non-B non-C Hepatocellular Carcinoma Patients Research Articles

Preoperative ALBI grade predicts the outcomes in non-B non-C HCC patients undergoing primary curative resection

BackgroundThe albumin–bilirubin (ALBI) grade has been validated as a significant prognostic predictor for hepatocellular carcinoma (HCC). However, there is little information about the ALBI grade in patients with non-B non-C HCC (NBNC-HCC) receiving surgery.AimThis study aimed to evaluate the prognostic significance of the ALBI grade in patients with NBNC-HCC after primary curative resection.MethodFrom January 2010 to April 2016, 2137 patients with HCC who received hepatectomy were screened for study eligibility. Finally, a total of 168 NBNC-HCC patients who received primary curative resection were analyzed. The impacts of the ALBI grade on disease-free survival (DFS) and overall survival (OS) were analyzed by multivariate analysis.ResultsThere were 66 (39.3%), 98 (58.3%), and 4 (2.4%) patients with an ALBI grade of I, II, and III, respectively. Patients with an ALBI grade II/III were older (p = 0.002), more likely to have hypoalbuminemia (p < 0.001), and more commonly had Child–Pugh class B (p = 0.009) than patients with an ALBI grade I. After a median follow-up of 76 months, 74 (44%) patients experienced recurrence, and 72 (42.9%) patients died. Multivariate analysis revealed that alpha-fetoprotein (AFP) > 200 ng/mL (p = 0.021), number of tumors (p = 0.001), and tumor stage (p = 0.007) were independent prognostic factors for DFS. Additionally, AFP > 200 ng/mL (p = 0.002), ALBI grade II/III (p = 0.002), and tumor stage (p < 0.001) were independent risk factors for poor OS.ConclusionThe preoperative ALBI grade can be used to predict mortality in patients with NBNC-HCC after primary curative resection.

Increased Visceral Adipose Tissue and Hyperinsulinemia Raise the Risk for Recurrence of Non-B Non-C Hepatocellular Carcinoma after Curative Treatment.

Simple SummaryWith the increasing prevalence of obesity and diabetes in most countries, the increase in hepatocellular carcinoma (HCC) associated with these factors has recently become a serious healthcare problem. HCC can often emerge in the non-cirrhotic liver among obese patients, and it might suggest that the conventional surveillance strategies for HCC, which is mainly targeted at cirrhotic patients with hepatitis B or C virus, might be insufficient in the overnutrition era. We tried to extract factors that affect recurrence-free survival in patients with non-viral HCC, among obesity and diabetes factors, together with the established recurrence risk factors, using a decision-tree analysis.We investigated the factors affecting recurrence-free survival in patients with non-B non-C hepatocellular carcinoma (HCC) who received curative treatment. Decision-tree analysis was performed in 72 curative cases of non-B non-C HCC to extract the risk factors for recurrence. The reliability of the extracted risk factors was evaluated using the Kaplan–Meier method and the Cox proportional hazards model. The decision-tree analysis extracted three factors—visceral adipose tissue (VAT) index (VATI; <71 and ≥71 cm2/m2), which was the cross-sectional areas of VAT on the computed tomographic image at the umbilical level, normalized by the square of the height, fasting immunoreactive insulin (FIRI; <5.5 and ≥5.5 µU/mL), and alpha-fetoprotein (AFP; <11 and ≥11 ng/mL). The Cox proportional hazards model showed that VATI (hazard ratio (HR): 2.556, 95% confidence interval (CI): 1.191–5.486, p = 0.016), FIRI (HR: 3.149, 95% CI: 1.156–8.575, p = 0.025), and AFP (HR: 3.362, 95% CI: 1.550–7.288, p = 0.002) were all independent risk factors for HCC recurrence. Non-B non-C HCC patients with a higher VATI (≥71 cm2/m2) or higher FIRI (≥5.5 µU/mL) and AFP (≥11 ng/mL) if VATI was <71 cm2/m2 are prone to recurrence after curative treatment.

Early detection of hepatocellular carcinoma in patients with diabetes mellitus.

