Masami Asakawa

Imaging Study of Early Hepatocellular Carcinoma: Usefulness of Gadoxetic Acid–enhanced MR Imaging

PURPOSE To describe imaging findings of early hepatocellular carcinoma (HCC) at gadoxetic acid-enhanced magnetic resonance (MR) imaging, dynamic contrast material-enhanced computed tomography (CT), CT during arterial portography (CTAP), and CT during hepatic arteriography (CTHA) and to compare the diagnostic performance of each modality for small (≤ 2 cm) HCC. MATERIALS AND METHODS The institute ethics committee deemed study approval unnecessary. One hundred eight resected small lesions in 64 patients were diagnosed as a dysplastic nodule (DN) (n = 12), progressed HCC (n = 66), or early HCC (n = 30). All but two patients underwent all imaging examinations. The imaging characteristics of the lesions with each modality were determined. To evaluate the diagnostic performance of the modalities, two radiologists graded the presence of HCC with use of a five-point confidence scale. The area under the receiver operating characteristic curve (A(z)), sensitivity, and specificity of each modality were compared. RESULTS The imaging features that are statistically significant for differentiating an early HCC from a DN include fat-containing lesions at dual-echo T1-weighted MR imaging (seen in 16 of the 30 early HCCs and none of the DNs), low attenuation at unenhanced CT (seen in 13 of the 30 early HCCs and none of the DNs), low attenuation at CTAP (seen in 11 of the 30 early HCCs and none of the DNs), and low signal intensity at hepatocyte phase gadoxetic acid-enhanced MR imaging (seen in 29 of the 30 early HCCs and none of the DNs). The diagnostic performance of gadoxetic acid-enhanced MR imaging (A(z), 0.98 and 0.99) was significantly greater than that of contrast-enhanced CT (A(z), 0.87) and CTHA-CTAP (A(z), 0.85 and 0.86) owing to its significantly higher sensitivity (P < .001). CONCLUSION Gadoxetic acid-enhanced MR imaging is the most useful imaging technique for evaluating small HCC, including early HCC.

Predictive Power of Biomarkers of Oxidative Stress and Inflammation in Patients with Hepatitis C Virus-Associated Hepatocellular Carcinoma

BackgroundThis study evaluated the relationship between inflammation, intra-hepatic oxidative stress, oxidative DNA damage and the progression of liver carcinogenesis in hepatitis C virus (HCV)-infected humans.MethodsNon-cancerous liver tissues were collected from 30 patients with an HCV-associated solitary hepatocellular carcinoma (HCC) who received curative tumor removal. After surgery, the patients were followed at monthly intervals at the outpatient clinic. Distribution of the inflammatory cells (CD68+), the number of 8-hydroxydeoxyguanosine (8-OHdG) DNA adducts and 4-hydroxynonenal (HNE) protein adducts and the expression of apurinic/apyrimidinic endonuclease (APE) were determined by immunohistochemical analysis in serial liver sections from tumor-free parenchyma at the surgical margin around the tumor.ResultsSignificant positive correlations were observed between the number of CD68+ cells, the amount of HNE protein adducts, and the number of 8-OHdG adducts in liver tissue of patients with HCC and HCV. The cumulative disease-free survival was significantly shorter in patients with the highest percentage of 8-OHdG-positive hepatocytes. Using a Cox proportional hazard model, 8-OHdG, HNE and CD68 were determined to be good biomarkers for predicting disease-free survival in patients with HCC and HCV.ConclusionsThese results support the hypothesis that HCV-induced inflammation causes oxidative DNA damage and promotes hepatocarcinogenesis which directly affects the clinical outcome. Since patients with greater intra-hepatic oxidative stress had a higher incidence of HCC recurrence, we suggest that oxidative stress biomarkers could potentially be used as a useful clinical diagnostic tool to predict the duration of disease-free survival in patients with HCV-associated HCC.

Double-dose gadoxetic Acid-enhanced magnetic resonance imaging in patients with chronic liver disease.

