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Background and aims Some follow-up studies of large regenerative nodules (LRNs) and dysplastic nodules (DNs) were reported previously. However, the pre-malignant potentiality of LRNs has remained controversial up to now. No LRNs showed malignant transformation in our previous study. We aimed to evaluate the pre-malignant potentiality of LRNs and DNs with a greater number of cases and longer follow-up periods. Methods From 1982 to 2005, 1,500 consecutive nodular lesions up to 2 cm in diameter were subjected to US guided thin-needle biopsy in cirrhotic patients at Chiba University Hospital. Of these lesions, 68 LRNs in 60 cases and 20 DNs in 22 cases were followed up for more than 6 months without any anti-cancer therapy. The last US examination was in 2010. The total study period was 28 years. We analyzed the histological findings and the clinical data of all cases retrospectively. The outcome of the lesions was examined. Results The mean follow-up period was 38.9 (16–119) months in LRNs and 31.9 (6–101 months) in DNs. Rate of nodule enlargement was higher in DNs (8/24 nodules, 33 %) than LRNs (11/68 nodules, 16 %), (p = 0.0743, not significant). Rate of malignant transformation was also higher in DNs (10/24 nodules, 42 %) than LRNs (9/68 nodules, 13 %), (p = 0.0040, significant). The rate of disappearance in images was similar between LRNs and DNs. Conclusions We should recognize LRN as low risk pre-malignant lesions whereas DNs as high risk lesions.

Background and Aim: Although hypervascular appearance is characteristic in hepatocellular carcinoma (HCC), hepatic nodules without hypervascular appearance are sometimes found in patients with chronic liver disease (CLD). The aim of the present study was to clarify the efficacy of contrast-enhanced ultrasound (CEUS) with Levovist to characterize small, non-hypervascular hepatic nodules on contrast-enhanced computed tomography (CECT) in patients with CLD. Methods: The subject was 41 hepatic nodules (

To evaluate the efficacy of contrast-enhanced ultrasound for the localization of ultrasonically invisible hypervascular lesions in the liver to facilitate percutaneous ultrasound-guided treatment.Forty patients with 47 ultrasonically invisible hypervascular lesions (5-20mm) diagnosed on contrast-enhanced computed tomography were enrolled in the retrospective study. Contrast-enhanced ultrasound (CEUS) with Levovist was performed to localize the lesions both in the early phase and liver-specific phase. Diagnosis of was confirmed by percutaneous needle biopsy where feasible, and on the basis of on treatment outcomes or changes in computed tomography findings in those not amenable to biopsy.Thirty-two lesions were diagnosed as hepatocellular carcinoma (HCC). Contrast-enhanced ultrasound localized hepatocellular carcinoma in 24/32 (75%) lesions, the mean diameter (15.1+/-4.9mm), as measured using computed tomography, being significantly larger than that of the remaining eight lesions (10.5+/-2.1mm). Ultrasound-guided treatment was performed in 19 of the 24 lesions, and transarterial chemoembolization (TACE) was applied for the other five lesions because of difficult percutaneous access. Five of the eight non-visualised lesions were treated by transarterial chemoembolization, and the other three by surgical resection. The beneficial effect of CEUS was significantly greater when the reason for poor initial visualisation was the coarse liver architecture (17/17) than when it was due to adverse location (seven of 15, p0.005). Fifteen of the CT-detected hypervascular lesions were considered to represent false positives for HCC, based on their behaviour during follow-up.Contrast-enhanced ultrasound with Levovist facilitates the application of percutaneous ultrasound-guided treatment by improving localization of ultrasonically invisible hypervascular hepatocellular carcinomas in the liver.

Purpose. To demonstrate that liver metastases with a diameter of ≤40 mm show characteristic features on three-dimensional (3D) fusion sonographic images and that these sonographic findings can be correlated with histopathologic features of surgical specimens. Methods. Liver metastases measuring ≤40 mm were examined via contrast-enhanced 3D fusion sonography. The characteristic sonographic findings of 17 tumor nodules in 11 patients with a histopathologically confirmed diagnosis of liver metastases were investigated, and their correspondence to the pathologic features were examined in 12 resected nodules. Results. On sonograms, central vessels were visualized in all 17 tumor nodules and peripheral vessels were visualized in 12 nodules. On histopathologic examination, the portal triad vessels corresponded to the central vessels and were located at the center of the tumors. A thin layer of peritumoral hepatocytes showing various changes was also observed, and a group of tiny vessels were seen running along this layer of cells. Conclusions. Liver metastases measuring 40 mm or less in diameter were characterized by the presence of both central and peripheral vessels on contrast-enhanced 3D fusion sonography. There was good correlation between sonographic and histopathologic findings. © 2006 Wiley Periodicals, Inc. J Clin Ultrasound 2007

