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Background and Aim: Antemortem diagnosis of hepatocellular carcinoma (HCC) with cardiac metastasis is uncommon. To clarify the clinical manifestation and survival of HCC patients with cardiac metastases, we initiated the present study. Methods: We retrospectively analyzed 48 HCC patients with metastases into cardiac cavity diagnosed antemortem. The baseline clinical characteristics, echocardiogram, treatment modality and the outcome data were collected. Results: The most common symptoms of cardiac metastasis included asymptomatic in 19 cases (39.5%), bilateral lower leg edema in 18 cases (37.5%) and exertional dyspnea in 15 cases (31.3%). The median and mean survival times from the time of diagnosis of cardiac metastasis were 102 days and 161 days, respectively. Compared with another cohort of 48 patients with age-, gender-, and stage-matched HCC patients without cardiac metastasis, the median survival in the cardiac metastasis group was similar to the control group (68 days) ( P = 0.67). The cause of death was HCC in 29, hepatic failure in seven, multiple organ failure in four, gastrointestinal bleeding in three, sepsis in two, pulmonary embolism in one, respiratory failure in one, and acute myocardial infarction in one. Conclusions: Hepatocellular carcinoma patients with cardiac metastases were in the advanced stages. These patients had limited survival from the diagnosis of cardiac metastases. The most common cause of death was related to HCC per se or the underlying liver disease. Only a few patients expired because of cardiac metastases. [ABSTRACT FROM AUTHOR]

Liver progenitors, so-called oval cells, proliferate remarkably from periportal areas after severe liver injury when hepatocyte regeneration is compromised. These cells invade far into the liver parenchyma. Molecular mechanisms underlying these behaviors of oval cells remain poorly understood. In this study, we treated rats with 2-acetylaminofluorene/carbon tetrachloride to induce hepatic oval cells. By expression microarray analysis, we investigated global gene expression profiles in liver tissue, with an emphasis on adhesion molecules, extracellular matrix proteins, matrix metalloproteinases (MMPs), growth factors/cytokines, and receptors that might contribute to the distinct behaviors of oval cells. Genes upregulated at least twofold were selected. We then performed immunostaining to verify the microarray results and identified expression of MMP-7 and CD44 in oval cells. Staining of cytokeratin (CK)-19, an oval-cell marker, was similar between oval cells located next to periportal areas and those located far within the parenchyma. In contrast, CD44 staining was more intense in the parenchyma than in periportal areas, suggesting a role of CD44 in oval-cell invasion. Moreover, newly differentiated CK-19+ hepatocytes within foci did not show CD44 staining, suggesting that CD44 is related to the undifferentiated oval-cell phenotype. We then investigated oval-cell reactivity in CD44-deficient mice fed an oval cell-inducing diet of 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Results showed significantly reduced oval-cell reactivity in CD44-deficient mice. Thus, oval cells express MMP-7 and CD44, and CD44 appears to play critical roles in the proliferation, invasion, and differentiation of hepatic oval cells in rodents. [ABSTRACT FROM AUTHOR]

We tried to image obstructive cholestasis by using a newly developed imaging system to measure the alterations of hepatobiliary function in living mice with their bile ducts ligated. A hepatic imaging window was installed on the upper abdomen soon after the mice underwent ligation of the common bile duct. On the next day, the mice received intravenous injection of rhodamine B isothiocyanate-dextran and carboxyfluorescein diacetate. The later would be transformed into fluorogenic carboxyfluorescein (detected at ∼500-550 nm) by hepatocytes and then excreted into bile canaliculi. The images were acquired by multiphoton microscopy. The fluorescence intensities at ∼500-550 nm within hepatocytes or sinusoids were measured in time series. In mice with bile duct ligation, bile canaliculi failed to appear during the whole observation period over 100 mm following carboxyfluorescein diacetate injection, whereas the fluorescence was retained much longer within sinusoids. Furthermore, the fluorescence intensities in sinusoids were persistently higher than in hepatocytes during the course. Bile duct ligation impedes hepatocytes to excrete carboxyfluorescein into bile canaliculi. The kinetics of fluorescence intensities in hepatocytes and sinusoids indicated there is an active machinery operating backflow of this fluorogenic bile solute from hepatocytes into sinusoids in the liver with obstructive cholestasis. [ABSTRACT FROM AUTHOR]

