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PubMed1990

[Pathomorphologic study on early hepatocellular carcinoma (HCC)--a study of cell density in well-differentiated HCC of the early stage].

In order to clarify the histologic characteristics of well-differentiated hepatocellular carcinoma (HCC), a comparative morphometric study on cell density was performed in 15 HCCs smaller than 2 cm in diameter, 6 HCCs with marked fatty and/or clear cell change, 7 hyperplastic nodules, 5 hyperplastic nodules containing foci of HCC, and non-cancerous areas of the livers bearing small HCC. In well-differentiated HCC, marked increase of cell density accompanying by decrease of cell size and increase of nuclear cytoplasm ratio were prominent, and the cell density was approximately two times larger than that of the non-cancerous area in most cases. In HCCs with marked fatty and/or clear cell change, as an increase of cell density was not evident because of swelling of the cytoplasm due to fat and/or glycogen accumulation, it should be careful to differentiate them from non-cancerous nodular lesions including hyperplastic nodule with marked fatty change. Hyperplastic nodules could be divided into two groups; those with marked increase of cell density, and those without increase of cell density. In the former group, 5 of the 7 nodules contained cancerous foci.

Carcinoma, Hepatocellular↗
PubMed1996

Low prevalence of hepatitis C infection in hepatocellular carcinoma (HCC) cases and population controls in Guangxi, a hyperendemic region for HCC in the People's Republic of China.

Southern Guangxi, China has one of the highest incidences of hepatocellular carcinoma (HCC) in the world. Serum samples collected from subjects of an earlier case-control study (39 cases, 41 controls) and from a random sampling of a residential male cohort (n = 100) were tested for antibodies for the hepatitis C virus (anti-HCV) using ELISA version 2.0 with confirmation by RIBA version 2.0. Only one of 141 (0.7%, upper 95% confidence limit, 3.2%) control subjects and none of 39 (upper 95% confidence limit, 6.07%) HCC cases tested positive for anti-HCV. Our results indicate that hepatitis C infection is not an important environmental determinant of HCC risk in this hyperendemic region.

Adult↗
PubMedDate not supplied

Newly developed hepatocellular carcinoma (HCC) in chronic liver disease: MR imaging findings before the diagnosis of HCC.

PURPOSE: The purpose of this work was to describe the initial magnetic resonance (MR) imaging findings obtained before an imaging diagnosis of overt hepatocellular carcinoma (HCC) in the chronically damaged liver. METHODS: One hundred fifty-two newly diagnosed HCCs diagnosed by dynamic computed tomography (n = 111) or by MR imaging (n = 41), in addition to digital subtraction hepatic arteriography, in 96 patients were subjected to analysis of their MR imaging features within the previous 2 years. RESULTS: Ninety-seven (64%) HCC cases showed no focal lesions distinguishable from background hepatic parenchyma in MR images taken before the indication of typical HCC. The remaining 55 (36%) lesions were readily identified in earlier images and were categorized into 3 groups: nonhypervascular lesions (category I, n = 6), lesions with partially hypervascular foci of "nodule-within-nodule" appearance (category II, n = 12), and homogeneously hypervascular and/or T2-weighted hyperintense lesions (category III, n = 37). The size and doubling time of category III lesions (0.7 cm, 154 days) were smaller and shorter than those of the other lesions (1.2 cm, 377 days). CONCLUSIONS: Before the imaging diagnosis of HCCs, the premalignant or early malignant lesions can be found on the prior MR images just in the minority of the lesions in the cirrhotic liver.

Adult↗
PubMed1991

Proto-oncogene expression in three human hepatoma cell lines, HCC-M, HCC-T and PLC/PRF/5.

Changes of nucleotide sequences and expressions of cellular oncogenes in human hepatoma cell lines, PLC/PRF/5, HCC-M and HCC-T cells, were examined by Southern and Northern blot analyses. The probes used are DNA fragment of myc, N-, H-, K-ras, fos, fms, raf, erb-A, erb-B, and erb-B2 genes and synthetic oligonucleotides corresponding to the part of N-, H-, K-ras genes. The results are as follows. DNA amplification and rearrangement were not detected in these three human hepatoma cell lines. Point mutations at codons 12, 13, and 61 in N- and K-ras genes were not demonstrated in these cell lines. N-, H-, K-ras and myc transcripts were detected in these three cell lines. However, fos gene transcript was detected only in PLC/PRF/5 and HCC-M cells which were derived from hepatitis B related hepatocellular carcinoma and having integrated hepatitis B virus (HBV) DNA. These data showed that there are no specific proto-oncogene expression into RNA except for myc and ras genes, nor DNA rearrangement in these 3 human hepatoma cell lines with regards to at least 10 different oncogenes examined and suggest the relationship between fos gene expression and integration of HBV DNA in host cell DNA.