It is desirable to diagnose hepatocellular carcinoma (HCC) in the early stages during its development since its treatment is usually difficult. We previously proposed a new diagnostic method that made use of the total metallothionein (MT), zinc (Zn), and copper (Cu) concentrations in the liver of the HCC patients. We recently found that MT-1 is involved in the metabolism or detoxification of toxic metals, such as cadmium; on the other hand, MT-2 is responsible for the homeostasis of essential metals such as copper, in experimental models such as Long Evans Cinnamon (LEC) rats. In order to device a better diagnostic method than the one we proposed previously, in this study, we newly propose an improved method that includes the discriminative determination data regarding the MT isomers, namely, MT-1 and MT-2, in the liver of patients with or without HCC as compared with the total MT level. The total MT and Zn concentrations in the HCC patients were confirmed to be significantly lower than those in patients without hepatic disorders (Ctrl). In contrast, Cu concentrations of the HCC patients were higher than those of the Ctrl patients. In addition, in the juxta-tumor portion with HCC, MT-1 concentrations were significantly higher than those of MT-2. In contrast, the MT-1 concentrations in the tumor portion were significantly lower than that in the juxta-tumor portion. In addition, MT-1/MT-2 ratio in the tumor portion was significantly lower than that of the juxta-tumor portion. By using parameters such as concentrations of Cu, Zn, total MT, and MT isomers, we performed the multivariate discriminative analysis (MDA). The results suggest that the concentrations of MT isomers change depending on the progress of the tumor, and information on MT isomers and trace elements is very useful in determining the stage of the chronic hepatic disorder.

To evaluate the therapeutic efficacy of percutaneous ethanol injection (PEI) for patients withor = 3 lesions of small (or = 3 cm diameter) hepatocellular carcinoma (HCC).PEI was applied to 270 patients with small HCC as the first-line treatment option during a 20-year period.(1) There was no treatment-related deaths, and only 2.2% of severe complications; (2) PEI induced a complete response of all HCCs according to CT evaluation performed within one month after the procedure, and the local recurrence rate at 3 years was 10%; (3) the overall 3- and 5-year survival rates after treatment were 81.6 and 60.3%, respectively, but the rates were higher, 87.3 and 78.3%, in Child A patients with a solitary tumoror = 2 cm in diameter; (4) factors significantly influencing survival were liver function (P = 0.0033) and serum alpha-fetoprotein level (P = 0.0014), and (5) the recurrence rate at remote sites in the liver was lower in patients with HCCor = 2 cm (P = 0.0395) and in those with a solitary HCC (P0.0001) according to Cox's proportional hazard model. (6) Radiofrequency ablation would not have been performed in approximately 25% of these patients.PEI is considered a reliable treatment for small HCC in terms of safety and efficacy.

It has been reported that the copper (Cu) content of hepatocytes increases in chronic liver diseases and small hepatocellular carcinoma (HCC). In cells, Cu exists mainly as Cu-metallothionein (MT) or Cu, zinc (Zn)-superoxide dismutase (SOD). In this study, we investigated the biochemical state of Cu in the hepatocytes of patients with HCC using high-performance liquid chromatography (HPLC). The subjects of present study were 23 patients with HCC who underwent liver resection. The cancerous tissue and non-cancerous hepatic parenchyma with chronic disease were analyzed. In addition, as a normal control, hepatic tissue was collected at autopsy from 13 patients with no liver disease. Each sample was diluted with buffer, chilled, homogenized, and centrifuged. The supernatant was fractionated using HPLC. The metal contents of each fraction were measured using a desktop-type inductively coupled plasma (ICP) emission spectrochemical analyzer. HPLC analysis showed that MT existed mainly as Zn-MT in the normal hepatic tissue. The case of Cu,Zn-MT was significantly greater than Zn-MT in the non-cancerous, but diseased hepatic parenchyma than in the normal hepatic tissue (p

We administered trientine hydrochloride, a drug used in the treatment of Wilson's disease, to patients with hepatocellular carcinoma after radical treatment with percutaneous ethanol injection or radiofrequency ablation, and examined its effect on the reduction of liver-tissue copper content. We enrolled 24 patients with 3 or fewer primary lesions of Child class A or B hepatocellular carcinoma with diameters of 3 cm or less who had undergone radical treatment with percutaneous ethanol injection or radiofrequency ablation. Trientine hydrochloride was orally administered in a single daily dose of 250 mg to 12 patients before a meal (at fasting, group 1) or at a total daily dosage of 750 mg, divided into 3 doses, to 12 patients (group 2). This study was a randomized between-groups comparative study of 12 weeks' duration. We used the particle-induced x-ray-emission method to determine liver-tissue mineral content. Urine copper and serum mineral levels were also measured, and transaminase levels were examined. Liver-tissue copper content decreased significantly, to 160.1 microg/g dry weight, after treatment, compared with the pretreatment level of 306.8 microg/g dry weight (P

