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PubMed1994

Prediction of recurrence after HCC resection. Faint oily deposits on preoperative Lipiodol-CT of remnant liver tissue.

In trying to clarify the high recurrence rate after removal of small hepatocellular carcinoma (HCC), we assessed the postoperative evolution of minute hepatic Lipiodol deposits which had been diagnosed as artifacts on the preoperative Lipiodol-CT. Of 27 patients with solitary HCC less than 5 cm in diameter, 14 had such Lipiodol deposits in the preoperative CT and 9 of them (64%) developed recurrent tumors. On the other hand, 6 of the 13 patients without deposits (46%) suffered recurrence, but in 5 of these 6 patients the HCC was metachronous multicentric. The cumulative survival rate of the non-deposit group was better than that of the deposit group (p < 0.1). The present study suggested that, even in patients with small HCC, minute concomitant tumors invisible by conventional imaging techniques may exist at the time of surgery. Some of these lesions without sufficient tumor vasculature showing a hypervascular blush on angiography appear to retain small, vague Lipiodol deposits.

Angiography↗
PubMed1993

[Effect of hepatocellular carcinoma-specific transfer factor (HCC-S-TF) on IL-2 activity and IL-2R expression].

HCC specific transfer factor (S-TF) was extracted from lymphoid tissues of goats immunized with HCC cell suspension. The effect of the S-TF on IL-2 activity and IL-2R expression was observed in vitro. The results showed that IL-2 activity and IL-2R expression in HCC patients but not in normal subjects could be increased by the S-TF. The IL-2 activities and IL-2R expressions in both normal subjects and patients with HCC could not be increased by normal transfer factor (N-TF). This may be one of the anti-tumor mechanisms of S-TF. It suggests that S-TF may be better than N-TF in immunotherapy of human tumors.

Adult↗
PubMed1996

[Application of radiolabeled anti-HBx monoclonal antibody for HCC targeting therapy].

OBJECTIVE: To explore the possibility of anti-HBx McAb as a carrier of HCC targeting therapy after we prepared successfully the anti-HBx monoclonal antibody by immunizing BALB/C mice with 17KD hepatitis B virus X protein. METHODS: The antibody was prepared, purified, identified, radiolabled and used in nude mice bearing human HCC and two HCC patients respectively for experimental and clinical trials. In the experimental study, 0.5mCi 131I-anti-HBx was injected peritoneally. In the clinical trial, the patients were treated with 131I-anti-HBx by injecting into the hepatic artery. After the treatment for one course, a total dose of 37.5 mCi was administered. RESULTS: The survival periods of the mice were prolonged and the tumors were suppressed significantly. The symptoms of the patients were improved significantly with decreased titre of AFP. The B-ultrasonic and CT scanning showed that the tumors became smaller. For these reasons, one of the two patients was reoperated. The tumor was removed and necrosis of the whole tumor was noted except few living tumor cells on the edge of tumor specimen. CONCLUSIONS: It is possible to use the anti-HBx monoclonal antibody as a carrier for human HCC targeting therapy.

Adult↗
PubMedDate not supplied

Metallothionein and apoptosis in primary human hepatocellular carcinoma (HCC) from northern China.

BACKGROUND: Metallothionein (MT), acting as an antioxidant and zinc binding protein, may play an important role in regulation of apoptosis. Its differential expression has been documented in various human tumours. MATERIALS AND METHODS: MT expression by immunohistochemical staining with a polyclonal antibody and apoptotic cells (APC) by TUNEL technique were investigated in 20 cases of hepatocellular carcinoma (HCC) and 2 normal livers from Northern China. Adjacent normal liver was available from 9 of these cases and 6 had adjacent cirrhotic tissue. There was no difference for MT staining and incidence of APC between normal liver and adjacent normal liver, and thus both were used as control liver. RESULTS: Control liver had consistent MT staining with very low incidence of APC. Adjacent cirrhotic liver showed the same intensity of MT staining, with a similar incidence of APC to control liver. Twelve of 20 HCC cases (60%) showed no MT staining, and the rest also showed a low grade of MT staining as compared with control or adjacent cirrhotic livers. The incidence of APC in HCC was markedly higher than that in control liver or adjacent cirrhotic liver. The negative correlation of numbers of APC with MT expression was statistically significant (p < 0.005). The high incidence of APC in liver with a low MT expression was confirmed in double staining for MT and APC. CONCLUSIONS: The present investigation from Northern Chinese samples has shown that MT expression in HCC was different from that in other human tumours, such as breast carcinoma. This suggests a different pattern of expression of MT protein in these two kinds of cancer. This investigation is important in understanding the mechanisms of the drug resistance of tumour cells, and may help to design better treatment strategies.