Blotting, Northern↗
PubMed2001

Hemofiltrate CC chemokines with unique biochemical properties: HCC-1/CCL14a and HCC-2/CCL15.

The hemofiltrate CC chemokines CCL14a (formerly HCC-1), CCL14b (formerly HCC-3), and CCL15 (formerly HCC-2) are encoded by mono- as well as bicistronic transcripts from a tandem gene arrangement on human chromosome 17q11.2. The transcription and splicing into several mono- and bicistronic transcripts of this gene complex are unique for human genes. No corresponding mechanism is known in nonprimate mammalian species such as mice and rats. The extremely high concentration of CCL14a in human plasma is exceptional for chemokines and led to the identification of this chemokine. Several molecular forms of CCL14a have been isolated and investigated. The mature propeptide CCL14a(1-74) is a low-affinity agonist of CCR1 which is converted to a high-affinity agonist of CCR1 and CCR5 on proteolytic processing by serine proteases. In contrast, CCL15 is characterized using molecular forms deduced from the mRNA/cDNA and shown to activate cells via CCR1 and CCR3, also dependent on the amino-terminal length. Hemofiltrate CC chemokines are chemoattractants for different types of leukocytes including monocytes, eosinophils, T cells, dendritic cells, and neutrophils. In this review, we emphasize the genomic organization, expression patterns, and biochemical properties of CCL14a, CCL14b, and CCL15. We report results of significance for the development of therapeutic strategies, especially concerning HIV infection and inflammatory diseases.

Amino Acid Sequence↗
PubMed2005

Expression of matrix metalloproteinases (MMPs) in cultured hepatocellular carcinoma (HCC) cells and surgically resected HCC tissues.

Matrix metalloproteinases (MMPs) relate to the growth and infiltration of cancer cells, but the frequency and amount of their expression are not yet fully examined in hepatocellular carcinoma. Expression of MMPs (MMP-2, MMP-7, MMP-9, MT1-MMP, MT2-MMP, MT3-MMP) and tissue inhibitors of metalloproteinase (TIMP: TIMP-1, TIMP-2) was investigated on cultured hepatocellular carcinoma (HCC) cells and surgically resected HCC tissues. The cultured cells and tissues expressed MMPs and TIMPs at various degrees, and high expression was observed for MMP-2, MMP-9, MT1-MMP and TIMP-2. Expression of MMP-7, MT2-MMP and TIMP-1 was found at a low frequency and a low amount in both the cells and the tissues. MMP-2 was expressed in various cells: HCC cells, vascular wall and sinusoidal endothelial cells in the cancer area of surgically resected tissues; and hepatocytes, bile duct cells, vascular wall, macrophages and Kupffer cells in the non-cancerous area. MMPs and TIMPs were expressed at a relatively high frequency in hepatocytes of the cancerous area and surrounding non-cancerous area as well as in the other cells and tissues. MMPs and TIMPs may be involved in the progression of hepatocellular carcinoma including the infiltration of cancer cells.

Bile Ducts↗
PubMed1992

Radioiodinated anti-hepatocellular carcinoma (HCC) ferritin. Targeting therapy, tumor imaging and anti-antibody response in HCC patients with hepatic arterial infusion.

Radioimmunoimaging and radioimmunotherapy with radioiodinated anti-(hepatocellular carcinoma ferritin) antibody (131I- or 125I-FtAb) have been applied in patients with primary liver cancer. A total of 41 patients with surgically unresectable hepatocellular carcinoma (HCC) and receiving hepatic artery ligation and cannulation during exploratory laparotomy were treated with this regimen by intrahepatic arterial infusion. Compared with the control group, a decline of serum alpha-fetoprotein (65.7% versus 42.9%) and shrinkage of tumor (68.3% versus 33.9%) were observed in the treated group, and a higher second-look resection rate (31.7% versus 5.1%) and longer survival (1-year: 61.0% versus 37.3%, 3-year: 25.0% versus 6.9%) resulted. The administration of antibody through a hepatic arterial catheter (n = 16) was compared with intravenous injection (n = 17) in terms of the tumor-imaging sensitivity in 33 patients with liver cancer. The results indicated that hepatic arterial infusion was superior to intravenous injection. The sensitivity 7 days after the administration was 100% in the i.a. group and 76.5% in the i.v. group, the uptake ratio of tumor to liver being 1.74 +/- 0.57 in the former and 1.34 +/- 0.29 in the latter. Furthermore, intrahepatic arterial infusion revealed a lower anti-antibody detection rate than intravenous injection (0/14 versus 4/11).

