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PubMed1992

[Evaluation of radioimmunotherapy in the multimodality treatment of hepatocellular carcinoma (HCC)].

The evaluation of radioimmunotherapy using 131I-anti HCC isoferritin IgG antibody in the multimodality treatment of HCC was reported. Forty three patients with surgically verified unresectable HCC have been treated by radioimmunotherapy as a part of multimodality treatment during 1985-1990. The short-term responses and prolong survival were compared with that in control group of 39 patients with HCC receiving conventional multimodality treatment. The rates of tumor shrinkage, AFP level decline and second resection in radioimmunotherapy group were 67.4% (29/43), 69.6% (16/23) and 30.2% (13/43) respectively, significantly higher than those in control group 23.1% (15/39), 40.0% (8/20) and 10.3% (4/39) respectively. The 1, 3, 5-year survival rates were 61.5%, 40.4% and 35.5% in radioimmunotherapy group, however, in control group were 51.3%, 20.1% and 15.5%, respectively. The results suggested that radioimmunotherapy is one of modalities of choice, particularly for the treatment of unresectable HCC in the multimodality treatment regimen.

Adult↗
PubMed2005

Correlation of HBV and HCV with CH, LC, HCC in liver biopsied tissue at Rajavithi Hospital.

Retrospective study in Clinicopathology of 66 surgical liver tissue from adult Thai patients admitted at Rajavithi Hospital, in Bangkok, during December 2002-September 2003 (10 month periods). The main purposes are: 1) To find the correlation of HBV, HCV with CH, LC, HCC. 2) To compare the correlation of Hepatocyte, AFP, CEA (IHC) in malignant cells, which one is the best usage to confirm the diagnosis of HCC in both primary and metastasis. 3) To review the clinicopathology of all these 66 liver samples. The results were significant correlation of HBsAg (serology) with HCC (p = 0.010), and also significant correlation of HBsAg (IHC in liver tissue) with CH, LC (p = 0.038, 0.021 respectively). Although no significant correlation (p > 0.05) of HCV (positive anti HCV) with CH, LC, HCC; the causes due to the small sample sizes and short period study are possibly bias factors. The authors concluded that Hepatocyte or Hep-Par I is the best immunocellular marker for malignant liver cells both in primary and metastasis (p < 0.001). The AFP, CEA show no correlation (p = 0.999, 0.670). The authors found other interesting non-viral related liver disease, common, uncommon, tumor and tumor-like (pseudotumor) lesions in the liver from the present study. The results of significant correlation of HBV (HBsAg) with CH, LC, HCC is one good evidence to further support The National HBV Vaccine Program for the uninfected population, which has been sponsored by the Thai Government, The Ministry of Public Health since 1992 and be one of the best and successful Thai Public-Health Policy.

Adolescent↗
PubMed1991

[The relation of lectin receptor's activity of hepatocellular carcinoma (HCC) with the recurrence after curative hepatectomy].

Recurrence is an important factor affecting the survival rate of patients with hepatocellular carcinoma (HCC) after curative hepatectomy. Twelve types of lectin receptors in 33 cases of HCC tissues were determined by avidin-biotin-peroxidase complex (ABC) method. The relationship between lectin receptors, HCC grading and recurrence time after curative hepatectomy was investigated. The results showed that tumor-free period of patients after the resection of HCC was not closely related to the size of resected tumors, their pathological gradings as well as most lectin receptors. However, tumors that recurred longer than two years after curative hepatectomy had Bandeiraea simplifolia agglutinin I (BSAI) receptors obviously fewer than those recurring within two years. It is suggested that BSAI receptors in tumor tissues might be a useful index in the prognosis of HCC patients after hepatectomy.

Adolescent↗
PubMed1990

[Lipiodol-CT for the detection of small hypovascular HCC].

