Association between the presence of H pylori in the liver and hepatocellular carcinoma： A meta-analysis

AIM： To evaluate the arguments for and against the possible roles of H pylori in hepatocellular carcinoma （HCC）.
METHODS： We performed a systematic review of all relevant studies published in the literature. A total of 103 clinical trials and reports were identified, but only 10 trials qualified under our selection criteria. A metaanalysis was carried out by a biostatistician according to the Cochrane Reviewers＇ Handbook recommended by The Cochrane Collaboration.
RESULTS： Nine case-control studies and one retrospective cross sectional study were included in the final analysis. Overall the prevalence of H pylori infection was 53.3% （129 of 242） in cases and 10.4% （29 of 280） in controls, and the summary odds ratio for the association of H pylori infection with the risk for HCC （using the fixed-effects model, which accounted for the homogeneity across the 10 studies） was determined to be 13.63 （95% CI, 7.90-23.49）.
CONCLUSION： Our analysis showed a positive association between F1 pylori infection and the risk of HCC, with an indication of possible publication bias and possible confounders due to study designs that showed results of less pronounced associations.     

Relationship between microvessel density and telomerase activity in hepatocellular carcinoma

AIM:To study the relationship between microvessel density(MVD),telomerase activity and biological characteristicsin hepatocellular carcinoma(HCC).METHODS:S-P immunohistochemical method andtelomeric repeat amplification protocol(TRAP)wererespectively used to analyze the MVD and telomeraseactivity in 58 HCC and adjacent normal tissues,RESULTS:The MVD in HCC with metastasis,lowerdifferentiation or without intact capsule was significantlyhigher than that in HCC with intact capsule,higherdifferentiation,or without metastasis,While MVD had norelationship with tumor size,hepatic virus infection andother clinical factors.Telomerase activity was related todifferentiation degree,but not to tumor size or histologicalgrade.MVD in HCC with telomerase activity was higherthan that in HCC without telomerase activity.CONCLUSION:MVD and telomerase activity may serveas diagnostic criteria of HCC in earlier stage.Meanwhile,there may be a cooperative effect between MVD andtelomerase on the growth and metastasis of HCC.     

Gender difference in clinicopathologic features and survival of patients with hepatocellular carcinoma

AIM: To determine the influence of gender on theclinicopathologic characteristics and survival of patients withhepatocellular carcinoma (HCC).METHODS: A retrospective analysis of medical records wasperformed in 299 patients with HCC and their clinicopathologicfeatures and survival were compared in relation to gender.RESULTS: There were 260 male (87%) and 39 femalepatients (13%),with a male-to-female ratio of 6.7:1.Femalepatients had lower mean serum bilirubin levels (P=0.03),lower proportion of alcohol abuse (P=0.002),smaller meantumor size (P=0.02),more frequent nodular type but lessfrequent massive and diffuse types of HCC (P=0.01),wereless advanced in Okuda's staging (P=0.04),and lessfrequently associated with venous invasion (P=0.03).Themedian survivals in females (14 too) were significantly longerthan that of male patients (4 mo) (P=0.004,log-rank test).Multivariate analysis demonstrated that high serum alpha-fetoprotein levels,venous invasion,extrahepatic metastasisand lack of therapy were independent factors related tounfavorable prognosis.However,gender did not constitutea predictive variable associated with patient survival.CONCLUSION: Female patients tend to have highersurvival rates than males.These differences were probablydue to more favorable pathologic features of HCC at initialdiagnosis and greater likelihood to undergo curative therapyin female patients.     

α-Fetoprotein,tissue polypeptide antigen and ferritin in diagnosing primary hepatocellular carcinoma in patients with liver cirrhosis

