple steatosis and nonalcoholic steatohepatitis (NASH), as compared with MR in-phase/out-of-phase imaging. The correlations between the MR features and histological characteristics were preliminarily investigated. MATERIALS AND METHODS: From April 2008 to October 2011, 25 patients (13 simple steatosis and 12 NASH) who underwent both EOB-MRI and in-phase/out-of-phase imaging were analyzed. The hepatobiliary-phase enhancement ratio and signal intensity loss on opposed-phase T1-weighted images (fat fraction) were compared between the simple steatosis and NASH groups. In the simple steatosis and NASH groups, the correlations between enhancement ratio and histological grade/stage were explored. In the NASH group, fat fraction was correlated with the steatosis score. RESULTS: The enhancement ratio in NASH was significantly lower than that in simple steatosis (P = 0.03). In the simple steatosis and NASH groups, the enhancement ratio was significantly correlated with the fibrosis stage (r = -0.469, P = 0.018). Fat fraction in NASH was strongly correlated with the steatosis score (r = 0.728, P = 0.007). CONCLUSION: In simple steatosis and NASH, the hepatobiliary-phase enhancement ratio of EOB-MRI showed significant association with fibrosis stage, and may be a useful discriminating parameter compared with the fat fraction measured by in-phase/out-of-phase imaging. J. Magn. Reson. Imaging 2012;. © 2012 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 11/2012; · 2.57 Impact Factor
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    ABSTRACT: PURPOSE: To reveal the incidence and degree of intrahepatic periportal high intensity (PHI) on hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in patients with or without various hepatobiliary diseases. MATERIALS AND METHODS: Patients with normal liver (N = 256) and those with hepatic disorder (N = 857) who underwent EOB-MRI were the subjects in this study. Incidence of PHI was evaluated among the patients with normal liver and those with hepatic disorder. Degree of PHI was categorized into four grades and compared among the various hepatic diseases. Enhancement ratios (ER) of the PHI area, background liver with PHI, and background liver in control cases without PHI were evaluated. RESULTS: PHI was observed in 2.7 % of the patients with hepatic disorder. No PHI was observed in the patients with normal liver. The incidence rates of PHI among various hepatobiliary diseases were as follows; liver cirrhosis 3.1 %, chronic hepatitis 1.0 %, primary biliary cirrhosis 12.5 %, idiopathic portal hypertension 33.3 %. The ER of the PHI area and background liver were 3.92 and 2.48 (p = 0.0002). There were no significant differences between the ER of the PHI area and the ER of background liver in the noncirrhotic control without PHI. CONCLUSION: In 2.7 % of the patients with a hepatic disorder, the periportal area was saved from decrease of EOB uptake and it showed PHI.
    Japanese journal of radiology 10/2012; · 0.73 Impact Factor
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    ABSTRACT: We report a male case of beta-catenin-activated hepatocellular adenoma (HCA) focusing on findings of gadoxetic-acid-enhanced magnetic resonance imaging (EOB-MRI) and discussing the molecular background and possible clinical significance. The patient was a 31-year-old man in whom computed tomography (CT) showed a large nodule of 14 cm in diameter in the right liver lobe. On dynamic contrast-enhanced CT, heterogeneous and slight to moderate enhancement was observed during the early phase, with washout in the late phase. Focal fat deposits and a scar-like portion in the lesion were also seen. Most of the lesion was slightly hyperintense compared with the background liver on the hepatobiliary phase of EOB-MRI. After operation, this patient was confirmed pathologically as having beta-catenin-activated HCA with a portion suggestive of malignant transformation. In addition, intense organic anion transporter polypeptide 8 expression was observed throughout the tumor by immunohistochemical staining.