To evaluate the diagnostic value of Lipiodol-CT for small hypovascular HCC, we injected 3 ml or less Lipiodol into the hepatic artery of patients with chronic liver disease and small SOL in the liver detected on echogram but not on angiogram. About seven days after injection CT was used to check for accumulation of Lipiodol in the liver SOL. We found that the sensitivity of this method for detection of hypovascular HCC is only 25%. We assume that Lipiodol does not accumulate in small hypovascular HCC lesions because they have little vascular stroma. Lipiodol-CT has high diagnostic value for the detection of small hypervascular daughter HCC lesions, but this method should not be relied on for the detection of small hypovascular HCC.

Adult↗
PubMed1994

[A comparative study of the expression of ras oncogenic protein P21 and oncofetal protein AFP, CEA in human hepatocellular carcinoma (HCC)].

The expression of P21, AFP and CEA were detected in human hepatocellular carcinoma and its surrounding nontumor tissues by immunohistochemical staining on serial sections. The significance of AFP and P21 in HCC auxiliary diagnosis was discussed. The results are as follows: (1) AFP and P21 were more closely related with HCC than CEA. Both AFP and P21 were expressed simultaneously in more than half the cases. The distribution of these two antigens in HCC was similar. (2) The positive incidence of AFP in tumor tissues was higher than that in surrounding nontumor tissues, but vice versa for P21. Based on the results of this study, we regard that AFP is a relatively specific marker of HCC, better than P21 in auxiliary diagnosis of HCC. The hepatocytes which surround the tumor and can simultaneously express AFP and P21, are likely to be precancerous cells which have been initiated and possess the ability of neoplastic growth but lack phenotype transformation.

Adult↗
PubMed1994

[Etiologic study on the relationship between HBV, HCV and HCC].

A total of 110 HCC patients were sampled randomly in 20 townships of Qidong county (a higher incidence area of HCC in China) from Mar. to Sept. 1989. Each patient was paired with two healthy persons as control. The results showed that the prevalences of HBV and HCV in 110 patients were 85.45% and 17.27% respectively, and were significantly higher that in control (50.45% and 4.09%). Using Conditional Logistic Regression Model. we found that the main risk factors of HCC in Qidong were HBsAg and Pre-S2 for HBV and anti-HCV for HCV. The OR value were 10.22, 2.96 and 2.63, respectively. Drinking tea was the only protective factor (OR = 0.36). Among 110 HCC patients. 13.64% were positive for both HBV and HCV. The OR value was the highest (6.48). 88.18% patients were either HBV or HCV positive. The OR values were similar (3.90 and 3.89). It suggests that the most important risk factor of HCC in Qidong was HBV infection because it had a higher prevalence among the population while the HCV infection having an equal OR value was also a risk factor.

Carcinoma, Hepatocellular↗
PubMed1998

Characterization of a novel CC chemokine, HCC-4, whose expression is increased by interleukin-10.

We have identified and characterized a human beta (CC) chemokine, designated HCC-4, that is most closely related to HCC-1 and which demonstrates chemotactic activity for monocytes. Northern analysis of multiple tissue blots and of activated monocytes mRNA shows expression of a 500-bp mRNA. A 1,500-bp mRNA was highly expressed in monocytes activated 12 hours in the presence of interleukin-10 (IL-10) but was absent in monocytes activated for only 1 hour regardless of the presence or absence of IL-10. The upregulation of expression in the presence of IL-10 is in contrast to the downregulatory effects of IL-10 on expression of most other chemokines. Recombinant HCC-4 demonstrated chemotactic activity for human monocytes and THP-1 monocyte cells but not for resting lymphocytes or neutrophils. HCC-4 also induced a Ca2+ flux in THP-1 cells that was desensitized by prior exposure to RANTES. Taken together, these data indicate that HCC-4 is a novel chemokine whose expression is uniquely upregulated by IL-10.

Amino Acid Sequence↗
PubMed2004

Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors.