Objectives:To determine the effect of double-dose gadoxetic-acid (Gd-EOB-DTPA) on lesion-liver contrast ratio in arterial- and hepatocyte-phase images and arterial-phase image quality in patients with chronic liver disease. Materials and Methods:The ethics committee at our institute approved this study. This study included 28 patients (13 with Child-Pugh class A and 15 with class B) with 54 hepatocellular carcinomas. All patients received the standard Gd-EOB-DTPA dose (0.025 mmol/kg bodyweight) and double dose (0.050 mmol/kg bodyweight). The lesion-liver contrast ratio was evaluated in arterial- and hepatocyte-phase images. The artifacts in arterial-phase images were evaluated with a 4-point scale. Wilcoxon signed-rank test were used for comparisons. Results:The hepatocyte-phase lesion-liver contrast ratio after the double dose was significantly higher than that after the standard dose in patients with Child-Pugh class B disease(standard dose vs. double dose; 0.20 ± 0.16 vs. 0.25 ± 0.17; P < 0.0001); however, the ratio after both the standard and double doses was equivalent in patients with Child-Pugh class A disease (0.35 ± 0.18 vs. 0.35 ± 0.14; P = 0.3038). The double dose significantly increased the arterial-phase lesion-liver contrast ratio (0.34 ± 0.19 vs. 0.58 ± 0.33; P < 0.0001). The artifacts in the arterial-phase images were more prominent after the standard dose (2.7 vs. 2.4 for reader 1, 2.8 vs. 2.4 for reader 2; P = 0.0195 and 0.0010). Conclusions:Administration of double dose of Gd-EOB-DTPA provided better arterial enhancement of hepatocellular carcinomas in patients with chronic liver disease, and also improved the lesion-liver contrast in hepatocyte-phase images in patients with Child-Pugh class B disease.

Protective Effects of Medium-Chain Triglycerides on the Liver and Gut in Rats Administered Endotoxin

ObjectiveTo determine if medium-chain triglycerides (MCTs) prevent organ injuries and mortality in rats administered endotoxin and to investigate effects of MCT on the gut. Summary Background DataSince dietary MCTs prevent alcohol-induced liver injury by inhibiting activation of Kupffer cells in the enteral feeding model, the authors hypothesized that MCT could prevent deleterious conditions in endotoxemia. MethodsAfter a preliminary experiment determined the optimal dose of MCT, rats were given MCT (5 g/kg per day) or the same dose of corn oil by gavage daily for 1 week. Then, lipopolysaccharide (LPS) was administered intravenously and survival was assessed for the next 24 hours. For analysis of mechanisms, rats were killed 9 hours after LPS injection and serum and liver sections were collected. To investigate effects of MCT on the gut, pathologic change, permeability, and microflora were assessed. Kupffer cells isolated by collagenase digestion and differential centrifugation were used for endotoxin receptor CD14 immunoblotting, phagocytic index, and TNF-&agr; production assay. ResultsAll rats given corn oil died after LPS administration; however, this mortality was prevented by MCT in a dose-dependent manner. Rats given corn oil showed liver injury after LPS administration. In contrast, MCT prevented this pathologic change nearly completely. MCT blunted CD14 expression on the Kupffer cells and TNF-&agr; production by isolated Kupffer cells; however, there were no differences in phagocytic index between the two groups. The length of the intestinal epithelium was increased in the MCT group compared to the corn oil group. Further, after LPS administration, increases in gut permeability and injury were prevented by MCT. Importantly, MCT also prevented hepatic energy charge and gut injuries in this condition. ConclusionsEnteral feeding using MCT could be a practical way of protecting the liver and intestine during endotoxemia.

Role of interleukin-18 and its receptor in hepatocellular carcinoma associated with hepatitis C virus infection

Interleukin (IL)‐18 is a proinflammatory cytokine that is up‐regulated in patients with hepatitis C virus (HCV) infection, which is the most common underlying disease in hepatocellular carcinoma (HCC). The purpose of our study was to investigate the role of IL‐18 in HCC associated with HCV infection. Sixty‐five patients with HCC and HCV infections who received curative surgical resections were examined in our study. The expression of the IL‐18 receptor was investigated in HCC tissues obtained from these patients and in 2 HCC cell lines. Nuclear factor (NF)‐κB activity and the expression of Bcl‐xL and xIAP mRNA were tested in the cell lines using recombinant human (rh) IL‐18. The IL‐18 receptor was expressed in both the HCC tissues and the cell lines. NF‐κB activation and the expression of Bcl‐xL and xIAP mRNA were increased by rhIL‐18. Moreover, rhIL‐18 suppressed the apoptosis of HCC cells which was induced by etoposide in vitro. The overall survival rate (55.4%) was significantly worse in the IL‐18 receptor‐positive patients than in the IL‐18 receptor‐negative patients (p = 0.015). In a Cox multivariate analysis, the expression of the IL‐18 receptor was found to be a significant predictor of a poor outcome in HCC patients. The expression of the IL‐18 receptor and an antiapoptotic mechanism involving NF‐κB activation in HCC cells may be implicated in a poor patient outcome.

The Kupffer cell protects against acute lung injury in a rat peritonitis model: role of IL-10.