Adult↗
PubMedDate not supplied

Clinical trials of HCC in Taiwan.

Tumors of the liver represent one of the most common malignancies in the world. Little has changed in the past 5 years to alter the statistics. Published census from the Department of Health in Taiwan, 1993, showed that cancer death was 107/100,000 population. Hepatoma is the number one cause of cancer death with 24.05/100,000 population. It increased 11.23% in comparison with last year's survey. About 5,000 people die from hepatoma each year in Taiwan. Both case control studies and cohort studies have shown a strong association between chronic hepatitis B carriage rate and an increased incidence of hepatocellular carcinoma (HCC). Although up to a 200-fold excess incidence of HCC was found in Taiwan, the association of chronic hepatitis B virus in different populations of Southeast Asia who have HCC is somewhat varied. Many treatment modalities for hepatoma have been attempted. Chemotherapy is usually given to patients with metastatic disease or for persistent or recurrent disease. The consensus is that no single drug or combination of drugs given systemically leads to a reproducible response rate of more than 25% or has any effect on survival, or survival beyond that of untreated control. The identification of new, effective chemotherapy drugs and other modality treatments for advanced stage HCC is urgently required. We report here the results regarding response rates, toxicities, and survivals of 14 on-going and finished Phase I, II and III clinical trials on hepatoma. These include chemotherapy and/or biological modifier, radioisotope, hormone, and hepatic infusion. Nine future therapies and gene therapies will also be discussed.

Antineoplastic Agents↗
PubMed2005

Combined endostatin/sFlt-1 antiangiogenic gene therapy is highly effective in a rat model of HCC.

Hepatocellular carcinoma (HCC) is regarded as a suitable target for antiangiogenic strategies. However, antiangiogenic agents aimed at single targets can be neutralized by upregulation of other proangiogenic factors. Therefore, combined approaches addressing at least two angiogenic targets should be more effective. Employing an appropriate rat hepatoma model, we examined the effects of sFlt-1 (soluble vascular endothelial growth factor [VEGF] receptor 1 as an indirect inhibitor of angiogenesis) and endostatin (a direct inhibitor of angiogenesis) in both single-agent as well as combined approaches under in vitro and in vivo conditions. Similar to human HCC, rat Morris hepatoma (MH) cells secreted high levels of VEGF, but no endogenous sFlt-1. Parental MH or MHES(r) cells, stably expressing rat endostatin, were adenovirally transduced either with AdsFlt-1 (encoding sFlt-1) or control vector Adnull (containing no transgene), followed by subcutaneous inoculation into syngeneic ACI rats. Compared with MH/Adnull cells, expressing no antiangiogenic factors at all, tumor weights were reduced fourfold in the MHES(r)/Adnull group, 19-fold in the MH/AdsFlt-1-group, and 77-fold in the MHES(r)/AdsFlt-1 combination therapy group. Analysis of variance did not show a significant interaction between the effects of the two factors ES(r) and sFlt-1; their effects multiplied. In conclusion, combined expression of sFlt-1 and endostatin effectively suppresses HCC growth under in vivo conditions. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

Angiogenesis Inhibitors↗
PubMed2006

Overexpression of pituitary tumor transforming gene 1 in HCC is associated with angiogenesis and poor prognosis.