Antibody Formation↗
PubMedDate not supplied

The HepCar registry: report on a one-year registration program of hepatocellular carcinoma (HCC) in Belgium. What is daily practice in HCC?

INTRODUCTION: Due to a rise in HCV induced liver cirrhosis, hepatocellular carcinoma becomes more prevalent in Western European countries. The HepCar registry is an initiative in which patients with hepatocellular carcinoma, their treatment and follow up are registered. MATERIALS AND METHODS: Belgian physicians were asked to report all new cases of hepatocellular carcinoma which were seen between January 2003 and December 2003. Reporting was done on a voluntary basis. Data reported were: demographic figures, the nature of the underlying liver disease, presentation characteristics of the tumour, laboratory findings and choice of therapy. Every six months, a reminder was sent to determine survival. RESULTS: 131 patients (94 male/37 female) were reported. Mean age was 63 years +/- 13. Underlying liver disease was HCV (n = 54, 41%), HBV (n = 22, 17%), alcoholic liver disease (n = 39, 30%) and miscellaneous (n =16, 12%). Diagnosis of hepatocellular carcinoma was made by surveillance in 47 (36%) patients. After logistic regression, survival was 5 times better for patients inside the Milan criteria (one lesion less than 5 cm in diameter or less than 3 nodules each less than 3 cm in the absence of vascular invasion and metastasis). DISCUSSION: Tumours inside the Milan criteria have a better survival. The majority of the patients have an underlying cirrhosis as background for the development of a HCC.

Age Distribution↗
PubMedDate not supplied

The medical management of hepatocellular carcinoma (HCC) in Japan: a review with implications for HCC seen in the west.

The problem and approaches to the treatment of hepatocellular carcinoma as seen in Japan are reported. Current Japanese methods for the detection of hepatocellular carcinoma and the methods used to treat hepatocellular carcinoma are described. Included in the latter discussion is a description of the untoward effects of each treatment. Finally an alogorithm for the treatment of hepatocellular carcinoma is presented based upon the Japanese experience.

Antineoplastic Agents↗
PubMed2005

Identification of HCC-22-5 tumor-associated antigen and antibody response in patients.

BACKGROUND: Serological identification of antigens by recombinant expression cloning (SEREX) is a promising method used to analyze tumor-associated antigen (TAA). Nineteen primary HCC-associated antigens have been found from a HCC cDNA library using autogenous serum by the SEREX approach. We searched for HCC-associated antigens and applied them to HCC diagnosis. METHODS: Nine of 19 primaries HCC-associated antigens identified by SEREX method were tested their immune response again with distinct allogeneic sera. One of the screened HCC-associated antigens, HCC-22-5 was recombined and expressed and made the frequency analysis of its seropositivity in various patients using the methods of Western-blot and ELISA. RESULTS: SEREX analysis showed that 9 primary HCC-associated antigens had high-titered IgG antibody in the majority of HCC patients. Western-Blot method confirmed that 3/7 HCC patients had antibodies against HCC-22-5, which demonstrated that expressed HCC-22-5 antigen had the character of antigen. Sera samples from 341 patients and 80 normal individuals have been tested for autoantibodies against HCC-22-5 by ELISA method. The results found that 51/128 of HCC, 11/76 of chronic hepatitis, 11/22 of liver cirrhosis and 8/54 of nasopharynx cancer patients had antibodies against HCC-22-5. No antibody response to HCC-22-5 had been found in the sera of 7 lung cancers, 54 gastric-intestine patients and 80 normal individuals. The groups of HCC and liver cirrhosis had higher antibody positive rate than that of other groups (p<0.05). In the HCC sera with alpha-fetoprotein (AFP) negative, the positive rate of HCC-22-5 was as high as 78.9%. CONCLUSIONS: HCC-22-5 can be used for HCC serologic screening, especially for the patients with AFP negative.