    Japanese journal of radiology 08/2012; · 0.73 Impact Factor
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    ABSTRACT: OBJECTIVES: To analyze intranodular signal intensity pattern of hypovascular high-risk borderline lesions of HCC that illustrate multi-step hepatocarcinogenesis within the nodule on Gd-EOB-DTPA-enhanced MRI. METHODS: A total of 73 nodules showing hypervascular foci in hypovascular high-risk borderline lesions identified by angiography-assisted CT were included in this study. The intranodular signal intensities of both the hypervascular foci and the hypovascular high-risk borderline lesions were evaluated on hepatobiliary-phase EOB-enhanced MRI obtained 20min after intravenous injection of contrast media. RESULTS: Among 59 hypervascular foci within hypointense hypovascular high-risk borderline lesions, 6 showed more hypointensity, 32 isointensity, and 21 hyperintensity compared to the surrounding hypointense, hypovascular portion of the nodules. Among 14 hypervascular foci within isointense hypovascular high-risk borderline lesions, 5 showed isointensity, and 9 hypointensity compared to the surrounding isointense hypovascular high-risk borderline lesions. No hypervascular foci showed hyperintensity compared to the surrounding isointense hypovascular high-risk borderline lesions. CONCLUSIONS: In most of the hypovascular high-risk borderline lesions containing hypervascular foci within the nodule, the signal intensity was decreased in hypervascular foci as compared with hypovascular high-risk borderline lesions and the surrounding background liver parenchyma. This supports the concept of signal intensity decrease during the dedifferentiation process in multistep hepatocarcinogenesis. However, around 30% of the nodules did not follow this rule, and hypervascular foci showed hyperintensity relative to the hypovascular high-risk borderline lesions.
    European journal of radiology 08/2012; · 2.65 Impact Factor
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    ABSTRACT: To elucidate the incidence of signal intensity patterns of borderline lesions of hepatocellular carcinoma (HCC) on hepatobiliary phase Gd-EOB-DTPA (EOB) enhanced MRI and clarify the natural histories of these lesions. Total 99 borderline lesions of HCC were identified by angiography-assisted CT. The signal intensity of borderline lesions on hepatobiliary phase of EOB-enhanced MRI was analyzed. Progress rate from borderline lesions to hypervascular HCC was calculated with the Kaplan-Meier method among each signal intensity groups of nodules. On hepatobiliary phase of EOB-enhanced MRI, 41.4% of the borderline lesions showed hypo-, 42.4% showed iso-, and 16.2% showed hyperintense, compared to background liver. Overall progress rates from borderline lesions to HCC were 10% in 1-year, 14% in 2-year and 20% in 3-year follow-up period. Progress rates to HCC in hypointense borderline lesions were 17% in 1-year, 28% in 2-year and 41% in 3-year follow-up period, and in isointense borderline lesions were 7% in 1-year, 7% in 2-year and 7% in 3-year follow-up period. No hyperintense borderline lesions progressed to HCC in follow-up period. Although borderline lesions of HCC may show hypo-, iso- and hyperintensity on hepatobiliary phase of EOB-enhanced MRI, hypointense borderline lesions are high risk to progress HCC.
    European journal of radiology 06/2012; 81(11):3002-9. · 2.65 Impact Factor
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    ABSTRACT: Our aim was to evaluate the hepatocyte transporters in focal nodular hyperplasia (FNH) and FNH-like lesions and to correlate the grade of its expression with signal intensity on the hepatobiliary phase (HB phase) of gadoxetic-acid-enhanced magnetic resonance imaging (EOB-MRI). Thirteen histopathological confirmed cases including eight with EOB-MRI were studied. Immunohistochemical staining for transporter was performed and its grade semiquantitatively analyzed. Histopathologically, ten cases showed almost equal organic anion transporter polypeptide (OATP) 8 expression relative to the surrounding liver; the remaining three showed stronger OATP8 expression. In eight cases with EOB-MRI, two demonstrated more hyperintensity on the HB phase, and their OATP8 expression was stronger compared with the surrounding liver. The remaining six cases showed isointensity on the HB phase and revealed almost equal OATP8 expression. The expression of export transporter multi-drug-resistant proteins (MRP) 1 and 2 were almost equal relative to the surrounding liver in most cases (11/12, 92 %; 11/12, 92 %, respectively), whereas MRP3 focally overexpressed in 75 % (9/12) of cases. FNH and FNH-like nodules revealed equal or stronger OATP8 expression than background liver. OATP8 expression showed significant correlation with signal intensity on the HB phase.