Background and Aim: Peritoneal metastasis is an uncommon manifestation of hepatocellular carcinoma (HCC). The aim of the present paper was to investigate the characteristics and survival of HCC patients with peritoneal metastases. Methods: From January 1985 to December 2004, we retrospectively reviewed the records of 53 Taiwanese HCC patients with peritoneal metastases. Results: Peritoneal metastases were detected at the time of HCC diagnosis (synchronously) in 10 patients and after the initial therapy for the primary tumors (metachronously) in 43 patients. The mean time for development of the metachronous peritoneal metastases was similar whether the primary cancer was treated with surgery (24 months) or transarterial chemoembolization (22.2 months). The single patient whose primary cancer was treated with supportive care alone developed peritoneal metastasis only 7.5 months after detection of the primary cancer. Surgical resection of the peritoneal metastases was possible in two-thirds of the 43 metachronous patients. The median survival for those who received surgery for these metastases was 12.5 months vs. 2.1 months for those without surgery ( P = 0.0013). However, there was no difference in survival if patients were stratified to Child-Pugh grade. Conclusions: Peritoneal metastases of HCC are rare and can occur synchronously or metachronously. Though increased long-term survival was found in patients who had surgical removal of peritoneal metastases, the main determinant of better survival is Child-Pugh grade. [ABSTRACT FROM AUTHOR]

Partial hepatectomy or carbon tetrachloride (CCl4) injury, following treatment of rats with 2-acetylaminofluorene (2-AAF) to inhibit proliferation of hepatocytes, induces proliferation of oval cells and possibly their differentiation into nodular foci of hepatocytes when higher doses of 2-AAF are used. Unfortunately, immunohistochemistry in previous studies failed to show oval cell markers in these foci, and thereby to demonstrate the precursor–product relationship between oval cells and hepatocytes. Immunohistochemistry on livers of rats treated with high dose 2-AAF/CCl4 was used. We found 7.6% of the hepatocyte foci were positive for an oval cell marker cytokeratin 19 (CK-19). These foci were positive for alpha-fetoprotein, less positive for carbamoylphosphate synthetase 1, and more positive for laminin in the basement membrane lining. Rarely present transitional foci had weaker expression of CK-19 and discontinuous laminin. Focal hepatocyte differentiation of oval cells was characterized by cell hypertrophy, membranous CK-19, and positive hepatocyte nuclear factor 4 (HNF-4). HNF-4+ small oval cells surrounding CK-19+ foci were frequently seen, suggesting that a paracrine mechanism(s) may be responsible for the enlargement of CK-19+ foci. In conclusions, oval cells appear to differentiate to CK-19+ foci and then to CK-19− foci in the high dose 2-AAF/CCl4 model. [ABSTRACT FROM AUTHOR]

OBJECTIVE:: To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study.METHODS:: A total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter ≤3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency.RESULTS:: Follow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.CONCLUSIONS:: Percutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

An accurate staging system is required to assess hepatocellular carcinoma (HCC) patients in order to benefit from hepatic resection before surgery. Cancer of the Liver Italian Program (CLIP) score was considered to be better than the Okuda staging system to predict survival. Japan Integrated Staging Score (JIS score) includes tumor, nodes, metastases (TNM) stage and Child–Pugh grade as a new staging system for HCC. The purpose of the present paper was to compare the CLIP, Okuda, TNM and JIS staging systems for HCC patients undergoing surgery.From 1991 to 1995, 599 patients undergoing hepatic resection for HCC from four medical centers in Taiwan were evaluated. All patients were classified by Okuda, CLIP, TNM and JIS systems. Factors associated survivals were analyzed.There was no statistical difference in survival between CLIP 0 and 1 patients, or among CLIP 2–4 patients. The prognostic validation of the Okuda and CLIP scoring systems in discriminating survival in HCC patients undergoing surgery was not satisfied. The TNM system was successful in predicting survival for HCC patients undergoing surgery. The JIS score could also differentiate survivals for those patients except for JIS 3. By multivariate analysis, age≥60 years old, serum albumin<3.5 g/dL, tumor size>5 cm and TNM stage were associated with survival.Both the Okuda and CLIP systems are not superior to TNM staging for HCC patients who undergo surgical resection. Whether JIS score is feasible for those patients with advanced HCC needs further evaluation. [ABSTRACT FROM AUTHOR]