Amino Acid Sequence↗
PubMed2000

Posttranslationally processed forms of the human chemokine HCC-1.

HCC-1 is the only CC-chemokine known so far which circulates in nanomolar concentrations in human plasma. Its physiological function is not well defined. Posttranslational processing of HCC-1 was shown to modulate its biological properties. In this study several different processed forms of HCC-1 were isolated. Western blot analysis of human plasma extracts revealed a HCC-1 immunoreactive double band at 8-10 kDa indicating the presence of two distinct HCC-1 peptides. These peptides were isolated from a peptide library of human blood filtrate and represent predominantly HCC-1 (1-74) and glycosylated HCC-1 (1-74). Glycosylated HCC-1 exhibits a molecular mass of 9621 Da due to O-glycosylation at position 7 (Ser-7) with two N-acetylneuraminic acids and the disaccharide N-acetylgalactosamine galactose. Furthermore N-terminally truncated HCC-1 (3-74) and HCC-1 (4-74) were identified in the peptide library. In hemofiltrate approximately 3% of total HCC-1 represents HCC-1 (3-74) and approximately 1% represents HCC-1 (4-74) whereas the major products are nonglycosylated HCC-1 (1-74) and glycosylated HCC-1 (1-74). Our data imply that HCC-1 (1-74), HCC-1 (3-74), HCC-1 (4-74) and glycosylated HCC-1 (1-74) circulate in human blood. The N-terminal processing and modification of HCC-1 might be of importance in displaying its full biological activity.

Amino Acid Sequence↗
PubMed2026

Integrated multi-omics analysis of metabolomics and proteomics uncovers dysregulated amino acid metabolism in HCC metastasis.

BACKGROUND: Metastasis is the primary cause of treatment failure and adverse prognosis in hepatocellular carcinoma (HCC), and the molecular basis of HCC metastasis remains poorly defined. This work investigated the potential mechanisms underlying HCC metastasis through integrated multi-omics analysis of metabolomics and proteomics. METHOD: This retrospective study included 105 individuals with HCC, with comparative analysis between metastatic and non-metastatic cases. We further evaluated the effects of metastasis on serum metabolomics and proteomics in HCC patients. RESULT: Widespread disturbances in amino acid metabolism were identified via untargeted metabolomics in HCC patients with metastasis, closely governing inflammation-related metabolic remodeling and oxidative stress responses. Specifically, we identified 91 and 59 distinct differential metabolites capable of indicating HCC metastasis, with the screening criteria set as log2 fold change > 1.5, adjusted P value < 0.05, and VIP > 1.5 in positive and negative modes, respectively. The alanine, aspartate and glutamate metabolism pathway correlated with HCC-associated lung metastasis, while the gluconeogenesis pathway was linked to HCC-associated bone metastasis. Compared with HCC (non-metastatic hepatocellular carcinoma), the key molecular alterations in the multi-omics network of HCC_M (HCC with metastasis) are implicated in inflammatory metabolic reprogramming, oxidative stress response, gluconeogenesis, glycolysis, and the tricarboxylic acid (TCA) cycle. Twenty-five proteins, including PKM2, PERCK, ALDH2, CPS1, GLS1, GLUD1, GOT1, and SLC38A2, were identified as potential biomarkers for HCC metastasis. CONCLUSION: By integrating untargeted metabolomic and proteomic profiling, we identified distinct metabolic and proteomic changes linked to HCC metastasis. This work also characterized the pathological characteristics and core pathways underlying HCC metastasis, while identifying potential therapeutic candidates.

Humans↗
PubMed2000

Recurrence or metastasis of HCC:predictors, early detection and experimental antiangiogenic therapy.