Summary This study was undertaken in order to compare the usefulness of three indices of tumour proliferation in detecting primary hepatocellular carcinoma (HCC) and in differentiating this neoplasm from liver cirrhosis. In 10 patients with HCC and in 63 with liver cirrhosis serum -fetoprotein (AFP), tissue polypeptide antigen (TPA) and ferritin were assayed. Increased levels of AFP but not of TPA and ferritin were observed in HCC as compared to liver cirrhosis. The receiver-operating characteristic curves demonstrated that AFP is more discriminating between HCC and liver cirrhosis than the other two markers. Correlations between liver function tests and serum markers were observed in liver cirrhosis but not in HCC. We can conclude that AFP is more useful than TPA and ferritin in detecting HCC in patients with liver cirrhosis, owing to the high frequency of false positive results of the latter two indices in liver cirrhosis. Liver dysfunction is probably involved in increasing all these markers of malignancy, thus reducing the specificity of these tests.Abbreviations AFP -tetoprotein - TPA tissue polypeptide antigen - HCC primary hepatocellular carcinoma Partially supported by a grant of the Italian National Research Council, Special Project Oncology, contract 87.01.541.04. Under the auspices of the R. Farini association for gastroenterological research     

Combined measurement of serum tumor markers in patients with hepatocellular carcinoma

ＣｏｍｂｉｎｅｄｍｅａｓｕｒｅｍｅｎｔｏｆｓｅｒｕｍｔｕｍｏｒｍａｒｋｅｒｓｉｎｐａｔｉｅｎｔｓｗｉｔｈｈｅｐａｔｏｃｅｌｕｌａｒｃａｒｃｉｎｏｍａＣＡＩＷｅｎＸｉｕ，ＺＨＥＮＧＨｕｉ，ＳＨＥＮＧＪｉａｎａｎｄＹＥＱｉｎｇＬｉｎＳｕｂｊｅｃｔｈ...     

Impairment of IFN-a production capacity in patients with hepatitis C virus and the risk of the development of hepatocellular carcinoma

AIM: To determine the utility of interferon (IFN) -α production capacity in patients with hepatitis C virus (HCV) infection for the measurement of immuno-surveillance potential and for the early detection of hepatocellular carcinoma (HCC) by investigating the Sendai virus (HVJ) stimulated IFN-α production capacity of patients with HCV infection. METHODS: HVJ stimulated IFN-α production was determined in a large number of patients with HCV infection and the development of HCC was monitored for 3 years in patients with liver cirrhosis (LC). RESULTS: IFN-α production capacity decreases gradually with the progression of liver disease from chronic hepatitis (CH) to HCC. A significant correlation between the duration of HCV infection and impaired IFN-α production capacity was observed. IFN-α production in patients who developed HCC within 3 years was significantly lower than that of patients who remained in LC without developing HCC. CONCLUSION: Measurement of IFN-α production in LC patients may be useful for the early detection of HCC.     

Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy： Potential role of insulin

AIM： To investigate the relationships between Type 2 diabetes mellitus （DM2） and the risk of hepatocellular carcinoma （HCC）.
METHODS： We studied the association between DM2 and HCC in a large case-control study that enrolled 465 consecutive Caucasian patients with HCC （78.3% males, mean age 68.5 ± 8.9 years） compared with an age and sex matched control group of 490 subjects. RESULTS： Prevalence of DM2 was significantly higher in HCC patients （31.2% vs 12.7%; OR = 3.12, 95% CI： 2.22-4.43） and in HCC cases with alcohol abuse. DM2 has been diagnosed before the appearance of HCC in 84.1% of diabetic HCC subjects with mean duration of 141.5 mo, higher in cases treated with insulin than in those with oral antidiabetic agents （171.5 vs 118.7 mo）. Compared to controls, males DM2 with HCC were more frequently treated with insulin （38.1% vs 17.6%, P = 0.009） and with sulfonylurea with or without metformin than with diet with or without metformin （84% vs 68.3%, P = 0.049）. CONCLUSION： DM2 in our patients is associated with a 3-fold increase risk of HCC. In most of our cases DM2 pre-existed to HCC. Patients with DM2 and chronic liver disease, particularly insulin treated males, should be considered for HCC close surveillance programs.     

Decreased serum levels of β-carotene in patients with hepatocellular carcinoma

The serum levels of β-carotene were determined in patients with liver disease. β-Carotene levels in the patients with chronic hepatitis (CH) were comparable with the reported normal values. However, the levels decreased significantly in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Furthermore, the β-carotene levels of the HCC patients were significantly lower than those of the LC patients. The male patients had significantly lower levels of β-carotene than the female patients with CH and LC, but not with HCC. Possible contribution of the lower serum levels of β-carotene to the pathogenesis of hepatocellular carcinoma is discussed.     