In order to present new findings of imaging studies and pathology, we describe nontypical lesions rather than well-known typical lesions such as focal nodular hyperplasia (FNH), hepatocellular adenoma, nodular regenerative hyperplasia (NRH) and large regenerative nodules in liver with idiopathic portal hypertension (IPH). Nontypical lesions are not definitively diagnosed as any of the above typical well-known lesions. These lesions are not rare, and are clinically important since they must be differentiated from hepatocellular carcinoma. These lesions can be formed by hyperperfusion of either the artery or the portal vein. They are found in either the hilar area or peripheral area. The extranodular liver (background liver) shows various histological findings, being nearly normal in some cases but showing a clearly abnormal vasculature in others. The lesions, therefore, present various patterns in imaging. Pathological examination also shows variation in the size of the lumen of portal veins and arteries. Abnormal arrangement of arteries and portal veins are also demonstrated, while parenchymal nodular liver tissues are uniformly nonneoplastic benign hyperplastic tissues. These nontypical lesions and well-known typical lesions (FNH, NRH and IPH) are explained by a single etiological mechanism of anomaly of the portal tract. They can be collectively called anomalous portal tract syndrome. For their definitive diagnosis, the structure and hemodynamics of the nodules need to be clarified by images. Biopsy is also necessary to confirm that the lesions consist of benign hepatic tissues. Subsequently, these findings should be evaluated comprehensively.

Aim: To study whether cancer cell differentiation in small hepatocellular carcinoma (HCC) can be assessed by computed tomography (CT) and magnetic resonance (MR) imaging. Methods: We retrospectively evaluated the relationship between cancer cell differentiation in 127 HCC 3 cm or less in diameter (113 patients) and CT and MR images. Images were reviewed in a consensus conference by three authors (SA, TY, and ME). Histopathological diagnosis of HCC was made from liver specimens obtained by sonographically guided biopsy. Results: The degree of histological differentiation of cancer cells was significantly different between HCC that were isodense with liver parenchyma in both artery-dominant and equilibrium phases in contrast-enhanced CT and tumors that were hyperdense in the artery-dominant phase and iso- or hypodense in the equilibrium phase (P = 0.0054), as well as tumors that were iso- or hypodense artery-dominant and hypodense equilibrium (P = 0.0002). Histological differentiation of lesions that were hyperintense in T1-weighted images and hypointense in T2-weighted images differed significantly from those with the opposite MR characteristics (P = 0.0122). In T1-weighted fat-suppression images and T2-weighted images, respectively, the degree of histological differentiation was significant between the hypointense/hyperintense and the hyperintense/hypointense patterns (P

Background/Aims: The aim of this study was to investigate the relationship between trace metals and the prevalence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis or hepatic cirrhosis caused by hepatitis C virus (HCV). Methods: We measured the contents of copper, iron, and zinc in HCC tissue (n = 112), dysplastic nodules (n = 7), and liver parenchyma in patients with (n = 112) and without (n = 12; 7 with grade F3 fibrosis, 5 with grade F4 fibrosis) HCC. Metals were quantified in thin-needle biopsy specimens using the particle-induced X-ray emission method (PIXE). Results: Copper level in liver parenchyma was higher in patients with HCC than in those without HCC (p < 0.01), while there was no such difference in hepatic iron. In patients with grade F4 fibrosis, copper content in the liver parenchyma was higher in the presence of HCC than in its absence (p < 0.05). Multiple regression analysis showed that the only factor significantly associated with the coexistence of HCC in HCV-positive patients with chronic liver disease was the copper level in the liver parenchyma. Conclusions: Hepatic copper overload may contribute to the development of HCC in HCV-positive patients with chronic hepatitis or cirrhosis.

The aim of this study was to determine the metabolizing activities in the liver of patients with hepatocellular carcinoma (HCC). Thin-layer chromatography autoradioluminography was used to measure metabolizing activities. Succinate-producing activity (SPA) was used as an indicator of metabolizing activity of the tricarboxylic acid (TCA) cycle in mitochondria, and diazepam-N-demethylating activity (DZ-DA), diazepam-3-hydroxylating activity (DZ-HA) and tolbutamide-methyl-hydroxylating activity (TB-HA) as indicators of drug metabolizing activities by P-450. SPA and drug-metabolizing activity of HepG2 cells were examined to compare with those of human liver specimens. Liver biopsy specimens of 30 patients and surgical specimens of eight patients with HCC were studied. SPA of HepG2 cells was as high as that of human tumor tissue, and DZ-DA, DZ-HA and TB-HA were undetectable in HepG2 cells. SPA and DZ-HA of non-tumor tissue in biopsy samples were significantly higher than those in resected liver specimens (P < 0.05). In biopsy specimens, SPA was significantly higher in tumor tissue than in non-tumor tissue (P < 0.05), and DZ-DA, DZ-HA and TB-HA were significantly lower in tumor tissue (P < 0.01). SPA was significantly higher in large tumors (≥30 mm) than in small tumors