Diabetes mellitus is a risk factor for non-B, non-C hepatocellular carcinoma (NBNC-HCC); however, the number of diabetes mellitus patients is too large to examine tumor occurrence with periodic imaging modalities. Thus, the aim of this study was to develop a novel strategy for early detection of NBNC-HCC in diabetes mellitus patients. Ninety-three diabetes mellitus patients who had a single NBNC-HCC tumor less than 2 cm in diameter were selected from 6789 HCC patients. As controls, 172 tumor-free diabetes mellitus patients were enrolled. Characteristics were compared between groups. Furthermore, the efficacy of FIB4A, a new integrated score with FIB4 and alpha-fetoprotein, was analyzed as a marker for the early diagnosis of NBNC-HCC. Age, percentage of males, alcohol consumption, total bilirubin, transaminases, γ-glutamyl transpeptidase, FIB4 index, alpha-fetoprotein, and des-gamma-carboxy-prothrombin were higher in NBNC-HCC patients, whereas albumin and platelet counts were higher in the diabetes mellitus control group. Among these factors, the FIB4 index showed the highest odds ratio [OR: 20.0, 95% confidence interval (CI): 9.60-41.7] followed by alpha-fetoprotein (OR: 12.8, 95% CI: 6.53-25.4). A newly developed score, FIB4A, showed the highest area under the receiver operating characteristic curve (0.959) among the factors examined. The sensitivity was 86.2% at a Youden index cutoff (3.5) and it increased to 95.4%, while keeping high specificity (70.9%) when a cutoff of 2.5 was used. FIB4A is a potential marker for early detection of NBNC-HCC in patients with diabetes mellitus. However, further studies are needed to confirm these findings.

Outcomes of Non-B Non-C Hepatocellular Carcinoma with Reference to Patients with Interferon-Induced Hepatitis C Virus Eradication

PurposeThis study aimed to evaluate survival outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC) with reference to patients with HCC achieving sustained virological response (SVR) by preoperative interferon (IFN) treatment for chronic hepatitis C. MethodsWe examined 781 patients who underwent hepatic resection for HCC. They were classified into NBNC-HCC, SVR-HCC, and non-SVR HCC groups. ResultsMultivariate analysis for recurrence-free survival (RFS) and overall survival (OS) revealed that the adjusted hazard ratios (HR) of NBNC-HCC and non-SVR HCC groups with reference to the SVR-HCC group were 1.46 (p = 0.10) and 2.10 (p < 0.001), respectively, for RFS, and 1.69 (p = 0.024) and 2.11 (p < 0.001), respectively, for OS. Worsening of Child–Pugh grade at recurrence was confirmed in 21 patients (17.1%) with NBNC-HCC but not in those with SVR-HCC (p = 0.017, SVR vs. NBNC). In the NBNC-HCC group, hepatic resection for intrahepatic recurrence was adopted in 17.4% of patients without worsening of Child–Pugh grade at recurrence, whereas hepatic resection was not adopted in those with grade worsening. Among patients with alcoholic hepatitis, Child–Pugh grade worsening at recurrence was more frequently observed in patients with sobriety than those without sobriety (14.3% vs. 46.2%, p = 0.049). ConclusionsNBNC-HCC patients had an increased risk for overall death as compared with those with SVR-HCC. Worsening of background liver function may reduce the chances of re-hepatic resection for recurrence and increase the risk for overall death in NBNC-HCC patients. For alcoholic hepatitis patients, sobriety may prevent deterioration of liver function after surgery.

Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection: a subgroup analysis of patients without chronic hepatitis viral infection

BackgroundStatins have been reported to reduce the risk of hepatocellular carcinoma (HCC). The effect of perioperative statin use on the prognosis of HCC patients undergoing liver resection remains unclear. MethodsWe retrospectively analyzed 643 patients who underwent curative liver resection for HCC. Patients negative for hepatitis B surface antigen and hepatitis C antibody were classified as the non-B non-C HCC subgroup (n = 204). Perioperative statin users were defined as patients preoperatively receiving statin medications and maintaining > 28 cumulative defined daily doses after liver resection. The recurrence-free survival (RFS) and overall survival (OS) according to statin use were analyzed in the overall HCC cohort or in the non-B non-C HCC subgroup. ResultsAmong a total of 643 (HCC) patients, 43 patients (6.7%) received perioperative statin medications. In statin users, the proportion of non-B non-C HCC patients was significantly higher than in nonstatin users. Statin users had a high prevalence of obesity and diabetes, as well as dyslipidemia. The liver function of statin users was better than that of nonstatin users. The multivariate survival analysis revealed that use of statins was significantly associated with improvement of RFS (hazard ratio [HR], .42; 95% confidence interval [CI], 0.25–0.71; P = .001), but not with OS (HR, 0.62; 95% CI, 0.30–1.27; P = .19). In the subgroup analysis of the non-B non-C HCC cohort, statin use was significantly associated with improvement of RFS (HR, 0.47; 95% CI, 0.22–0.99; P = .04). ConclusionPerioperative statin use was associated with an improvement of RFS in HCC patients undergoing curative liver resection.