Clinicopathological characteristics of 15 patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancer, and clinicopathological features of cHCC-CC have seldom been reported in detail. This study was undertaken to explore the diagnosis and clinicopathological characteristics of cHCC-CC in comparison with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), respectively. METHODS: The clinical data from 15 patients with cHCC-CC, 132 patients with HCC and 44 patients with CC who had undergone hepatic resection were analyzed retrospectively. Clinicopathological characteristics of cHCC-CC, HCC and CC such as hepatitis B viral infection, serum hepatitis C virus (HCV) antibody, serum alpha-fetoprotein (AFP) level, cirrhosis, vascular invasion, lymph node metastasis, surgical procedure and adjuvant treatment were also analyzed. Follow up was carried out in the patients, and their 1-, 3-, and 5-year survival rates were calculated. RESULTS: Two patients with cHCC-CC were correctly diagnosed by enhanced CT before operation, the other 13 patients were diagnosed by histology and immunohistochemistry after operation. Radical (8/15) and conservative hepatectomy (7/15) for cHCC-CC was similar to that for HCC and CC (P>0.05). Pathologically cHCC-CC showed more significantly vascular invasion and lymph node metastasis than HCC (P<0.05), and a similarity to CC (P>0.05). Hepatitis B viral infection, serum HCV antibody, cirrhosis, and serum AFP level of cHCC-CC patients were similar to those of HCC patients(P>0.05) but different from CC patients (P<0.05). The cumulative 1-, 3-, and 5-year survival rates in patients with cHCC-CC were poorer than in patients with HCC or CC (P<0.05). CONCLUSIONS: Patients with cHCC-CC are seldom diagnosed before operation. The progression of cHCC-CC is more rapid than that of HCC or CC. Survival rate of patients with cHCC-CC after hepatic resection is poorer than that of patients with HCC or CC.     

Transcatheter arterial infusion chemotherapy with cisplatin–lipiodol suspension in patients with hepatocellular carcinoma

Purpose  

The aim of this study was to investigate the antitumor efficacy of treatment, identify prognostic factors, and construct a prognostic index in patients with hepatocellular carcinoma treated by transcatheter arterial infusion chemotherapy (TAI) using cisplatin suspended in lipiodol.     

Impairment of IFN-α production capacity in patients with hepatitis C virus and the risk of the development of hepatocellular carcinoma

AIM: To determine the utility of interferon (IFN)-alpha production capacity in patients with hepatitis C virus (HCV) infection for the measurement of immuno-surveillance potential and for the early detection of hepatocellular carcinoma (HCC) by investigating the Sendai virus (HVJ) stimulated IFN-alpha production capacity of patients with HCV infection.METHODS: HVJ stimulated IFN-alpha production was determined in a large number of patients with HCV infection and the development of HCC was monitored for 3 years in patients with liver cirrhosis (LC).RESULTS: IFN-alpha production capacity decreases gradually with the progression of liver disease from chronic hepatitis (CH) to HCC. A significant correlation between the duration of HCV infection and impaired IFN-alpha production capacity was observed. IFN-alpha production in patients who developed HCC within 3 years was significantly lower than that of patients who remained in LC without developing HCC.CONCLUSION: Measurement of IFN-alpha production in LC patients may be useful for the early detection of HCC.     

Can large cell change and high proliferative activity predict hepatocellular carcinoma in patients with hereditary hemochromatosis?