Hepatocyte nuclear factors (HNF) play a critical role in development of the liver. Their roles during liver tumorigenesis and progression of hepatocellular carcinomas (HCC) are, however, poorly understood. To address the role of HNFs in tumor progression, we generated a new experimental model in which a highly differentiated slow-growing transplantable mouse HCC (sgHCC) rapidly gives rise in vivo to a highly invasive fast-growing dedifferentiated variant (fgHCC). This in vivo model has allowed us to investigate the fundamental mechanisms underlying HCC progression. A complete loss of cell polarity, a decrease in cell-cell and cell-extracellular matrix (ECM) adhesion, elevation of telomerase activity, and extinction of liver-specific gene expression accompanies tumor progression. Moreover, cells isolated from fgHCCs acquired the ability to proliferate rapidly in culture. These alterations were coupled with a reduced expression of several liver transcription factors including HNF4, a factor essential for hepatocyte differentiation. Forced re-expression of HNF4alpha1 in cultured fgHCC cells reversed the progressive phenotype and induced fgHCC cells to re-establish an epithelium and reform cell-ECM contacts. Moreover, fgHCC cells that expressed HNF4alpha1 also re-established expression of the profile of liver transcription factors and hepatic genes that are associated with a differentiated hepatocyte phenotype. Importantly, re-expression of HNF4alpha1 in fgHCC reduced the proliferation rate in vitro and diminished tumor formation in congenic recipient mice. In conclusion, loss of HNF4 expression is an important determinant of HCC progression. Forced expression of this factor can promote reversion of tumors toward a less invasive highly differentiated slow-growing phenotype.

Animals↗
PubMed2007

Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study.

UNLABELLED: Although numerous treatment modalities have been explored in patients with advanced HCC, the therapeutic options are still limited. Somatostatin has been shown to have antimitotic activity in endocrine as well as in a variety of nonendocrine tumors. Expression of somatostatin receptors is found in HCCs, but the efficacy of the somatostatin analogue octreotide remains controversial. Therefore, a randomized double-blind placebo-controlled multicenter trial was performed to assess the efficacy of long-acting octreotide for the treatment of advanced HCC. One hundred twenty untreated patients with histologically confirmed HCC were randomized to receive either long-acting octreotide (Sandostation LAR 30 mg) intramuscularly every 4 weeks or placebo. The study groups were comparable with respect to clinical characteristics. There was no difference in the cumulative survival. The median survival time was 4.7 months in the octreotide group compared with 5.3 months in the control group. Six-month survival rates were 41% for octreotide patients and 42% for control patients, respectively. The unadjusted relative risk for mortality in the octreotide group compared with patients in the control group was 1.11 (95% CI 0.76-1.63; P = 0.59). When adjusted for Okuda, CTP, and Cancer of the Liver Italian Program (CLIP) scores, the relative risk for octreotide did not change markedly and was 1.05 (95% CI 0.71-1.55; P = 0.83). The CLIP score seems to predict survival better than both Okuda and CTP score. CONCLUSION: The randomized controlled double-blind HECTOR trial showed no survival benefit for HCC patients treated with long-acting octreotide compared with placebo.

Aged↗
PubMed1997

A case-control study on GB virus C/hepatitis G virus infection and hepatocellular carcinoma. Brescia HCC Study.

A new hepatitis-associated RNA virus of the Flaviviridae family has been identified and named GB virus C/ hepatitis G virus (HGV). We carried out a case-control study to evaluate the association of HGV infection with hepatocellular carcinoma (HCC). We recruited 170 patients hospitalized for HCC (143 male and 27 female, mean age 64 years) and 306 patients hospitalized for nonliver diseases (controls) in Brescia, Italy. HGV RNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) and antibodies against HGV E2 protein (anti-E2) by an immunoassay test. HGV RNA was found in 8 cases (4.7%) and 4 controls (1.3%). The relative risk (RR) for HGV RNA positivity adjusted for demographic variables and hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, and alcohol was 7.3 (95% confidence interval, 1.7-30.6; P = .009). No HGV RNA-positive subject was also positive for anti-E2. Anti-E2 prevalence did not differ significantly between cases (20%) and controls (15.3%), and no RR increase was found by this marker. Among subjects with HGV exposure (HGV RNA plus anti-E2 positive), a greater proportion of cases (40%) than controls (14%) had transfusion history. The possible role of HGV in HCC etiology seems modest because the population-attributable risk is lower (4%) than those for HBsAg (22%), HCV RNA (36%), and heavy alcohol intake (52%). This study supports the hypothesis of an association between HGV infection and HCC, although at present there are insufficient data on the causality of the association.