Metallothionein (MT) has been described as a cell-protective protein that binds several heavy metals. In mammals, MT plays an important physiological role that includes detoxifying heavy metals, accumulating essential trace elements in cells to maintain homeostasis, and scavenging reactive oxygen species or free radicals. In contrast, the generation of hydroxyl radical (·OH) has been reported in the reaction of hydrogen peroxide and copper (Cu)-MT separated from the livers of Long–Evans Cinnamon (LEC) rats, an animal model of human hepatic injury with unusual accumulation of Cu-MT in the liver. On the other hand, Cu has been reported to accumulate in human hepatocellular carcinoma (HCC). Thus, we investigated whether the induction of MT, accumulation of Cu, and enhancement of oxidative stress are relevant to the development of human HCC, similarly to the observations in the liver of LEC rats. Although the kinetic behaviors of metal and MT levels were different in the livers of humans and LEC rats, Cu-MT induction in the tumor portion of human HCC tissues was suggested to occur similarly to that in the liver of LEC rats. In addition, it was found that oxidative stress in terms of the level of thiobarbituric acid-reactive substances was enhanced in the tumor portion of human HCC, corresponding well with increasing in the age of LEC rats, which developed jaundice and hepatitis. On the basis of these results, we conclude that the induction of Cu-MT in human HCC might be related to the hepatic oxidative stress, which in turn develops hepatic injury involving carcinoma. J. Trace Elem. Exp. Med. 15:31–45, 2002. ©2002 Wiley-Liss, Inc.

Serum metal levels and their ratios are frequently reported to be good signals for diagnosing various diseases. These parameters are not always specific to the disease, however, it is necessary to use other serum parameters for an exact diagnosis. We examined whether the monitoring of these serum parameters such as metallothionein, copper, and zinc levels are useful in diagnosing hepatic disorders. Metallothionein levels of patients with liver cirrhosis and hepatocellular carcinoma were found to be significantly lower than those of patients with chronic hepatitis and those of controls. In contrast, copper levels of the patients with liver cirrhosis and hepatocellular carcinoma were significantly higher than those with chronic hepatitis and controls. Zinc levels of the patients with chronic hepatitis and hepatocellular carcinoma were lower than those of controls. Using these three parameters, we are introducing a new parameter, (Cu/Zn)/MT, by which we can discriminate between patients in the [control+miscellaneous diseases+chronic hepatitis] group and those in the [liver cirrhosis+hepatocellular carcinomal group. The new parameter does not, however, allow us to clearly distinguish between the liver cirrhosis and hepatocellular carcinoma groups. Multivariate discriminant analysis was found to be very useful, with combinations of two discriminant functions having been designed to discriminate both between chronic hepatitis and liver cirrhosis and between liver cirrhosis and hepatocellular carcinoma. This method recognizes the differences between hepatic disorder, including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma groups. On the basis of these results, we propose here that the diagnosis of hepatic disorders should be made based on a combination of three serum levels such as those of metallothionein, copper, and zinc.

Ultrasound is a possible mechanical method to deliver small molecules into target cells. In order to evaluate the therapeutic potentials provided by ultrasound irradiation, we compared anti-tumor effects of electroporation- and ultrasound-mediated chemotherapy and efficacy of gene transfer by the two methods. Electric pulses (5 Hz, 100 V/cm, 8 square-wave/100 μsec) or ultrasound (1 MHz, 2 W/cm2, 5 min) was delivered to subcutaneous solid tumors of murine lymphoma after the tumor-bearing mice received an intraperitoneal injection of bleomycin (BLM) (2.5 mg) or intratumoral injection of plasmid DNA containing the luciferase reporter gene. Administration of BLM alone did not affect the subsequent tumor growth but additive treatment with ultrasound irradiation suppressed the growth to the same level as electroporation. The luciferase activity of the DNA-injected tumors showed that ultrasound irradiation achieved better transfection efficiency than plasmid DNA injection alone but the efficacy was not as great as that by electroporation. The low energy level of ultrasound that is currently used for a diagnostic purpose and physical therapy in clinical fields can thereby increase the in vivo chemosensitivity of treated tumors but further modifications are necessary to achieve better efficacy of the ultrasound-mediated gene transfer.

Acoustic properties of living tissues are an important parameter for quantitative estimation of the tissue structure. It is very important to determine the relationship between the physical and the chemical change of tissue structure and the change of acoustic properties. In this paper, using a new system with high density measuring points, we present the relationship diagram between the speed of sound and attenuation of human heart and liver tissues at 25 MHz. To compare normal and diseased tissues, we investigate the relationship between the sound speed and the attenuation of tissue. A characteristic relationship of the tissue is found in cirrhotic liver and aortic regurgitation tissue.