The pituitary tumor transforming gene 1 (PTTG1) protein is cell-cycle regulated and is identified as a human securin that inhibits sister chromatid separation and is involved in transformation and tumorigenesis. PTTG1 has very low or undetectable expression in most normal human tissues, but it is abundantly expressed in malignant cell lines and pituitary tumors. In this study, we investigated human PTTG1 expression in 62 hepatocellular carcinoma (HCC) specimens using quantitative real-time reverse transcription polymerase chain reaction analysis. We found that, compared with corresponding noncancerous liver tissues, PTTG1 was remarkably overexpressed in HCCs (PTTG1/beta-actin; 0.443 +/- 0.073 vs. 0.068 +/- 0.007; P < .0001). Furthermore, we found a significant correlation between PTTG1 expression and serum alpha-fetoprotein level (P < .001). Univariate and multivariate analyses revealed that the PTTG1 messenger RNA (mRNA) expression was an independent prognostic factor for disease-free (odds ratio 2.70; P = .037) and overall (odds ratio 5.35; P = .007) survival. Moreover, we discovered a significant relationship between PTTG1 expression and intratumoral microvessel density. Our data supported an important role for PTTG1-mediated upregulation of fibroblast growth factor (FGF)-2, one of angiogenesis and modulation of tumor progression, in hepatocarcinogenesis. In conclusion, PTTG1 might be critically involved in the development of HCCs through the promotion of angiogenesis. PTTG1 is overexpressed in HCC and our results suggest that PTTG1 mRNA expression has prognostic significance for the survival of postoperative patients with HCC.

Adult↗
PubMed2007

Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.

UNLABELLED: Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A, and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53. In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to beta-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression. CONCLUSION: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies.

Adenoma↗
PubMed1983

Establishment of a cell line (HCC-M) from a human hepatocellular carcinoma.

A continuous human cell line was established from a hepatocellular carcinoma of an HBsAg-positive Japanese male. The cell line, designated HCC-M, grows as an adhering monolayer with a doubling time of 24 h in medium RPMI-1640 supplemented with 10% FCS and grows with 30% clonal efficiency in soft agar. The cells have been shown by light and electron microscopy to be of epithelial type. When they were transplanted subcutaneously into the back of athymic nude mice (BALB/c, nu/nu), tumors developed at the sites of inoculation, which were shown to be hepatocellular carcinoma, similar in morphology to the original tumor from which they were derived. HCC-M had a chromosome mode of 63 with five identifiable marker chromosomes. HCC-M produced albumin at the 10th passage but this property was lost by the 30th passage. This cell line has not secreted alpha-fetoprotein. Hepatitis B viral particles or HBsAg have not been demonstrated in the cells from the primary culture nor in several subsequent subcultures tested.

Adult↗
PubMed1992

Liver transplantation for small HCC in cirrhosis.

Segmental liver resection is generally considered the treatment of choice for small HCC in cirrhotic livers. Although in selected patients with small encapsulated nodules and low alpha-fetoprotein levels long-term survival can be expected after resection, Western experience is still limited, and follow-up studies too short so that the data presently available cannot be considered satisfactory. The true value of alcoholization as a possible alternative therapy in these patients is still to be ascertained. When using these treatment modalities, the major problem is the high tumour recurrence within the liver. Three main reasons could explain these clinical observations: 1. inadequate resection of the original tumor; 2. unrecognized multifocal HCC; 3. newly generated tumours in the remnant cirrhotic parenchyma. The rationale for liver transplantation is the oncological accuracy of the ablation of the liver, and the possibility of a simultaneous cure of the associated cirrhosis. In our programme of liver transplantation, begun in 1985, we accepted as an indication small HCC in cirrhotic livers. We present here our initial experience with 19 cases.

Carcinoma, Hepatocellular↗
PubMed1995

A case of an intra-atrial tumor thrombus from hepatocellular carcinoma (HCC), first indicated by 67Ga-citrate scintigraphy.