    Japanese journal of radiology 05/2012; 30(6):499-508. · 0.73 Impact Factor
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    ABSTRACT: To clarify the changes in organic anion-transporting polypeptide 8 (OATP8) expression and enhancement ratio on gadoxetic acid-enhanced MR imaging in hepatocellular nodules during multistep hepatocarcinogenesis. In imaging analysis, we focused on 71 surgically resected hepatocellular carcinomas (well, moderately and poorly differentiated HCCs) and 1 dysplastic nodule (DN). We examined the enhancement ratio in the hepatobiliary phase of gadoxetic acid enhanced MR imaging [(1/postcontrast T1 value-1/precontrast T1 value)/(1/precontrast T1 value)], then analysed the correlation among the enhancement ratio, tumour differentiation grade and intensity of immunohistochemical OATP8 expression. In pathological analysis, we focused on surgically resected 190 hepatocellular nodules: low-grade DNs, high-grade DNs, early HCCs, well-differentiated, moderately differentiated and poorly differentiated HCCs, including cases without gadoxetic acid-enhanced MR imaging. We evaluated the correlation between the immunohistochemical OATP8 expression and the tumour differentiation grade. The enhancement ratio of HCCs decreased in accordance with the decline in tumour differentiation (P < 0.0001, R = 0.28) and with the decline of OATP8 expression (P < 0.0001, R = 0.81). The immunohistochemical OATP8 expression decreased from low-grade DNs to poorly differentiated HCCs (P < 0.0001, R = 0.15). The immunohistochemical expression of OATP8 significantly decreases during multistep hepatocarcinogenesis, which may explain the decrease in enhancement ratio on gadoxetic acid-enhanced MR imaging.
    European Radiology 05/2011; 21(10):2056-66. · 4.34 Impact Factor
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    ABSTRACT: Cytokeratin (CK) 19-positive hepatocellular carcinoma (HCC) has been reported to have a poor prognosis. The mechanism of the development of CK19-positive HCC remains to be studied. To clarify this, in vitro experiments were performed using human HCC cell lines (PLC-5, HepG2), and the phenotypic changes after stimulation with several growth factors were examined using quantitative reverse transcriptase PCR, western blotting, and immunofluorescence staining. In vivo experiments using human HCC specimens obtained from a total of 78 patients and clinicopathological analysis were also performed. Among the growth factors tested, epidermal growth factor (EGF) had prominent effects on inducing CK19 expression in PLC-5 and HepG2, which was accompanied by the reduced expression of α-fetoprotein in PLC-5. The induction of CK19 expression after EGF stimulation was accompanied by the phosphorylation of c-Jun-N-terminal kinase (JNK)/stress-activated protein kinase, which was blocked by the addition of JNK inhibitors. EGF also increased proliferative abilities and invasive properties of the HCC cell lines. In vivo, 9 (12%) of 78 HCC cases showed positive immunohistochemical staining of CK19. The extent of positive immunohistochemical signals of EGF, EGF receptor (EGFR), and JNK expression was significantly intense in CK-19-positive HCC than those of CK19-negative HCC. Clinicopathological analysis showed that CK19-positive HCC had a high incidence of portal vein invasion, extrahepatic metastasis and an early relapse, which was associated with the worsened 2-year disease free survival. These results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of CK19-positive HCC, and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients.