Background: Extracorporeal shock-wave lithotripsy (ESWL) is a treatment that preserves the gallbladder. Problems after ESWL treatment include stone recurrence and the development of biliary symptoms. Methods: Two hundred and sixty-two patients with cholesterol-type gallstones, the best indication for ESWL treatment, and 42 control patients with cholesterol-type gallstones who received no treatment entered this study. We evaluated the factors associated with recurrence of gallstones after stone clearance and the development of biliary symptoms after ESWL treatment. Results: The 3-, 5- and 7-year cumulative probabilities of gallstone recurrence were 20.6, 27.1 and 33.1%, respectively, with the recurrence probability significantly lower in patients with good gallbladder contractility. In patients with recurrence, ursodeoxycholic acid (UDCA) treatment was effective. In 69 patients with residual gallstones, the 3-, 5- and 7-year cumulative risks of biliary symptoms were 17.3, 24.9 and 30.5%, respectively. With residual gallstones, the risk of biliary symptoms developing was significantly lower in patients with a ≤ 3 mm fragment size at the end of ESWL treatment and in those treated consistently with UDCA for 6 months or more after treatment with ESWL. The risk of biliary symptoms was significantly lower in ESWL-treated patients with residual stones who had a ≤ 3 mm fragment size after treatment compared to those of control patients. Conclusions: Ursodeoxycholic acid was effective in clearing stones in patients with gallstone recurrence. In patients with residual stones, the fragmentation of stones to ≤ 3 mm and UDCA administration effectively reduced the risk of subsequent biliary symptoms.

Aims: This study evaluated the connection between the progression of hepatic fibrosis and trace metals, the distribution profiles of copper(Cu) and Zinc (Zn) and the generation of hydroxyl radicals from Cu- metallothionein (MT) purified from human hepatocellular carcinoma (HCC). Methods: We measured the metal contents in HCC tissue and liver parenchyma in patients with HCC. The content of metals in the liver was measured by particle induced X-ray emission (PIXE). Distribution profiles of Cu and Zn in human liver was evaluated by high-performance liquid chromatography (HPLC). The generation of hydroxyl radicals was measured by electron spin resonance (ESR) spin-trapping technique. Results: Hepatic copper content increased with the progression of hepatic fibrosis. Copper level in liver parenchyma was higher in patients with HCC than in those without HCC (p < 0.01). MT was mainly present as Zn-MT in normal liver, Cu,Zn-MT in surrounding liver parenchyma and Cu-MT in HCC (p < 0.01). The signal intensity of the ESR spectrum in HCC was stronger than those in normal liver and surrounding liver parenchyma. Conclusions: Copper accumulation in the liver parenchyma seems to relate to hepatocarcinogenesis.

By reviewing previous surgical specimens of hepatocellular carcinoma, 17 cases with hyperplastic foci (HPF) characterized by discernible increase in nuclear densities, could be histologically selected. Nuclear densities of HPF and control hepatic parenchyma were assessed quantitatively by counting the nuclear number of hepatic cells, and proliferating cell nuclear antigen labeling index was measured. HPF occurred multifocally, confined within a lobular unit, smoothly merging into surrounding hepatic parenchyma. Nuclear densities of HPF were 1.71 times greater than those of control hepatic parenchyma. The hepatocytes of HPF also showed significantly higher proliferative activities than those of control parenchyma. In addition, noticeable structural distortions, such as focal trabecular thickening or microacinar formation of hepatocytes, were sometimes observed in HPF. However, these HPF seemed to be distinguished from minute de novo hepatocellular carcinoma (HCC) or intrahepatic HCC metastasis, because of paucity of distinctive atypical changes, and intimate correlation with neighboring hepatocytes. Several adjacent HPF were aggregated to form a much larger unit of a hyperplastic area with loss of fibrous septa of liver cirrhosis. It was suggested that grossly detectable large regenerative nodules are produced via fusion of several adjacent HPF.

Accumulation of copper (Cu) in hepatocellular carcinoma (HCC), especially in small tumors, is greater than that in the surrounding liver parenchyma. Metallothionein (MT) is considered to be present as Cu-MT, Zn,Cu-MT or Zn-MT. The aim of this study was to determine the presence and localization of Cu-MT and Zn-MT in HCC and surrounding liver parenchyma.In 16 HCC patients, surgically resected specimens including HCC and surrounding liver parenchyma were evaluated.The level of Cu present in small HCC (4 cm in diameter) was significantly greater than that in the surrounding liver parenchyma (p0.05). However, the level of Cu in large HCC (4 cm in diameter) was similar to that in the surrounding liver parenchyma. Analysis by Sephadex G-75 gel filtration revealed that the peak fraction due to Cu was identical to that due to MT in 14 (87.5%) of 16 HCC, the peak fraction due to Cu and Zn was identical to that due to MT in 2 (12.5%) HCC, and the peak fraction due to Zn was identical to that of MT in none of 16 HCC.Accumulation of Cu in small HCC, in which Cu was present as Cu-MT or Zn, Cu-MT, was greater than that in the surrounding liver parenchyma. Cu accumulation and the presence of MT in the liver may be related to carcinogenesis of HCC, because of the similarity of these findings in the experimental data of Long-Evans rats with a cinnamon-like coat color who develop HCC spontaneously.