Aged↗
PubMed1992

Visualization of oxidative processes at the cellular level during neutrophil-mediated cytotoxicity against a human hepatoma cell line, HCC-M.

Human neutrophil-mediated oxidative processes against a human hepatoma cell line, HCC-M, was visualized at the cellular level by using a silicon-intensified target camera and subsequently processing with a computer-assisted digital-imaging processor. Neutrophils were activated by a streptococcal preparation, OK-432. A hydroperoxide-sensitive tracer, dichlorofluorescein diacetate, was loaded in HCC-M and temporal and spatial changes of lipid peroxides in this cell after addition of stimulated neutrophils were analyzed. The luminol-dependent chemiluminescence activity of neutrophils was significantly enhanced and continued for at least 2 hr by stimulation with OK-432, and its activity was shown to be accumulated at the site where a neutrophil attached with HCC-M. The intensity of dichlorofluorescein fluorescence in HCC-M rapidly increased after adding stimulated neutrophils, and their reaction was significantly attenuated by superoxide dismutase. The number of non-viable cells was increased as the dichlorofluorescein fluorescence increase. It is suggested that oxidative stress may play an important role in neutrophil-mediated tumor-cell damage.

Carcinoma, Hepatocellular↗
PubMed2006

Identification of metastasis candidate proteins among HCC cell lines by comparative proteome and biological function analysis of S100A4 in metastasis in vitro.

Widespread metastasis of hepatocellular carcinoma (HCC) was a complex cascade of events, which is still beyond full appreciation. Screening key proteins, which play a critical role in metastasis, using high-throughput proteomics approach help discover valuable biomarkers and elucidate the mechanism of metastasis. This study was to find out some metastasis candidate proteins among HCC cell lines with various metastatic potential by comparative proteomics, and then further validate the biological function of these proteins in metastasis in vitro. The protein profiles of metastatic HCC cell lines (MHCC97H and MHCC97L) displayed obvious differences compared with nonmetastatic ones (Hep3B). Twenty-six metastasis candidate proteins, which were identified by on-line LC-ESI-MS/MS, such as S100 calcium-binding protein A4 (S100A4), annexin 1, etc., might have much application in diagnostic procedures and prognosis evaluation. S100A4, as a leading different metastasis candidate protein, which overexpressed only in the metastatic cells, was selected for further investigation. A series of assays related to invasion and metastasis in vitro, including cell motility, invasion, and matrix metalloproteinases (MMPs) secretion, were performed in MHCC97H/antisense recombinant plasmid to S100A4 (pcDNA3.1(+) AS S100A4) and the mock controls. All the data in the present study suggested that S100A4 might contribute to HCC invasion and metastasis through two paths of matrix metalloproteinase (MMP9) secretion regulation and strengthened motility and invasion properties.

Apoptosis↗
PubMed2000

Targeting a recombinant adenovirus vector to HCC cells using a bifunctional Fab-antibody conjugate.

We developed a specific adenoviral gene delivery system with monoclonal antibody (mAb) AF-20 that binds to a 180 kDa antigen highly expressed on human hepatocellular carcinoma (HCC) cells. A bifunctional Fab-antibody conjugate (2Hx-2-AF-20) was generated through AF-20 mAb crosslinkage to an anti-hexon antibody Fab fragment. Uptake of adenoviral particles and gene expression was examined in FOCUS HCC and NIH 3T3 cells by immunofluorescence; beta-galactosidase expression levels were determined following competitive inhibition of adenoviral CAR receptor by excess fibre knob protein. The chimeric complex was rapidly internalized at 37 degrees C, and enhanced levels of reporter gene expression was observed in AF-20 antigen positive HCC cells, but not in AF-20 antigen negative NIH 3T3 control cells. Targeting of recombinant adenoviral vectors to a tumor associated antigen by a bifunctional Fab-antibody conjugate is a promising approach to enhance specificity and efficiency of gene delivery to HCC.