Associations between antibody to hepatitis B core antigen positivity and outcomes in hepatocellular carcinoma patients undergoing hepatic resection.

We aimed to evaluate the effect of antibody to hepatitis B core antigen (HBcAb) positivity on clinical outcomes after hepatic resection in hepatocellular carcinoma (HCC) patients with negative hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb), termed non-B, non-C HCC (NBNC-HCC), or with HCV-related HCC. Two hundred and sixty-three patients who underwent hepatic resection for HCC and measurements of HBsAg, HCVAb, and HBcAb were enrolled in this study. The percentages of HBcAb positivity were 52.3% (n = 57) and 56.9% (n = 66) in patients with NBNC- and HCV-related HCC, respectively. The proportion of multiple NBNC-HCCs was significantly greater in patients with HBcAb positivity compared to HBcAb negativity (P = 0.028). There were no significant differences in the recurrence-free and overall survival rates between NBNC-HCC patients with HBcAb positivity versus negativity (P = 0.461 and P = 0.190, respectively). Furthermore, for HCV-related HCC patients, there were no significant differences in the baseline factors between patients with positive versus negative HBcAb. The proportion of patients with HBcAb-positive HCV-related HCC who underwent anatomical resection of the liver was significantly greater than that of HBcAb-negative patients, whereas the recurrence-free and overall survival rates were not significantly different (P = 0.158 and P = 0.191, respectively). In our study, the presence of HBcAb had no impact on surgical outcomes after hepatic resection in patients with NBNB- and HCV-related HCC. Occult HBV infection might be associated with hepatocarcinogenesis in patients with NBNC-related HCC.

Clinical characteristics and prognosis of non-B, non-C hepatocellular carcinoma: The impact of patient sex on disease-free survival - A retrospective cohort study

BackgroundThe number of patients with hepatocellular carcinoma (HCC) negative for both hepatitis B virus surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb) has increased recently. The purpose of the present study was to investigate the clinical characteristics and prognoses of non-B non-C HCC (NBNC-HCC) patients. Materials and methodsFrom January 2000 to December 2013, 154 patients with NBNC-HCC and 560 patients with HBsAg or HCVAb positive (BC)-HCC who underwent curative resection were analyzed retrospectively. The clinical features of NBNC-HCC and BC-HCC were compared, and the prognoses of NBNC-HCC patients were analyzed. ResultsIn comparison to patients with BC-HCC, patients with NBNC-HCC had better liver function but higher pathological tumor stages. The disease-free survival (DFS) duration was significantly higher in patients with NBNC-HCC than it was in those with BC-HCC. In patients with NBNC-HCC, aspartate aminotransferase ≥40 IU/L, albumin level <3.5 g/dL, and multiple tumors were independent risk factors of overall survival; and male sex and multiple tumors were independent risk factors of DFS. ConclusionPatients with NBNC-HCC had significantly longer DFS durations than those with BC-HCC. The patient sex had an impact on the postsurgical outcomes of patients with NBNC-HCC in DFS.

Impact of smoking habit on surgical outcomes in non-B non-C patients with curative resection for hepatocellular carcinoma.