Background and Aims: Relationships between chronic liver disease and trace metals have not been clearly understood. To examine connections between severity of hepatic fibrosis in chronic hepatitis C and copper, iron and zinc we measured the contents of these metals in liver tissue and serum in the patients. Methods: Forty-one patients (26–62 years), 13 with fibrosis representing grade F1, 16 with F2, seven with F3, and five with F4, entered this study. Metals were quantified in needle liver-biopsy specimens by particle-induced X-ray emission. In serum, metals were measured by flameless atomic absorption spectrometry. Results: Hepatic copper content increased with progression of hepatic fibrosis (P < 0.05). The copper content correlated positively with bilirubin (r = 0.466, P = 0.0023), and with type IV collagen (r = 0.402, P = 0.0086) and correlated negatively with albumin (r = – 0.404, P = 0.080). However, hepatic iron and zinc contents did not show a significant differences between grades of fibrosis. Conclusions: Copper accumulation in fibrotic livers caused by chronic hepatitis C may contribute to hepatic injury. The real mechanism is not known at present, but excess copper may damage the liver by oxidative stress.

Features of enhanced color flow images in small hepatocellular carcinoma (HCC) are not fully elucidated. The purpose of this study was to clarify the characteristic vascular images in small HCC observed by enhanced color Doppler.Enhanced color Doppler using the contrast agent Levovist was performed on 13 patients with HCC smaller than 30 mm. Enhanced color flow appearance was compared with angiographic findings. Time-intensity changes after injection of the contrast agent were analyzed in HCC nodules.Significant improvement in the detection of color flow signals was obtained in small HCC using Levovist, from 33% in precontrast to 92% in postcontrast (p0.005). Three patterns of enhanced color flow images, which were related to the angiographic findings, were observed. The time-intensity curve was classified into two types by "time to peak" and "time on plateau" and was associated with the patterns of enhanced images.Enhanced color flow imaging promises to be a useful method for evaluating tumor vascularity noninvasively and to contribute to the elucidation of the hemodynamics in small HCC.

The detectability of early liver injury induced by irradiation was studied using magnetic resonance (MR) imaging enhanced with superparamagnetic iron oxide (SPIO), a tissue-specific contrast agent against the reticuloendothelial system (RES). In rat, 3 days after focal irradiation (0–10 Gy), MR imaging was performed and specimens were obtained to observe the phagocytic function of RES. The irradiated portion of the liver was visualized with a clear demarcation from the nonirradiated part by SPIO-enhanced MR images as a decrease in negative enhancement reflecting the function of RES (P

62歳の男性, 動悸, 息切れを主訴として来院. 1990年12月に肝細胞癌の初回治療 (経皮的エタノール注入療法) を受け, 1996年3月～5月に右肩甲骨転移及び左腸骨転移に対して放射線療法を施行されている. 入院時の肝障害度はChild Bに相当し, α-フェトプロテイン (AFP) の著明高値がみられた. 心エコーで右室腔内に6×4cmの腫瘤がみられ, 肝細胞癌の右室転移による両心不全と診断し, 対症療法を行ったが入院後23日目に死亡した. 剖検では, 肝内に肝細胞癌の再発はみられず, 心臓は, 右室内腔にEdmondsonII～III型の肝細胞癌が充満し, 心内膜及び心筋への浸潤もみられた. 肝静脈, 下大静脈, 右房からの連続進展はみられなかった. 肝内に再発がみられず, 右室へ孤立性の転移を生じた肝細胞癌例は極めて稀であり, 文献的考察を加えて報告する.

Cellular adhesion regulatory molecule (CMAR) enhances the adhesiveness of cells to collagen and laminin and is considered to be a candidate anti-oncogene. The purpose of the present study was to investigate the relationship between the expression of CMAR and clinical features of hepatocellular carcinoma (HCC). Small amounts of liver tissue were obtained from HCC and non-cancerous portions of the liver in 29 patients and from normal liver in seven patients with metastatic liver tumour by biopsy under ultrasound guidance. RNA was extracted with acid guanidinium thiocyanate-phenol-chloroform. Expression of CMAR was assessed by quantitative PCR using beta-actin as an internal standard. A 4 b.p. insertion polymorphism at nucleotide 241 of the CMAR coding region was then investigated using extracted RNA to assess the relationship between the expression of variant mRNA of CMAR and HCC carcinogenesis. The relative expression of CMAR was significantly reduced in HCC compared with non-cancerous and normal livers and had a relationship with certain clinical background factors. The reduced expression of CMAR was thought to be closely associated with the progression of HCC. However, the 4 b.p. insertion polymorphism pattern of CMAR was the same between HCC and non-cancerous liver in all cases in which it was found. These results suggest that progression of HCC may be predicted based on the relative expression of CMAR.