3T3 Cells↗
PubMed1991

Molecular cloning and immunolocalization of two variants of the major basic nuclear protein (HCc) from the histone-less eukaryote Crypthecodinium cohnii (Pyrrhophyta).

Two clones that encode variants (HCc1 and HCc2) of the major basic nuclear protein of the dinoflagellate Crypthecodinium cohnii, were identified by immunoscreening of a cDNA expression library. The first clone carries a full-length cDNA with an open reading frame (HCc1) encoding 113 amino acids. The cDNA from the second clone lacks some of the 5' end, and the coding sequence is only 102 residues. The two proteins display 77% sequence similarity and their NH2-ends are homologous to the NH2-peptide of the HCc protein determined by P. Rizzo. The amino acid composition, which confirms the basic nature of lysine-rich HCc proteins, differs markedly from other known DNA-binding proteins such as histones, HMGs or prokaryotic histone-like proteins. No convincing homology was found with other proteins. HCc antigens were localized on C. cohnii by immunofluorescence, and by electron microscopy (EM) with immunogold labelling. HCc proteins are mainly detected at the periphery of the permanently condensed chromosomes, where active chromatin is located, as well as in the nucleolar organizing region (NOR). This suggests that these basic, non-histone proteins, with a moderate affinity for DNA, are involved at some level in the regulation of gene expression.

Amino Acid Sequence↗
PubMed2005

[Esterase activity of human organotypic cornea construct (HCC) as in vitro model for permeation studies].

Organotypic cornea equivalents are used as in vitro models for permeation studies. Many ophthalmic drugs are applied as ester prodrugs to achieve a higher bioavailability. The esterase activity of three corneal human cell lines (epithelial, stromal, endothelial cells) as well as of excised porcine cornea, human donor cornea and human cornea construct (HCC) was investigated and compared. Esterase activity was determined using p-nitrophenyl acetate and hydrocortisone acetate (HCA) as esterase substrates. Hydrocortisone acetate permeation across porcine cornea, human donor cornea and HCC was studied in vitro using Franz-diffusion cells. Corneal epithelial cells showed the highest esterase activity and only small differences to keratocytes and endothelial cells were detectable. The permeation barrier properties of the different corneal tissues were very similar in the case of HCA permeation whereas HCA metabolism rates were in the ranking order of porcine cornea > HCC > human donor cornea. Permeation and metabolism studies indicate that the in vitro permeation model HCC is able to adequately convert hydrocortisone acetate to hydrocortisone.

Aged↗
PubMed2004

Relationship between tumour growth rate and carbogen-based functional MRI for a chemically induced HCC in mice.

We previously performed MRI studies of HCC (hepatocellular carcinomas) in mice showing the feasibility of measuring a carbogen effect. In the present study carbogen response of the whole tumour was compared with growth characteristics during longitudinal follow-up. HCC were chemically induced. The imaging protocol at 4.7 T comprised a fast spin-echo sequence for high-resolution screening and measurement of growth curves, and a fast gradient echo sequence allowing an entire T2*w image acquisition per respiratory cycle to perform fMRI under carbogen breathing. A new parameter, T+, the fraction of tumour voxels with increased intensity under carbogen was measured on manually defined ROIs. Twenty-two HCC were followed for 3-10 weeks. Tumours were divided into two groups, "regularly" and "irregularly" growing tumours. A linear correlation between T+ and tumour growth rate was observed only for "regularly" growing HCC. These results suggest a link between tumour growth rates and tumour fractions exhibiting signal increase upon carbogen breathing. They are compatible with observations by others that rapidly growing tumours are more hypoxic than slowly growing ones. Combined measurement of T+ and tumour growth may become a useful noninvasive follow-up approach for assessment and/or management of therapies involving vasculature-targeting and anti-proliferative drugs.