    Laboratory Investigation 02/2011; 91(2):262-72. · 3.96 Impact Factor
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    ABSTRACT: To understand the hemodynamics of hepatocellular carcinoma (HCC) is important for the precise imaging diagnosis and treatment, because there is an intense correlation between their hemodynamics and pathophysiology. Angiogenesis such as sinusoidal capillarization and unpaired arteries shows gradual increase during multi-step hepatocarcinogenesis from high-grade dysplastic nodule to classic hypervascular HCC. In accordance with this angiogenesis, the intranodular portal supply is decreased, whereas the intranodular arterial supply is first decreased during the early stage of hepatocarcinogenesis and then increased in parallel with increasing grade of malignancy of the nodules. On the other hand, the main drainage vessels of hepatocellular nodules change from hepatic veins to hepatic sinusoids and then to portal veins during multi-step hepatocarcinogenesis, mainly due to disappearance of the hepatic veins from the nodules. Therefore, in early HCC, no perinodular corona enhancement is seen on portal to equilibrium phase CT, but it is definite in hypervascular classical HCC. Corona enhancement is thicker in encapsulated HCC and thin in HCC without pseudocapsule. To understand these hemodynamic changes during multi-step hepatocarcinogenesis is important, especially for early diagnosis and treatment of HCCs.
    Abdominal Imaging 01/2011; 36(3):264-72. · 1.91 Impact Factor
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    ABSTRACT: PURPOSE To analyze the changes of the uptake transporter of gadolinium-ethoxybenzyl-diethylene-triamine-pentaacetic-acid (Gd-EOB-DTPA), organic anion transporting polypeptide 8 (OATP8), expression during multistep hepatocarcinogenesis. METHOD AND MATERIALS One hundred and forty surgically resected hepatocellular carcinomas (HCCs) and dysplastic nodules (DNs) were histologically classified into 6 grades of differentiation as follows: low grade DN (n=3), high grade DN (n=18), early HCC (n=6), well differentiated HCC (n=25), moderately differentiated HCC (n=92) and poorly differentiated HCC (n=13). Immunohistological staining of OATP8 was performed on all resected specimens, and we semiquantitatively evaluated the intensity of OATP8 expression on tumor cellular membrane in comparison with that of non-neoplastic hepatocytes as follows: 0, no expression; 1+, decreased expression; 2+, equivalent expression; and 3+, increased expression. Then we analyzed the correlation between the intensity of OATP8 expression and the tumor differentiation. We also examined the enhancement ratio ([post enhancement-pre enhancement signal intensity]/pre enhancement signal intensity) of 59 HCCs (well differentiated [n=3], moderately differentiated [n=49] and poorly differentiated [n=7]) on the hepatobiliary phase (after 20 minutes) of Gd-EOB-DTPA enhanced MRI (EOB-MRI). We similarly analyzed the correlation between the enhancement ratio and tumor differentiation. Statistical analysis was performed of each result. RESULTS The immunohistological expression of OATP8 gradually decreased from DNs to poorly differentiated HCCs (P<0.05). On the hepatobiliary phase of EOB-MRI, the enhancement ratio also decreased with decline of tumor differentiation (P<0.05). Moderately differentiated HCCs commonly showed lower OATP8 expression than that of background liver. However, 6 cases (6.5%) showed higher expression. These HCCs uniquely showed a high enhancement ratio on the hepatobiliary phase of EOB-MRI. CONCLUSION The immunohistochemical expression of OATP8 decreases during multistep hepatocarcinogenesis, underlying the decline of enhancement ratio on the hepatobiliary phase of EOB-MRI. CLINICAL RELEVANCE/APPLICATION We can expect the grade of differentiation of HCC by the enhancement ratio on the hepatobiliary phase of EOB-MRI.