OBJECTIVE: Patients with hereditary hemochromatosis are at high risk of developing hepatocellular carcinoma. This study was undertaken to define whether large cell change and nucleolar organizer regions proliferative index (marker of high proliferative activity) predict hepatocellular carcinoma development in hereditary hemochromatosis. METHODS: Histological staining for large cell change and high proliferative activity were done on baseline liver biopsies of 74 patients with hereditary hemochromatosis (52 with and 22 without cirrhosis), prospectively followed-up for 83 +/- 53 months (range, 1-230 months). RESULTS: Large cell change and high proliferative activity were found only in cirrhotic patients; 16 of 52 patients (31%) had either the large cell change or high proliferative activity. Large cell change was more frequent in patients with hepatitis B surface antigen than in those positive for hepatitis C virus (57% vs 14%, p = 0.04). Hepatocellular carcinoma developed in 7 of 16 (44%) and in 6 of 36 patients (16%) of the patients positive or negative for these morphological variables. The probability of developing hepatocellular carcinoma at 7 yr of follow-up was significantly higher in patients with large cell change or high proliferative activity than in those without. The length of follow-up from baseline histology to hepatocellular carcinoma occurrence was shorter in patients with large cell change or high proliferative activity than in those without these changes (46 +/- 36 and 109 +/- 34 months, p = 0.01). A multivariate analysis indicated that in patients with cirrhosis, large cell change or high proliferative activity (considered as a single variable), and age >55 yr were the only independent variables significantly associated with the risk of developing hepatocellular carcinoma, with a risk ratio of 4.8 (confidence interval 1.2-18.2) and 4.0 (confidence interval 1.1-15.6), respectively. CONCLUSIONS: In hereditary hemochromatosis, the presence of large cell change or high proliferative activity in patients older than 55 yr with cirrhosis should be considered a strong predictor of hepatocellular carcinoma development, especially if hepatitis B virus infection coexists.     

Inhibitory effect of dimeric β peptide on the recurrence and metastasis of hepatocellular carcinoma in vitro and in mice

AIM：To block the adhesion of tumor cells to the extracellular matrix, and prevent tumor metastasis and recurrence, the dimer of the β peptide （DLYYLMDLSYSMKG- GDLYYLMDLSYSMK, β2） was designed and synthesized and its anti-adhesion and anti-invasion effects on hepa- tocellular carcinoma cells were assessed. Additionally, its influence on the metastasis and recurrence of mouse hepatocellular carcinoma was measured.
METHODS：The anti-adhesion effect of β2 on the highly metastatic hepatocellular carcinoma cell line HCCLM6 cells and fibronectin （FN） was assayed by the MTT as- say. The inhibition of invasion of HCCLM6 cells by β2 was observed using a Transwell （modified Boyden chamber） and matrigel. Using the hepatocellular carcinoma metas- tasis model and LCI-D20 nude mice, the influence of β2 on the metastasis and recurrence of hepatocellular carci- noma after early resection was investigated.
RESULTS：HCCLM6 cells co-incubated with 100 mmol/L, 50 mmol/L, 20 mmol/L or 10 mmol/L β2 for 3 h showed an obvious decrease in adhesion to FN. The adhesion inhibition ratios were 11.8%, 21.7%, 29.6% and 48.7%, respectively. Additionally, HCCLM6 cells cultured with 100 mmol/L β2 had a dramatic decrease in cell invasion. β2 was also observed to inhibit the incisal edge recur- rence and the distant metastasis of nude mice hepato- cellular carcinoma after early resection （P 〈 0.05）.
CONCLUSION：The β2 peptide can specifically block the adhesion and invasion of HCCLM6 cells, and can inhibit HCC recurrence and metastasis of LCI-D20 model pos-thepatectomy in vivo. Thus, β2 should be further studied as a new anti-tumor drug.     

Performance of serum α-fetoprotein levels in the diagnosis of hepatocellular carcinoma in patients with a hepatic mass

Objectives

The role of serum α-fetoprotein (AFP) measurements in the diagnosis of hepatocellular carcinoma (HCC) remains controversial. Some guidelines have advised against the use of AFP in the diagnosis of HCC. This study was conducted to evaluate the performance of AFP in the diagnosis of HCC, and to identify the optimal cut-off value of serum AFP in the diagnosis of HCC in patients with a hepatic mass.

Methods

Patients who presented during the period from May 1997 to March 2003 with hepatic lesions, for whom paired data on serum AFP values at baseline and lesion histology were available, were reviewed. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis.

Results

Data for a total of 805 patients were evaluated. The mean AFP value was 26 900 ng/ml (range: 0–1 965 461 ng/ml). The histological diagnosis was HCC in 557 patients. The optimal AFP cut-off value was 10 ng/ml (for sensitivity of 82.6% and specificity of 70.4%). At a cut-off level of 200 ng/ml, sensitivity, specificity, and positive and negative predictive values were 47.7%, 97.1%, 97.5% and 44.4%, respectively. The diagnostic performance of AFP remains similar in patients with chronic hepatitis B virus infection, despite a lower negative predictive value. Common aetiologies of liver lesions associated with elevated AFP include cholangiocarcinoma and neuroendocrine tumours.