Loss of heterozygosity (LOH) on chromosomes 16q and 13q, associated with tumor development, is frequently found in hepatocellular carcinoma (HCC). In light of this, an attempt was made to use the LOH pattern determined by microsatellite markers on 16q and 13q to discriminate clonality.In an effort to locate the LOH region more precisely and select the appropriate markers, LOH studies on 88 HCC using a panel of 35 microsatellite markers on 16q were carried out. Nine independent regions of frequent LOH were defined. In combination with a previous study of deletion mapping of 13q by the same authors, 12 markers on 16q and 13q were selected and polymerase chain reaction amplification, from microdissection-extracted DNA, was used to allelotype microsatellite polymorphism as an indication of clonality.Two patterns of LOH were observed. In pattern A, in 8 of 16 (50%) patients, the LOH pattern of the first tumor was preserved in the second sample, with some tumors also showing additional LOH. In these patients, the original and second tumors are presumed to arise from the same original clone with or without progressive accumulation of LOH. In pattern B (8 of 16, 50%), LOH seen in the first tumor was not preserved in the second or recurrent tumors, as evidenced by retention of heterozygosity compared with the first tumor.The data suggest that the second tumor might have arisen from another independent clone. Moreover, this approach also provides a more sensitive and specific strategy to determine whether multiple or recurrent tumors are derived from the same or a different clone. [ABSTRACT FROM AUTHOR]

Huang Y-H, Chen C-H, Chang T-T, Chen S-C, Wang S-Y, Lee P-C, Lee H-S, Lin P-W, Huang G-T, Sheu J-C, Tsai H-M, Chau G-Y, Chiang J-H, Lui W-Y, Lee S-D, Wu J-C. The role of transcatheter arterial embolization in patients with resectable hepatocellular carcinoma: a nation-wide, multi-center study.Liver International 2004: DOI: 10.1111/j.1478-3231.2004.0941.x.© Blackwell Munksgaard 2004The role of transcatheter arterial embolization (TAE) for patients with resectable hepatocellular carcinoma (HCC) is controversial. Analyzing a cohort of nation-wide data can delineate the beneficial effect of TAE for those patients.From 1991 to 1995, 818 patients who had potentially resectable HCC from four medical centers in Taiwan were enrolled. Among them, 599 underwent curative resection, 157 received TAE and 62 received supportive treatment alone. The survivals among the three groups were compared.The 5-year survival rates for patients who underwent surgery, TAE and supportive treatment were 43.6%, 25.6% and 3.7%, respectively. Surgery offered the best survival for those patients. TAE could also prolong survival as compared with supportive treatment (P=0.0001). However, among patients who were in advanced tumor stage (Cancer and the Liver Italian Program (CLIP) score≥2), no statistical difference in survival was noted between patients who underwent TAE or supportive treatment. In multivariate analysis, single tumor, serum albumin≥3.5 g/dl, tumor size less than 5 cm, early-stage tumor (CLIP score=0–1) and aggressive treatment including surgery and TAE were independent factors associated with a better survival.Surgery is superior to TAE for patients with resectable HCC. In patients who refuse surgery, TAE can be considered for selected patients whose tumors are in early stage. [ABSTRACT FROM AUTHOR]