AIM:To investigate the predictors for recurrence or metastasis of HCC, and to evaluate the effect of antiangiogenic therapy on the growth of transplantable human HCC in nude mice.METHODS:RT-PCR was used to measure the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in 56 pairs of nontumorous liver and tumor samples. Sixty blood samples from human HCC were examined by nested RT-PCR to find out AFP mRNA. Recombinant human endostatin and polyclonal antibody against VEGF were administered to treat human HCC transplanted in nude mice.RESULTS:Thirty of 56 HCC samples showed stronger expression of MMP9 in tumorous tissues than in nontumorous tissues. Fifteen of the 26 patients with relative expression level of MMP-9 more than 0.34 developed tumor recurrence or metastasis, whereas only 7 of 30 patients with relative expression level less than 0.34 developed tumor recurrence (P < 0.05). There was no significant difference in the relative expression level of VEGF between patients with postoperative recurrence or metastasis and those without recurrence. AFP mRNA was detectable in 53.3% of patients with HCC. The sensitivity and specificity of AFP mRNA as a marker to detect hematogenous dissemination of HCC cells was 81.8% and 84.4%, respectively. Recombinant human endostatin and polyclonal antibody against VEGF inhibited the growth of transplantable HCC in nude mice by 52.2% and 45.7%, respectively.CONCLUSION: MMP-9 expression in HCC correlates with the postoperative recurrence or metastasis of HCC. Patients with high level of MMP-9 expression in HCC are susceptible to metastasis.AFP mRNA could serve as an indicator of hematogenous spreading of HCC cells in circulation and a predictor of recurrence or metastasis of HCC. Antiangiogenesis may be an adjuvant therapy for HCC.

Journal Article↗
PubMedDate not supplied

Utility of alpha-fetoprotein (AFP) in the screening of patients with virus-related chronic liver disease: does different viral etiology influence AFP levels in HCC? A study in 350 western patients.

BACKGROUND/AIMS: Dosage of serum AFP (alpha-fetoprotein) is widely used for HCC screening in patients with chronic liver disease. Virus-related chronic liver disease is the main cause of cirrhosis and HCC in Western and Far Eastern countries, but the relationship between viral etiology and AFP levels in HCC is still unclear. The aim of this study was to verify, in Western patients with post-viral chronic liver disease, the usefulness of AFP dosage for the detection of HCC, and the influence of viral etiology on AFP levels in HCC. METHODOLOGY: The study population included 350 patients with post viral chronic liver disease that underwent liver biopsy, serum AFP determination and ultrasound liver evaluation. Seven patients had normal liver histology, 197 had chronic hepatitis, 72 had cirrhosis, and 74 had cirrhosis and HCC. ROC (receiver operating characteristic) analysis was used to assess the best diagnostic AFP threshold value for HCC detection. Logistic regression analysis was performed to individuate independent predictors of HCC diagnosis. RESULTS: No difference was observed in AFP levels between HCV- and HBV-positive patients, neither in the whole population nor in the HCC patients only. ROC area under curve for AFP was 0.801 (95% CI: 0.721-0.867). The analysis individuated a best accurate AFP threshold value for HCC diagnosis of 50 ng/mL. HCC was detected with specificity > or = 95% only for AFP > 100 ng/mL. The sensitivity however was poor (25%). Male sex, age > 60, and AFP were independent predictors of HCC diagnosis. CONCLUSIONS: Serum AFP levels in HCC patients are not influenced by virus B or C hepatitis pattern. AFP dosage should not be used for HCC diagnosis in non-cirrhotic patients. Male patients with cirrhosis should be regarded with a more "aggressive" screening program compared to females.

Biomarkers↗
PubMedDate not supplied

Clinical features of patients with HCC who are negative for both HBV and HCV markers.

BACKGROUND/AIMS: The aim of this study is to clarify the clinical features of hepatocellular carcinoma that are negative for both hepatitis B surface antigen and anti-hepatitis C antibody. METHODOLOGY: Patients were classified according to viral markers: 45 patients (82%) had hepatitis B (B-HCC), 467 patients (82%) had hepatitis C (C-HCC), and 53 patients (9%) had neither hepatitis B nor hepatitis C (NBNC-HCC). Differences in clinical parameters among these three groups were analyzed. RESULTS: Patients with NBNC-HCC were older than B-HCC and C-HCC patients. The incidence of alcoholism in NBNC-HCC patients was higher than in C-HCC patients. Patients with NBNC-HCC had similar rates of positive antibody to hepatitis B core antigen as did patients with C-HCC. NBNC-HCC patients were further classified according to median age. The younger group showed a greater tendency towards alcoholism than did the aged group. Liver functioning in the younger group was worse than in the older group. The older group had larger tumors than the younger group. CONCLUSIONS: The livers of younger NBNC-HCC patients were more cirrhotic, possibly because of alcoholism. Older NBNC-HCC patients presented with larger tumors, possibly because they did not receive regular medical check-ups due to their relatively preserved liver function.

Adult↗