To objectively evaluate the parenchymal echo pattern of cirrhotic liver and chronic hepatitis, the authors applied an image analyzing system (IAS) using a neural network. Autopsy specimens in a water tank (n=13) were used to examine the relationship between the diameter of the regenerative nodule and the coarse score (CS) calculated by IAS. CS was significantly correlated with the diameter of the regenerative nodule (p

The clinical findings in 26 patients in whom hepatocellular carcinoma (HCC) was detected after the start of interferon (IFN) therapy for chronic hepatitis C were analysed. Histological study before IFN therapy showed that 34.6% of patients were categorized as stage 3 (septal fibrosis with architectural distortion; the 0-4 scale) and 80.8% demonstrated at least some evidence of septal fibrosis or more advanced features. The AFP levels examined before IFN therapy were more than 20 ng/mL in 13 patients (84.6% of those studied). One of 26 patients had a complete response to IFN therapy, while six of 26 patients had only a partial response. HCC was detected within 1 year after the start of IFN therapy in 76.9% of patients. Thus, the possibility of the early occurrence of HCC or its existence at the time of therapy should be seriously considered when IFN therapy is contemplated. Patients with stage 3 or 3-4 histology may already have a small undetectable HCC before IFN therapy. Thus, for this reason, every patient treated with IFN should be examined at short regular intervals for the development of HCC during and after IFN therapy.

千葉県富浦町にて年齢40歳以上の住民1,627名についてHCV感染の疫学調査を行い,同時にHCV抗体陽性であった184名に超音波検査による肝細胞癌の検診を実施した.HCV抗体陽性率は男性にて女性よりも,年齢50歳以上にて50歳以下よりも,職業別では漁業に従事する男性にて農業に従事する男性よりも高かった.HCV抗体陽性率は男性と女性ともに輸血,手術,覚醒剤注射,薬物自己注射,針治療などの既往歴を持つ例にて原因となる動機を待たない例よりも高かった.HCV抗体陽性者の超音波検査により肝細胞癌9例を検出した.9例のうち8例に輸血や手術などHCV感染の原因となる動機を認めた.9例のうち8例は腫瘍径が≦20mmであり,エタノール注入療法などの腫瘍の局所治療が有効であった.HCV抗体測定と超音波検査を組み合わせたスクリーニングが肝細胞癌の早期診断に役立つ結果であった.

門脈腫瘍塞栓を有する肝細胞癌34例において,カラードプラによる腫瘍塞栓の診断,病態の把握ならびに治療効果の判定を試みた.カラードプラにより,門脈両側に沿って流れる求肝性拍動性血流が15例(44%),腫瘍塞栓内遠肝性拍動性血流が15例(44%),門脈の拍動性逆流が5例(15%),求肝性門脈側副血行路が6例(18%)に見られた.門脈両側の求肝性拍動性血流あるいは腫瘍塞栓内遠肝性拍動性血流の所見は腫瘍塞栓に特徴的な所見であり,全体の74%に見られた.肝細胞癌に対する治療後にこれらの所見が残存した例には,腫瘍塞栓の進展を見た例が多く,予後は不良であった.門脈の拍動性逆流が見られた例では,肝機能障害と食道静脈瘤は高度であり,予後は不良であった.求肝性門脈側副血行路の発達がみられた例では,腫瘍占拠率は低く,肝機能障害は軽度であった.カラードプラは,門脈腫瘍塞栓の診断,臨床病態の把握ならびに治療効果の判定に有用であった.

肝動脈塞栓療法(TAE)後の虚血性肝障害に対する高圧酸素療法(HBO)の有用性について検討した.基礎実験で,HBOは門脈阻血により低下したラット部分阻血肝モデルの動脈血中ケトン体比(AKBR)を有意に改善した.肝硬変合併肝細胞癌症例44例を対象としたrandomised studyにおいて,TAE直後に低下したAKBRが,TAE直後よりHBOを施行した群(TAE-HBO群)で3時間後より有意に改善した.プロトロンビン時間はTAE-HBO群で有意に短縮した.血清アルブミン値,血清総ビリルビン値,治療後1年以内の主腫瘍の最大腫瘍縮小率において,TAE-HBO群とTAE単独治療群の間に有意差は認められなかった.以上のごとく,HBOはTAEの抗腫瘍効果に悪影響を与えず,TAE後の肝障害に対して,肝内エネルギー状態を反映するAKBRおよびPTを早期より有意に改善する治療法であることが明らかとなった.

A 28-year-old man complained of tarry stool. A series of examinations showed a submucosal tumor with bleeding at the papilla of Vater and a swollen # 17b lymph node, both of which indicated a hypervascular tumor. The pathological findings of the enucleated tumor specimens revealed gangliocytic paraganglioma with metastasis to the # 17b lymph node. Additional pancreaticoduodenectomy revealed another # 17b lymph node metastasis 7-mm in diameter. Although the majority of gangliocytic paragangliomas are benign, 7% of reported cases have lymph node metastases, as shown in the present case. These findings are important in treating patients with gangliocytic paraganglioma.