Conclusions

In Asian patients with suspicious liver lesions, the cut-off AFP level of 200 ng/ml is useful to achieve a diagnosis of HCC with high specificity and reasonable sensitivity. The measurement of serum AFP should not be excluded from guidelines for the diagnosis of HCC.     

A model to estimate survival in ambulatory patients with hepatocellular carcinoma: Can it predict the natural course of hepatocellular carcinoma?

BackgroundSeveral hepatocellular carcinoma (HCC) staging systems are available including the newly developed staging system, the Model to Estimate Survival in Ambulatory HCC patients (MESIAH); however, whether these staging systems could predict the natural course of HCC is largely unknown.Methods1013 patients with history of HCC treatment and 111 patients without any history of treatment till death or last follow-up at a single tertiary hospital were included.ResultsThe MESIAH score showed a better discrimination ability, with a C-statistic of 0.835 [95% confidence interval (CI), 0.810–0.861] in the group of treated patients compared to the Barcelona Clinic Liver Cancer (BCLC) staging system [0.739 (95% CI, 0.709–0.769)] before propensity score matching. However, the MESIAH score failed to stratify patients according to their risk of death in the group of untreated patients unlike the BCLC staging system. Propensity score matching analysis confirmed that the MESIAH score was most strongly influenced by whether treatment was given or not.ConclusionsAlthough the MESIAH score provided better prognostic stratification than other staging systems in treated HCC patients, it was not helpful in predicting the natural course of HCC. Since the treatment affects patient outcome and prognosis, it is necessary to develop a new staging system that can also reflect the natural course of HCC.     

Helicobacter species sequences in liver samples from patients with and without hepatocellular carcinoma

AIM:Only a minority of patients carrying a defined viralaetiologic agent develop cirrhosis and ultimatelyhepatocellular carcinoma(HCC),the mechanism underlyingthe worsening is still undefined.Experimental infection byHelicobacter hepaticus in mice causes chronic hepatitis andHCC and recently,more Helicobacterspecies(Helicobacterspp.)have been detected in the liver of patients sufferingfrom cholestatic diseases and HCC arising from non-cirrhoticliver.We investigated whether Helicobacterspp.sequencescould be detected in the liver of patients with cirrhosis andHCC compared to subjects with metastasis to liver fromcolon cancer.METHODS:Twenty-three liver samples from patientsoperated upon for HCC superimposed on hepatitis C virus(HCV)-related cirrhosis and 6 from patients with resectedmetastases from colorectal cancer,were tested by polymerasechain reaction for presence of genomic 16S rRNA ofHelicobacter genus using specific primers.DNA sequencingand cag A gene analysis were also performed.RESULTS:Genornic sequences of Helicobacter spp.werefound in 17 of 20(85%)liver samples from patients withHCC and in 2 of 6 samples from patients with liver metastasis.In three samples of the first group the result was uncertain.Hpyloriwas revealed in 16 out of 17 positive samples andHelicobacter pullorum in the other.CONCLUSION:Helicobacter spp.,carcinogenic in mice,were found at a higher frequency in the liver of patientswith HCV-related cirrhosis and HCC than those in patientswithout primary liver disease.     

Recommendations for the use of chemoembolization in patients with hepatocellular carcinoma: Usefulness of scoring system?

Several hepatocellular carcinoma (HCC) staging systems have been established, and a variety of country-specific treatment strategies are also proposed. The barcelona - clinic liver cancer (BCLC) system is the most widely used in Europe. The Hong Kong liver Cancer is a new prognostic staging system; it might become the reference system in Asia. Transarterial chemoembolization (TACE) is the most widely used treatment for HCC worldwide; but it showed a benefit only for intermediate stage HCC (BCLC B), and there is still no consensus concerning treatment methods and treatment strategies. In view of the highly diverse nature of HCC and practices, a scoring system designed to assist with decision making before the first TACE is performed or prior to repeating the procedure would be highly useful.