AIMTo analyzed the correlation between smoking status and surgical outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC), and we investigated the patients’ clinicopathological characteristics according to smoking status.METHODSWe retrospectively analyzed the consecutive cases of 83 NBNC-HCC patients who underwent curative surgical treatment for the primary lesion at Saga University Hospital between 1984 and December 2012. We collected information about possibly carcinogenic factors such as alcohol abuse, diabetes mellitus, obesity and smoking habit from medical records. Smoking habits were subcategorized as never, ex- and current smoker at the time of surgery. The diagnosis of non-alcoholic steatohepatitis (NASH) was based on both clinical information and pathological confirmation.RESULTSAlcohol abuse, diabetes mellitus, obesity and NASH had no significant effect on the surgical outcomes. Current smoking status was strongly correlated with both overall survival (P = 0.0058) and disease-specific survival (P = 0.0105) by multivariate analyses. Subset analyses revealed that the current smokers were significantly younger at the time of surgery (P = 0.0002) and more likely to abuse alcohol (P = 0.0188) and to have multiple tumors (P = 0.023).CONCLUSIONCurrent smoking habit at the time of surgical treatment is a risk factor for poor long-term survival in NBNC-HCC patients. Current smokers tend to have multiple HCCs at a younger age than other patients.

Compliance and problems with the surveillance program for HCC diagnosis.

We conducted a multicenter retrospective study for evaluating the background of and diagnostic opportunity for 651 patients with primary hepatocellular carcinoma (HCC). The etiologies were hepatitis B virus (HBV) in 20.0% of patients, hepatitis C virus (HCV) in 36.3%, and non-B non-C (NBNC) in 43.5%. The characteristics of non-alcoholic NBNC HCC patients included low frequency of liver cirrhosis and high frequency of life style-related diseases. The mean diameter of HCC was approximately 4cm. Most patients were diagnosed using ultrasonography and dynamic computed tomography (CT). However, 18.6% of patients were diagnosed using conventional contrast-enhanced CT. Compliance with the surveillance program for HCC diagnosis was 35.4% in HBV carriers and 49.2% in HCV carriers. The main causes of deviation from the program included undiagnosed HBV and HCV carriers, non-compliance with the surveillance program by physicians, and no medical care for HBV and HCV carriers. For an early diagnosis of HCC, it is essential to improve the diagnoses of HBV and HCV carriers, promote the follow-ups of HBV and HCV carriers in hospitals, re-educate physicians, and identify the risk factors of NBNC HCC.

Clinical characteristics and potential aetiologies of non‐B non‐C hepatocellular carcinoma in hepatitis B virus endemic area

We investigated potential aetiologies, clinical characteristics and prognosis of non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients in hepatitis B virus (HBV) endemic area, according to potential causes such as previous HBV exposure, chronic alcohol intake and metabolic syndrome. Among 4690 HCC patients treated at Asan Medical Center between 2007 and 2009, 523 were newly diagnosed with NBNC HCC, and their medical records and survival data were analyzed retrospectively. Among 321 NBNC HCC patients whose hepatitis B core antibody (anti-HBc) test results were available, 81.0%, 37.1% and 15.5% had anti-HBc positivity, chronic alcohol intake and metabolic syndrome respectively. One-hundred and fifty-two patients (47.4%) had previous exposure to HBV without chronic alcohol intake or metabolic syndrome. Hepatitis B surface antibody (anti-HBs) was positive in 48.0% of the 523 NBNC HCC patients, which was much lower than that in general Korean population, and 52.3% of anti-HBc-positive NBNC HCC patients were negative for anti-HBs. Anti-HBc-negative alcoholic patients presented with more advanced cirrhosis with Child-Pugh class B/C liver function than anti-HBc-positive patients (P = 0.002). In multivariate analysis, baseline liver function, alpha-foetoprotein levels and tumour stage were significant prognostic factors and aetiology did not affect patient survival. Prior HBV infection could be a potential aetiology in over 40% of NBNC HCC patients in HBV endemic area. Positivity for anti-HBc and negativity for anti-HBs may be a serologic surrogate marker for occult HBV infection in these area. The prognosis of NBNC HCC was determined by tumour stage and underlying liver function.

Clinical characteristics and prognosis of non-B non-C hepatocellular carcinoma patients with modest alcohol consumption.