Among 597 patients with nodular hepatic lesions who underwent ultrasonically guided needle biopsy, 305 were histologically confirmed as having hepatocellular carcinoma, and 37 patients had borderline lesions. Histological reexamination was correlated with morphometrical analysis on selected cases of well-differentiated, microtrabecular hepatocellular carcinomas (n = 29), borderline lesion (n = 10), typical (mid-sized and macrotrabecular) hepatocellular carcinomas (n = 15) and cirrhotic liver tissue obtained from extranodular hepatic parenchyma of hepatocellular carcinoma patients (n = 47). Morphometrical analyses revealed that the mean cell size and nucleocytoplasmic ratio were most useful for distinguishing well-differentiated, microtrabecular hepatocellular carcinoma from cirrhosis. These two parameters were well correlated with nuclear density. The grade of nuclear density, therefore, seemed to be a convenient semiquantitative indicator for diagnosing well-differentiated hepatocellular carcinoma. A comparison between intranodular and extranodular hepatic tissues was particularly important for its assessment. It is concluded from the results that hepatic nodules presenting a nuclear density larger than two times that of controls could be classified into the overt hepatocellular carcinoma group. From the statistical aspect, the possibility of microtrabecular hepatocellular carcinoma should be considered when a nodule has a nuclear density exceeding 1.3 times that of the extranodular tissue.

The aim of this study was to investigate whether exogenous dehydrocholic acid (DHCA) was useful to enhance the delineation of hepatolithiasis.Our study population comprised 9 patients. Magnetic resonance cholangiopancreatography (MRCP) was acquired before and after the administration of DHCA. Two different MRCP snap-shot techniques were applied: thick-slab two-dimensional (2D) (coronal) single shot turbo spin echo T2-weighted sequences and multisection thin-slab, 2D (coronal) single shot turbo spin echo T2-weighted sequences with three-dimensional (3D) maximum intensity projection (MIP) post processing.DHCA provided a better visualization of hepatolithiasis in 8 of 9 cases (88.9%).It was suggested that administration of DHCA could enhance the delineation of the hepatolithiasis on MRCP images.

To elucidate the diagnostic confidence of contrast-enhanced ultrasound (CEUS) with Levovist for hepatic hemangioma.The subjects were 34 patients with 38 hemangiomas and 12 patients with 15 hypervascular hepatocellular carcinomas. The early-phase (15-60 second) and liver-specific phase (after 5 min) were observed by the first injection. The 2nd injection was done for solo-phase method to observe liver-specific phase images without taking early-phase sonograms. The 3rd injection was done for changing posture method to observe liver-specific sonograms under left lateral ducubitus position.In the early-phase of hemangioma, nodular enhancement (NE) was found transiently in 13 lesions (34%) and continuously in 25 lesions (66%), while hepatocellular carcinoma (HCC, n = 15) did not show this pattern. Intratumoral arterioportal shunt was closely related to the short duration of NE. Two enhancement patterns were observed in the liver-specific phase of hemangioma, diffuse in 12 lesions (31%) and partial in 26 lesions (69%), which were dependent on the early-phase enhancement. Liver-specific findings were also affected by taking early-phase sonograms or changing the posture of the patient. This method provided sensitivity of 79% and specificity of 100% for the diagnosis of hemangioma.CEUS with Levovist may be promising method for the diagnosis of hepatic hemangioma.

The aim of this study was to investigate whether exogenous dehydrocholic acid (DHCA) was useful to enhance the delineation of anastomotic site.DHCA is a cholagogue which produces an immediate effect by acting directly on liver cells. Its choleretic effect is strong, appearing 1 to 3 minutes after intravenous injection, reaching the maximum level in 20 to 30 minutes. Our study population comprised 9 patients. Magnetic resonance cholangiopancreatography (MRCP) was acquired before and after the administration of DHCA. Two different MRCP snap-shot techniques were applied: thick-slab two-dimensional (2D) (coronal) single-shot turbo spin echo T2-weighted sequences and multisection thin-slab, 2D (coronal) single shot turbo spin echo T2-weighted sequences with three-dimensional (3D) maximum intensity projection (MIP) post processing.DHCA provided a better visualization of the anastomotic site in 7 patients (77.8%). The two patients without improvement in visualization of anastomotic site included 1 patient with liver cirrhosis secondary to portoenterostomy for congenital biliary dilatation and 1 patient, who was not eligible for the evaluation because of motion artifact caused by the difficulty of breath holding motion artifact.It was suggested that administration of DHCA could enhance the delineation of the anastomotic site on MRCP images.

Percutaneous ethanol injection (PEI) was applied to 120 lesions in 95 patients with hepatocellular carcinomas (HCC) smaller than 3 cm in the past 6 years. All main target tumours, in 67 patients who had been followed by sonography for more than 6 months after PEI, decreased in size; 28 tumours (41.8%) became undetectable and have remained so until now. The 1-, 2-, 3-, 4- and 5-year survival rates calculated by the Kaplan-Meier method were 93%, 81%, 65%, 52% and 28% respectively. These survival rates were better than those of patients with HCC smaller than 3 cm who did not receive anticancer treatment (P less than 0.01). The survival of patients of the Child's A or Child's B status was better than that of those with Child's C disease. Recurrence occurred in areas within the liver different from the original lesion in 34% in one year, 61% in two years and 66% in three years after PEI. PEI was then repeated in 61% of such patients.