We encountered a very rare case of an intra-atrial tumor thrombus from hepatocellular carcinoma (HCC). Conventional XCT and US gave evidence of HCC. In nuclear medicine studies performed incidentally, the first study with 99mTc-phytate liver scintigraphy showed 2 SOLs and evidence of chronic liver disease, and the second study with 67Ga-citrate scintigraphy demonstrated 2 hot lesions within the liver parenchyma, and also another unexpected hot area just above the left lobe of the liver, seemingly beyond the diaphragm. When echocardiography was performed, in addition to ECG, because the patient began to complain of dyspnea, an oblong mass lesion was detected within the right atrium. Reexamination with XCT and angiography clearly proved the existence of an intraatrial tumor thrombus. These results indicate the need for routine examination by echocardiography for HCC patients complaining of dyspnea.

Carcinoma, Hepatocellular↗
PubMed2005

Radiofrequency thermal ablation (RFA) after transarterial chemoembolization (TACE) as a combined therapy for unresectable non-early hepatocellular carcinoma (HCC).

The treatment of unresectable "non-early" (according to the BCLC classification) hepatocellular carcinoma (HCC) in cirrhotic patients with transcatheter arterial chemoembolization (TACE) followed by radiofrequency ablation (RFA) is retrospectively evaluated and possible prognostic factors of this combined therapy are investigated. Forty-six consecutive cirrhotic patients (Child-Pugh class A or B) with solitary or oligonodular HCC underwent RFA after TACE. The treated lesions were 51 overall (size 30-80 mm, mean 48.9). RFA was performed by a multitined expandable electrodes device after one TACE administration. Local efficacy was evaluated with multiphasic computed tomography (CT) performed an average of 2 months after treatment and then during follow-up. Patient survival rate was also evaluated (follow-up time 1-51 months, mean 15 months). Technical success (defined as complete devascularization during the arterial phase) was achieved in 34/51 lesions (66.7%) at the first CT check and in 29/51 (56.9%) during the succeeding follow-up. Among the considered prognostic factors, only lesion diameter (< or > = 50 mm) was statistically significant in the Fisher's exact test in terms of local control (85.2 vs. 45.8% at first CT, p=.0065; 70.4 vs. 41.7% during follow-up, p=.051). There were two major complications (6.5%): one hepatic failure and one death. A Kaplan-Meier analysis showed survival rates of 89.7% at 12 months and 67.1% at 24 months. Combined therapy for non-early HCC shows a relatively high complete local response (especially in lesions less than 5 cm in diameter) and promising mid-term clinical success. Its overall usefulness has yet to be established by a larger series and risk-benefit analysis.

Aged↗
PubMed2000

Recent developments in imaging diagnostics for HCC: CT arteriography and CT arterioportography evaluation of vascular changes in premalignant and malignant hepatic nodules.

We analyzed the hemodynamic properties and vascular supply changes in relation to the carcinogenesis of hepatocellular carcinoma (HCC), selecting 18 premalignant and malignant nodules less than 3 cm diameter (from 14 patients) for our study. The computed tomographic (CT) arteriography and CT arterioportography (CTAP) findings for these nodules were correlated with the histopathologic findings. The ratios of all microscopically counted arteries (normal hepatic and abnormal arteries), normal hepatic arteries, and portal veins in each nodule to those in the surrounding liver were calculated. Well differentiated lesions had low attenuation on CT arteriography and isoattenuation on CTAP. Moderately-to-poorly differentiated lesions had high attenuation on CT arteriography and low attenuation on CTAP. In well differentiated lesions, the ratios of all arteries, normal hepatic arteries, and portal veins were 1.17+/-0.10, 0.66+/-0.12, and 0.80+/-0.10, respectively. In moderately-to-poorly differentiated lesions, the ratios were 2.64+/-0.23, 0.09+/-0.03, and 0.07+/-0.03, respectively. We concluded that blood flow does not parallel the actual number of arteries seen on the histological examination of tumors. In well differentiated lesions, the combination of normal hepatic arterial degeneration and preserved portal veins results in low attenuation on CT arteriography and isoattenuation on CTAP. In advanced HCC, the combination of neoplastic (abnormal) arterial development by angiogenesis and obliteration of portal veins results in high attenuation on CTA and low attenuation on CTAP. These findings are characteristic of early and advanced stage HCC, and may reflect a combination of sequential changes in their hemodynamic states.