The possibility that Kupffer cells (KCs) play key beneficial and deleterious roles in multiple organ injury in sepsis has been discussed. The role of KCs in lung injury in a rat peritonitis model was investigated. Specifically, the involvement of interleukin (IL)‐10, which has anti‐inflammatory effects, was examined. Rats were given saline or gadolinium chloride (GdCl3), a KC toxicant, 24 h before cecal ligation and puncture (CLP). Survival was assessed for 7 days after CLP. The liver, lung, and serum were harvested, and the expression of cytokines was assessed. Macrophages were isolated from each organ after CLP, and the mRNA expression of inflammatory mediators was assessed. GdCl3 treatment increased lung injury and mortality. Plasma endotoxin levels were significantly greater, whereas serum IL‐10 levels were lower in the GdCl3 than in the control group after CLP. IL‐10 levels were significantly greater in the aorta than the hepatic vein. The mRNA expression of IL‐10 was less in KCs from the GdCl3 than the control group. In the liver, the expression of IL‐10 increased rapidly and continuously, up to 9 h in the control group, but values were significantly lower in the GdCl3 group. Rabbit anti‐rat IL‐10 antibodies were injected just after CLP to investigate the effects of immunoneutralization of endogenously produced IL‐10. In the antibody‐treated group, lung injury and mortality increased compared with animals treated with rabbit immunoglobulin G. Taken together, these results indicate that KCs play a protective role in lung injury in sepsis by production of IL‐10.

Decreased expression of CD28 coincides with the down‐modulation of CD3ζ and augmentation of caspase‐3 activity in T cells from hepatocellular carcinoma‐bearing patients and hepatitis C virus‐infected patients

Background and Aim:  Hepatitis C virus (HCV) infection causes chronic inflammation and increases the risk of hepatocellular carcinoma (HCC). This immunosuppressive state may be one reason why HCV‐infected patients often have multicentric cancers. Therefore, the purpose of the present study was to assess the cellular immune function in HCC‐bearing and HCV‐infected patients.

Lens culinaris agglutinin-reactive fraction of AFP is a useful prognostic biomarker for survival after repeat hepatic resection for HCC

Background and Aim:  Repeat hepatic resection for recurrent hepatocellular carcinoma (HCC) is effective in improving long‐term outcome in selected patients. In the present study, we attempted to identify the prognostic factors influencing overall and recurrence‐free survival after the second hepatic resection.

Decreased CD3 ζ molecules of T lymphocytes from patients with hepatocellular carcinoma associated with hepatitis C virus

Most hepatocellular carcinomas (HCC) occur in chronic liver disease. Under such conditions, an impaired cellular immune response is often observed, but the mechanisms of this deficiency are unclear. The down-modulation of CD3 ζ (a key molecule in signal-transducing factor of T cell receptor) leads to a reduction in the function of T cells. In this study, we demonstrated the decreased expression of CD3 ζ on T cells from hepatitis C virus (HCV) infected hosts and HCC patients and clarified the correlation between the expression of CD3 ζ and tumor progression. Flowcytometrical analysis of CD3 ζ on peripheral T lymphocytes from 12 HCV infected hosts and 36 HCC bearing patients showed a significantly lower CD3 ζ expression than normal controls. Compared with tumor infiltrating T lymphocytes (TIL), intrahepatic T lymphocytes (IHL) and peripheral T lymphocytes (PBL) from 11 HCC bearing patients, the expression of CD3 ζ on TIL was significantly lower than PBL, and the expression level of CD3 ζ on IHL was almost equal to that on TIL. These results suggest that the down-modulation of CD3 ζ of T lymphocytes in HCV infected hosts may be one of the reasons why multicentric occurrence and intrahepatic metastasis occur more frequently in HCC patients than another malignancies.

Complete remission of multiple recurrent hepatocellular carcinomas by oral administration of enteric-coated tegafur/uracil in a patient with huge hepatocellular carcinoma extending to the inferior vena cava after hepatic resection: analysis of mRNA expression of fluoropyrimidine metabolism enzymes in the primary tumor

We herein report the complete remission of multiple recurrent hepatocellular carcinomas (HCCs) by the oral administration of tegafur/uracil (UFT) alone. A 56-year-old Japanese man with two huge HCCs was admitted and underwent hepatic resection. Intraoperative ultrasonography revealed that the tumor thrombus extended to the inferior vena cava (IVC) with a small tumor in the left hepatic lobe. Right trisectionectomy of the liver, removal of the tumor thrombus in the IVC, and partial resection of the left lobe were performed. Microscopic examination revealed that the larger tumor was moderately to poorly differentiated HCC and the smaller tumor was well-differentiated HCC. The small tumor in the left lobe was diagnosed as an intrahepatic metastasis of the larger tumor. Two months after the surgery, computed tomography (CT) revealed multiple HCC recurrences in the remnant liver, but complete remission was achieved by the administration of UFT alone. To clarify the reason for the good response of the recurrent HCC to UFT, the mRNA expression level of several fluoropyrimidine metabolism enzymes was measured in resected specimens. A lower expression of thymidine phosphorylase (TP) might explain the good response to UFT. The patient is alive without intra- or extrahepatic recurrence more than 6 years after the hepatic resection.