To study the immunopathogenesis of chronic type B hepatitis, we used a panel of monoclonal antibodies to characterize the intrahepatic mononuclear cell infiltrates in 39 patients with various forms of chronic hepatitis induced by hepatitis B virus (HBV) and, for comparison, in 10 with non-A, non-B (NANB)-induced chronic hepatitis. In portal areas, the OKT4:OKT8 ratio reversed because of the relative increase of OKT8+ cells. The mean intraportal T4:T8 ratio was significantly lower in H BV-associated chronic active hepatitis (CAH) than in chronic persistent hepatitis induced by HBV or NANB viruses. OKT8+ cells were predominant in the infiltrates of periportal areas (piecemeal necrosis) and lobules. As to the activation status of the infiltrates, T10 was found much more frequently on mononuclear infiltrates of piecemeal necrosis and peripheral portion of portal areas in CAH cases, regardless of viral etiology, and its existence was correlated with the severity of CAH. Natural killer cells, killer cells, and B-cells played little role in the pathogenesis of hepatocytolysis. We conclude that T-cell cytotoxicity is the main mechanism of hepatocytolysis, either in lobules or in periportal regions, and that T10 antigen defines a group of cells which may play an important role associated with the formation of piecemeal necrosis. [ABSTRACT FROM AUTHOR]

Objectives: To present the clinical and microbiological features of liver abscess after transarterial embolization (TAE) for hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed records of 452 TAE procedures in 289 patients with HCC over a 2-yr period. Results: Four men and one woman with a mean age of 68.4 yr were diagnosed with liver abscess 1-8 wk (mean 4.6 wk) after the embolization. The incidence was 1.1% (5/452). Common symptoms included fever, chills, and right upper quadrant pain. Serum aminotransferase, alkaline phosphatase, and γ-glutamyltransferase levels and leukocyte count were frequently elevated. All the abscesses appeared as areas of hypodensity on CT scan and hypoechogenicity on ultrasonogram. The areas contained gas in the embolized tumor, which led to the suspicion and finally the diagnosis of abscess. In contrast to predominance of Gram-negative aerobes in sporadic pyogenic liver abscesses, the causative microorganism was predominantly Gram positive (60%). All patients were treated with parenteral antibiotics plus percutaneous aspiration, drainage, or operation, but one patient died from the abscess. Conclusions: For patients receiving TAE for HCC, few specific clinical or radiological features could readily differentiate patients complicated with liver abscess from those without. This may delay a timely diagnosis and lead to significant morbidity. Hence, in patients with risk factors, including old age, previous biliary tract disease, large tumor size (>5 cm), and gas forming in the embolized tumor, aspiration of the suspected focal hepatic lesion should be performed as soon as possible. [ABSTRACT FROM AUTHOR]

Conventionally, liver fibrosis is diagnosed using histopathological techniques. The traditional method is time-consuming in that the specimen preparation procedure requires sample fixation, slicing, and labeling. Our goal is to apply multiphoton microscopy to efficiently image and quantitatively analyze liver fibrosis specimens bypassing steps required in histological preparation. In this work, the combined imaging modality of multiphoton autofluorescence (MAF) and second-harmonic generation (SHG) was used for the qualitative imaging of liver fibrosis of different METAVIR grades under label-free, ex vivoconditions. We found that while MAF is effective in identifying cellular architecture in the liver specimens, it is the spectrally distinct SHG signal that allows the characterization of the extent of fibrosis. We found that qualitative SHG imaging can be used for the effective identification of the associated features of liver fibrosis specimens graded METAVIR 0 to 4. In addition, we attempted to associate quantitative SHG signal to the different METAVIR grades and found that an objective determination of the extent of disease progression can be made. Our approach demonstrates the potential of using multiphoton imaging in rapid classification of ex vivoliver fibrosis in the clinical setting and investigation of liver fibrosis–associated physiopathology in animal models in vivo. [ABSTRACT FROM AUTHOR]

Intravital imaging of hepatobiliary excretion is vital for elucidating liver metabolism. In this work, we describe a novel method to observe the intravital dynamics of the uptake, processing, and excretion of an organic anion, 6-carboxyfluorescein diacetate (6-CFDA) in the hepatobiliary system. This is achieved by the use of multiphoton microscopy and an intravital hepatic imaging chamber. The high-quality images show sequential uptake and processing of 6-CFDA from the hepatocytes and the subsequent excretion into bile canaliculi within approximately 50 min. This is a promising technique to study intravital hepatic physiology and metabolism. [ABSTRACT FROM AUTHOR]