Alcoholic hepatocellular carcinoma (ALD-HCC) accounts for the majority of non-B non-C HCC (NBNC-HCC) cases. Although alcohol is a potent carcinogen, there have been few reports on the influence of modest alcohol consumption in NBNC-HCC. This study aimed to investigate the clinical characteristics and prognosis of NBNC-HCC patients with modest alcohol consumption. From 2007 to 2010, 2283 HCC patients were evaluated at 10 hospitals. We collected detailed etiology data of 588 NBNC-HCC patients and compared the clinical characteristics and prognosis between ALD-HCC and modest alcohol-HCC patients. There were 69 HCC patients with modest alcohol consumption, accounting for 3% of all HCC patients evaluated. This patient group had significantly more women and higher prevalence of Child-Pugh class A, hypertension and advanced disease stage, and were diagnosed with HCC at an older age than the ALD-HCC group (266 patients). Additionally, among the modest alcohol-HCC patients, diabetes was significantly more common in the anti-hepatitis B core (HBc) negative subgroup than in the anti-HBc positive subgroup. However, no significant difference in survival was observed between the two patient groups regardless of significant differences in tumor staging. Alcohol consumption and metabolic factors were not significant independent predictors of survival. The clinical characteristics of modest alcohol-HCC included advanced staging, favorable liver reserve capacity and older age at diagnosis. HCC development in patients with modest alcohol consumption may relate to metabolic factors. Although approximately 30% of the evaluated HCC cases were in advanced stages, the prognosis of NBNC-HCC patients with modest alcohol consumption was relatively favorable.

Semiannual Imaging Surveillance Is Associated with Better Survival in Patients with Non-B, Non-C Hepatocellular Carcinoma.

Since it remains elusive whether and how the imaging surveillance affects the survival in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), we conducted this retrospective study which investigated the association between the semiannual surveillance prior to HCC diagnosis and the survival in patients with the initial diagnosis of HCC induced by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections (N = 141) and non-B, non-C etiology (N = 30). It was demonstrated that surveillance was less frequently performed in the NBNC-HCC patients compared to that in HCC patients with HBV and/or HCV infections (B/C-HCC patients), and the survival was unfavorable in NBNC-HCC patients. On the other hand, the survival of NBNC-HCC patients with semiannual surveillance was significantly favorable than those patients without semiannual surveillance, and the survival was similar between B/C-HCCs and NBNC-HCCs with semiannual surveillance. In conclusion, though NBNC-HCC patients compared to B/C-HCC patients had poorer prognosis overall, these NBNC-HCC patients with semiannual surveillance had a better survival almost equivalent to the survival of B/C-HCC patients with semiannual surveillance, demonstrating the clinical utility of the semiannual imaging surveillance program for NBNC-HCCs.

Clinical significance of the FIB-4 index for non-B non-C hepatocellular carcinoma treated with surgical resection.

The aims of the present study were to examine the relationship between the preoperative FIB-4 index and background liver fibrosis in non-tumor parts obtained from surgical specimens and to investigate whether the FIB-4 index can be a useful predictor for non-B non-C hepatocellular carcinoma (NBNC-HCC) patients treated with surgical resection (SR). A total of 118 patients with NBNC-HCC treated with SR with curative intent were analyzed. Receiver operating characteristic (ROC) curve analysis was performed for calculating the area under the ROC (AUROC) for the FIB-4 index, aspartate aminotransferase (AST) to platelet ratio index, AST to alanine aminotransferase ratio, serum albumin, total bilirubin and platelet count for cirrhosis. We also examined predictors linked to overall survival (OS) and recurrence-free survival (RFS) after SR. The mean patient age was 68.9±9.0 years (93 males and 25 females) with a median observation period of 3.2 years. In extracted surgical specimens, background liver cirrhosis (F4) was observed in 39 patients (33.1%). The mean maximum tumor size was 5.7±3.2 cm. The mean body mass index was 24.3±3.9 kg/m2. The FIB-4 index yielded the highest AUROC for cirrhosis with a level of 0.887 at an optimal cut-off value of 2.97 (sensitivity, 92.3; specificity, 69.6%). In the multivariate analysis, serum α-fetoprotein >40 ng/ml (P=0.026) was the only significant independent predictor linked to OS, while tumor number (P=0.002) and FIB-4 index >2.97 (P=0.044) were significant factors linked to RFS. In conclusion, preoperative FIB-4 index can be a useful predictor for NBNC-HCC patients who undergo SR.

Outcomes after curative hepatectomy in patients with non-B non-C hepatocellular carcinoma and hepatitis B virus hepatocellular carcinoma from non-cirrhotic liver.