Aged↗
PubMed1993

Comparison between Gd-DTPA, Gd-EOB-DTPA, and Mn-DPDP in induced HCC in rats: a correlation study of MR imaging, microangiography, and histology.

The behaviour of two liver-specific contrast MR agents, Gd-EOB-DTPA and Mn-DPDP and one nonspecific contrast agent, Gd-DTPA, was compared in a rat model of chemically induced hepatocellular carcinoma (HCC). The study included contrast enhanced MR imaging and the corresponding microangiography and histology. Analysis of the MR images showed similar degrees of maximum relative liver enhancement: 47.5 +/- 8.2% for Gd-EOB-DTPA (0.03 mmol/kg) at 5 min postinjection and 52.5 +/- 14.4% for Mn-DPDP (0.025 mmol/kg) at 15 min; both exceeded the value obtained with Gd-DTPA (34.8 +/- 13.6%, at 5 min), even at 0.3 mmol/kg. Gd-EOB-DTPA caused a similar "negative" enhancement of all types of HCC, independent of their differentiation and vascularization, i.e., lesion-to-liver contrast-to-noise ratio (CNR) of differentiated and undifferentiated HCC increased negatively from, respectively, 1.9 +/- 1.1 and -5.1 +/- 3.1 before contrast to -5.2 +/- 2.4 and -11.8 +/- 4.8 at 5 min after contrast. On Mn-DPDP enhanced images, the undifferentiated HCCs showed up negatively (CNR -5.5 +/- 4.7 before contrast to -13.7 +/- 10 at 15 min after contrast), whereas the more differentiated tumors showed up positively (CNR from 2.3 +/- 2.0 before contrast to 12.5 +/- 3.5 at 24 hr postcontrast) due to active uptake and delayed elimination of Mn-DPDP.

Angiography↗
PubMed2005

PKCalpha expression regulated by Elk-1 and MZF-1 in human HCC cells.

Our previous study found that PKCalpha was highly expressed in the poor-differentiated human HCC cells and associated with cell migration and invasion. In this study, we further investigated the gene regulation of this enzyme. We showed that PKCalpha expression enhancement in the poor-differentiated human HCC cells was found neither by DNA amplification nor by increasing mRNA stability using differential PCR and mRNA decay assays. After screening seven transcription factors in the putative cis-acting regulatory elements of human PKCalpha promoters, only Elk-1 and MZF-1 antisense oligonucleotide showed a significant reduction in the PKCalpha mRNA level. They also reduced cell proliferation, cell migratory and invasive capabilities, and DNA binding activities in the PKCalpha promoter region. Over-expression assay confirmed that the PKCalpha expression may be modulated by these two factors at the transcriptional level. Therefore, these results may provide a novel mechanism for PKCalpha expression regulation in human HCC cells.

Cell Line, Tumor↗
PubMed2005

Human cornea construct HCC-an alternative for in vitro permeation studies? A comparison with human donor corneas.