    Radiological Society of North America 2010 Scientific Assembly and Annual Meeting; 11/2010
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    ABSTRACT: To analyze the correlation between signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance (MR) imaging and the expression of hepatocyte transporters with histopathologic features in hepatocellular carcinoma (HCC). Institutional ethics committee approval and informed consent were obtained. Forty surgically resected HCCs were classified as hypointense (n = 32) or iso- or hyperintense (n = 8) on the basis of findings in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging. The following were compared between hypointense and iso- or hyperintense HCCs: the time-signal intensity curves at gadoxetic acid-enhanced MR imaging, the expression levels of seven transporters (four organic anion-transporting polypeptides [OATPs] and three multidrug-resistant proteins [MRPs]) at polymerase chain reaction (PCR) (for 22 nodules), results of immunostaining of OATP8, and histologic features. Statistical analysis (unpaired t test, Mann-Whitney test, chi(2) test, and Fisher exact test) was performed for each result. On the time-signal intensity curves, hypointense HCCs showed a decreasing pattern, whereas iso- or hyperintense HCCs showed an increasing pattern after the dynamic phase. PCR revealed that expression of OATP8 (an uptake transporter) in hypointense HCCs was lower and that in iso- or hyperintense HCCs was higher than in background liver (P < .001). The expression level of MRP3 (a sinusoidal export transporter) showed a similar trend to that of OATP8 (P < .001). Immunostaining revealed that OATP8 expression was weak in hypointense HCCs, whereas it was sustained in iso- or hyperintense HCCs (P < .001). At histologic examination, a pseudoglandular proliferation pattern with bile plugs was more commonly observed in iso- or hyperintense HCCs than in hypointense HCCs (P = .01 for proliferation patterns and P = .006 for bile plugs). The enhancement ratio of HCCs in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging positively correlated with expression levels of OATP8 and MRP3, indicating that gadoxetic acid is taken up by OATP8 and excreted by MRP3.
    Radiology 09/2010; 256(3):817-26. · 6.34 Impact Factor
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    ABSTRACT: The possible involvement of immunoglobulin G4 (IgG4) in the pathogenesis of idiopathic sclerosing lesions has been suggested. In this study, a clinicopathologic analysis was performed to reveal characteristics of retroperitoneal fibrosis relating to IgG4. The study involved 17 patients with retroperitoneal fibrosis. Immunohistochemistry revealed numerous IgG4-positive plasma cell infiltrates in 10 cases (IgG4-related), but only a few positive cells in 7 cases (non-IgG4-related). All patients with IgG4-related retroperitoneal fibrosis were male, whereas all except 1 with unrelated lesions were female. Histologically, eosinophilic infiltration (>5 cells per high-power field) and obliterative phlebitis were commonly observed in IgG4-related lesions. Serologically, serum IgG and IgG4 concentrations were significantly higher in the IgG4-related cases, with the IgG4 concentrations all over 135 mg/dL (the upper limit of the normal range). Steroid therapy was performed in 13 cases, and was effective irrespective of IgG4. Three patients had recurrence during the follow up. Five of 10 IgG4-related cases had sclerosing lesions at other sites. The only tests that reliably distinguish the 2 groups were serum IgG4 levels or IgG4/IgG ratio in the plasma cells in a tissue biopsy. The only major clinical difference was the striking male predominance in IgG4-related cases. In conclusion, this study revealed that retroperitoneal fibrosis could be classified as IgG4-related or not. This distinction seems important to help better characterize the biology/pathogenesis of both groups and better predict the possibility of other IgG4-related processes at other anatomic sites.
    The American journal of surgical pathology 12/2009; 33(12):1833-9. · 4.06 Impact Factor

Publication Stats

357 Citations
74.09 Total Impact Points

Institutions

  • 2009–2014
    • Kanazawa University
      • Department of Radiology
      Kanazawa, Ishikawa, Japan
    • King's College London
      Londinium, England, United Kingdom
  • 2006–2013
    • Kanazawa Medical University
      • • Department of Radiology
      • • Department of Pathology
      Kanazawa-shi, Ishikawa-ken, Japan
  • 2012
    • Osaka Red Cross Hospital
      Ōsaka, Ōsaka, Japan