Animals↗
PubMed2005

Consideration of role of radiotherapy for lymph node metastases in patients with HCC: retrospective analysis for prognostic factors from 125 patients.

OBJECTIVES: To evaluate the role of radiotherapy (RT) for hepatocellular carcinoma (HCC) patients with abdominal lymph node (LN) metastasis at our institution in the past 7 years. METHODS AND MATERIALS: We identified 125 patients with HCC metastasis to regional LNs treated with or without external beam RT (EBRT) between 1998 and 2004. Clinical characteristics collected included alpha-fetoprotein status, gamma-glutamyltransferase, status of intrahepatic tumors (size and number), previous therapy for intrahepatic tumors, metastatic LN status (location, number, and size), tumor thrombi, and Child-Pugh classification. Of the 125 patients, 62 received local limited EBRT and were classified as the EBRT group. They received locoregional LN irradiation. The tumor dose ranged from 40 to 60 Gy in daily 2.0-Gy fractions, 5 times weekly. Another 63 patients, who did not receive EBRT, were selected from hospitalized patients in the same period and were classified as the non-EBRT group. The parameters studied included survival rates and tumor response to EBRT both as demonstrated by clinical symptoms and as seen on CT. The Kaplan-Meier method was used to evaluate the survival rates, and the Cox regression model was used to identify predictors of outcome. RESULTS: After EBRT, partial responses and complete responses were observed in 37.1% and 59.7% of patients, respectively. The median survival was 9.4 months (95% confidence interval 5.8-13.0) for the EBRT group and 3.3 months (95% confidence interval, 2.7-3.9) for the non-EBRT group (p < 0.001). Multivariate analysis showed that multiple intrahepatic primary tumors, occurrence of tumor thrombi, no therapy for intrahepatic tumors, and greater Child-Pugh classification were related to a poorer prognosis in all patients. In the EBRT group, the survival periods decreased as the distance of LN involvement from the liver increased (following the natural flow of lymph) and was also associated with the intrahepatic primary tumor size. The incidence of death resulting from LN-related complications was lower in the EBRT group. CONCLUSION: Lymph node metastasis from HCC is sensitive to EBRT. EBRT with 25 fractions of 2 Gy is an effective palliative treatment for patients with LN metastases from HCC presenting with good performance status and may prolong overall survival.

Adult↗
PubMed2026

PCBP2 facilitates miR-93-5p-mediated repression of GDF11 in HCC cell lines.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-&#x3b2; superfamily, functions in skeletal muscle and neuronal regeneration and has been implicated in tumor suppression. In hepatocellular carcinoma (HCC), GDF11 expression is markedly downregulated, but the mechanisms responsible for this repression remain unclear. In this study, we examined whether the oncogenic miR-106b-25 cluster contributes to GDF11 suppression in HCC. We found that this cluster decreases GDF11 expression at both the mRNA and protein levels, with miR-93-5p acting as the dominant regulator. Inhibition of miR-93-5p with antisense oligonucleotides restored GDF11 expression and reduced HCC cell proliferation, migration, and invasion. Mechanistically, we identified the RNA-binding protein (RBP) PCBP2 as a key facilitator of miR-93-5p targeting of GDF11. PCBP2 binds a C-rich element adjacent to the miR-93-5p target site in the GDF11 3' UTR, thereby enhancing miR-93-5p-mediated repression. PCBP2 knockout attenuated miR-93-5p-mediated repression, whereas re-expression of PCBP2 restored it, supporting its modulatory role. Collectively, these findings identify PCBP2 as a modulator of miR-93-5p-mediated GDF11 repression and suggest that this regulatory interaction contributes to HCC cell proliferation, migration, and invasion. This work provides insights into the post-transcriptional control of the tumor suppressor and highlights the therapeutic potential of targeting miRNA-RBP interactions.

GDF11↗