Transcorneal in vitro permeation studies of ophthalmic drugs are normally performed with either excised animal corneas or latterly corneal cell culture models. A good correlation between these models and excised animal corneas regarding permeation behaviour of drugs has already been shown. However, comparisons between corneal in vitro models containing human cells and excised human corneas do not exist yet. Therefore in the present study the transcorneal permeation of six different model drugs (pilocarpine hydrochloride, befunolol hydrochloride, hydrocortisone, diclofenac sodium, clindamycin hydrochloride and timolol maleate) across our previously described three-dimensional organotypic human cornea construct (HCC) was tested using Franz diffusion cells and compared with permeation data obtained from human donor corneas. The HCC showed a similar permeation behaviour compared with human donor cornea for all substances. The permeabilities (permeation coefficients P) of the human cornea equivalent versus the human donor cornea were the same in the case of diclofenac, clindamycin, timolol, but marginally decreased for hydrocortisone and slightly increased for pilocarpine and befunolol. These small differences of permeation coefficients were expressed as factors and only varied from 0.8 to 1.4. The results indicate that the HCC may be an alternative for in vitro permeation studies and appropriate for predicting drug absorption into the human eye.

Cell Line↗
PubMed2002

Interplays between genetic and environmental mechanisms trigger tumorigenic VEGF signalling in human HCC cell lines: pilot study.

The 'angiogenic switch' concept has been used to discover various pro- and anti-angiogenic molecules as pharmacotherapeutic strategies for cancers and other ischemic and inflammatory diseases; however, surprisingly little is known about the 'tumor angiogenic switch' in response to complex interplay between environmental and genetic mechanisms that are most importantly, hypothesis-driven, largely unsolved at the postgenomic level. The present study's aim is to identify those interplays between the expressing green fluorescence protein (EGFP) transcript and redox-driven vascular endothelial growth factor (VEGF) upstream mechanisms that influence tumorigenic VEGF signalling, by using multifactorial orthogonal statistical analyses, the non-transfected and transfected human hepatocellular carcinoma (HCC) cell lines, and quantitative 'sandwich' Elisa immunoassays. The unique results indicate valuable findings on the postgenomic level as follows. Fusion of the EGFP significantly triggers tumorigenic VEGF signalling in three E3-, F11- and A(3-1)-transfected human HCC cell lines, compared with the parental EGFP-free malignant hepatocellular carcinoma (MHCC)1 cell line; Redox-regulated VEGF upstream mechanism interplays dramatically mediate dual responses, either down- or upregulating tumorigenic VEGF signalling, which depends on individual post-transcriptional regulation or upstream modification of the VEGF promoter in the three MHCC1, SMCC7721 and doxorubicin-resistance 7402/D+ non-transfected human HCC cell lines; and mechanism-based strategies for stimulating beta-adrenergic and P2-purinergic signal transduction and counteracting O2 and Ca2+-inflow significantly trigger tumorigenic VEGF signalling in ATRA/ATRP-driven networks, compared with controls of the non-transfected cell types examined. The contrast data offer first pilot paradigms of searching for hypothesis-driven multifactorial interplays on tumorigenic VEGF signalling, which are valuable for further deciphering postgenome-wide VEGF upstream regulatory networks of switching on the tumor angiogenesis, and developing mechanism-based novel pharmacotherapeutic strategies.

Carcinoma, Hepatocellular↗
PubMed1999

A case-control study on family history of liver cancer as a risk factor for hepatocellular carcinoma in North Italy. Brescia HCC Study.

OBJECTIVES: We carried out a case-control study to investigate the role of history of liver cancer in a first-degree relative as a risk factor for hepatocellular carcinoma (HCC). METHODS: Two hundred eighty-seven HCC incident cases and 450 subjects unaffected by liver disease (controls) were enrolled in the study. Family history of liver cancer and other malignancies and history of alcohol intake were collected by face-to-face interview. Blood samples were analyzed for HBsAg, anti-HCV and HCV RNA positivity. RESULTS: Family history of liver cancer was associated with HCC (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.2-4.7), whereas family history of other malignancies was not (OR = 1.0; 95% CI = 0.61.5). An increased OR for family history of liver cancer was found among subjects negative for the other risk factors (OR = 2.0; 95% CI = 0.6-6.9). A synergism of family history of liver cancer was also evident with hepatitis B and hepatitis C virus infection and with heavy alcohol intake. CONCLUSIONS: This study suggests a role of family history independent from and interacting with known risk factors for hepatocellular carcinoma.

Adult↗