There is controversy regarding liver function of non-B, non-C hepatocellular carcinoma (NBNC-HCC) patients, the biological behavior of their tumors, and the outcome after surgical treatment. The aims of the present study were to compare clinicopathologic data and long-term clinical outcomes between NBNC-HCC patients and hepatitis B virus HCC (HBV-HCC) patients from non-cirrhotic liver after curative hepatectomy. Data for HBV-HCC patients (n = 360) and NBNC-HCC patients (n = 103) were retrospectively reviewed. The median age of patients in the NBNC group was significantly higher than that of the HBV group (63 years vs. 53 years, P < 0.001). Tumor size in the NBNC group was greater than that in the HBV group (5.1 cm vs. 3.8 cm, P < 0.001). Regarding liver histology, the grade of lobular activity, periportal activity, and fibrosis in the HBV group was higher than in the NBNC group (P < 0.001, P < 0.001, and P < 0.001, respectively). There were no statistically significant differences in disease-free survival and overall survival between the two groups (P = 0.257 and P = 0.579, respectively). Multivariate analysis showed that increased tumor size, microvascular invasion, and intrahepatic metastasis were associated with tumor recurrence after curative liver resection. For patients with non-cirrhotic liver, clinical outcomes for NBNC-HCC were comparable to those for HBV-HCC after curative hepatectomy.

New Insights on Non-B non-C Hepatocellular Carcinoma in Mid Delta Region, Egypt

The rate of hepatocellular carcinoma (HCC) is increasing worldwide, including in Egypt. Hepatitis B (HBV) and C (HCV) viruses are major risks. Non-B non-C HCC was reported in some countries. We investigated non-B non-C HCC-independent risk factors and associated profiles in viral hepatitis endemic region. In a consecutive series, 281 patients were diagnosed with HCC and received for management, at Tanta University Hospitals, within the past 3 years. Demographic variables and environmental exposures were recorded by direct application of a modified questionnaire. Sera were tested for HCV (antibodies by ELISA and RNA by RT-PCR) and HBV (HBs Ag by ELISA and HBV DNA). Antinuclear antibody, serum copper, and iron were assessed in non-viral HCC. Liver biopsy was performed for HCC diagnosis and grading and liver tissue in all patients by histopathological and immunohistochemical methods to assess HBV and/or HCV etiology. Non-B non-C HCC patients were 13.87% of the total and were associated with multiple risks, predominantly pesticides (100%, p < 0.001) and super phosphate and ammonium sulfate fertilizers (94.87%, p < 0.001) with significant exposure in industry, farming, and residence. Their tumors were mainly solitary, smaller sizes, and of lower alpha-fetoprotein titers. The study showed insignificant increase in prevalence of non-B non-C HCC and had special characters. Multivariate analysis showed significance of pesticides and smoking as independent risks for non-B non-C HCC. Pesticides and smoking heavy exposure can be considered as primary risks for non-B non-C HCC. Phosphate and ammonium sulfate fertilizers were associations. The study will increase awareness for better prevention and management.

Serum anti-P53 antibodies and alpha-fetoprotein in patients with non-B non-C hepatocellular carcinoma

The rate of hepatocellular carcinoma (HCC) is increasing worldwide including Egypt. Non-B non-C HCC was reported in some countries. We aimed to investigate P53 antibodies and alpha-fetoprotein in patients with non-B non-C HCC in our region. In a case series study, included 281 patients with HCC and 20 patients with liver cirrhosis of matched age, sex and social factors were received for management at Tanta University Hospitals. Sera were tested for HCV and HBV markers by ELISA/PCR, alpha-fetoprotein (AFP) level and anti-p53 antibody were evaluated by ELISA. Antinuclear antibody, serum copper and iron were assessed in non-viral HCC. Liver scanning and biopsy were evaluated. Non-B non-C HCC patients were 13.87% of total. P53 antibody serum level in non-B non-C HCC patients showed insignificant difference (p>0.05) as compared to viral-associated HCC, while significant as compared to cirrhosis. They had significant decrease in serum AFP level (p<0.001) as compared to viral-associated HCC. Their tumors were mainly solitary, and have smaller-sizes. Sensitivity, specificity, PPV, NPV and accuracy test of anti P53 antibody positive patients were 91.52%, 84.63%, 90.34%, 80.2% and 74.8% respectively. It correlates positively with AFP, tumor size and staging, MELD score and Child-Pugh score.Non-B non-C HCC showed high serum prevalence of anti-p53 as viral-associated HCC suggesting an evidence of high onchogenecity. It appears of much benefit in diagnosis, follow up and differentiation from cirrhosis in presence of low levels of alpha-fetoprotein.

Up-regulation of dbpA mRNA in hepatocellular carcinoma associated with metabolic syndrome.

Metabolic syndrome (MS) is a group of recognized risk factors for the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. The aim of this study was to analyze the clinicopathological characteristics of HCC patients with MS and the risk factors for recurrence. Also, the aim was to investigate the cold shock protein: DNA-binding protein A (dbpA) expression in HCC patients with MS. A total of 243 patients who underwent curative resections for HCC were classified into two groups. dbpA expression was investigated in 66 HCC patients with MS and in 30 patients without MS by using real-time RT-PCR. Promoter methylation status was examined by using MS-PCR. The incidence of metabolic factors affect the HCC significantly higher in non-B non-C patients than in hepatitis B virus (HBV) or hepatitis C virus (HCV) patients (P<0.001). Univariate analysis of HCC patients with MS recurrence revealed aspartate amino transferase (AST), multiple tumors, liver damage, hepatic vein invasion, advanced cancer stages (P<0.01), alpha-fetoprotein (AFP) and diabetes mellitus type II (P<0.05) as risk factors. Multivariate analysis, AST, multiple tumors, and hepatic vein invasion (P<0.01) were identified as independent factors for the recurrence. dbpA mRNA was higher in patients with MS than in those without MS (P=0.016), and it was mostly upregulated in non-B non-C HCC patients with MS than in non-B non-C HCC patients without HBV or HCV. Especially, in HCC patients with diabetes mellitus type II, the mRNA and protein levels were highly upregulated. The dbpA expression was regulated by promoter methylation status (P<0.05). This study identifies that dbpA may accelerate the hepatocarcinogenesis in HCC patients with MS via inflammation-induced and oxidative stress pathways. The demethylation-related epigenetic activation may be one of the regulating factors for HCC patients with MS.

Molecular characteristics of non‐cancerous liver tissue in non‐B non‐C hepatocellular carcinoma

Although chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) are the most important risk factors for the development of hepatocellular carcinoma (HCC) worldwide, the proportion of HCC patients negative for the hepatitis B surface antigen and hepatitis C antibody, so-called "non-B non-C HCC", is rapidly increasing, especially in Japan. The background liver diseases of non-B non-C HCC patients can be multifactorial, including occult HBV infection and non-alcoholic steatohepatitis. It is reasonable to investigate the non-cancerous liver tissues to identify the potential molecular mechanisms responsible for the processes of hepatocarcinogenesis of non-B non-C HCC. However, to date, only a few studies have focused on this research concept based on the idea of "field cancerization". This review highlights the potential importance of the molecular analysis of non-cancerous liver tissues to clarify the molecular characteristics in patients with non-B non-C HCC. A better understanding of the molecular mechanisms underlying the individual predisposition to non-B non-C HCC will lead to improvements in the prevention, early diagnosis and treatment of this neoplastic disease.

Genomic mutations with amino acid substitutions of circulating hepatitis B virus found in non-B, non-C patients with hepatocellular carcinoma.

Most hepatocellular carcinoma (HCC) in Japan is caused by chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). HBV DNA has been detected in the serum and liver tissue of some proportion of those patients who are HBs antigen-negative and HCV antibody-negative; i.e., non-B, non-C (NBNC) patients with HCC. We sought to detect HBV DNA in the serum from NBNC HCC cases and to investigate genomic mutations of HBV in seronegative cases. The sera from 26 NBNC HCC patients were examined by polymerase chain reaction (PCR) followed by southern blotting for existence of HBV DNA. The precore/core and polymerase regions of the HBV genome in the sera from five seronegative cases were analyzed by direct sequence. HBV DNA was detected in 17 of 26 patients (65.4%). Demographic factors such as age, gender, anti-HBs positivity, anti-HBc positivity, complication with cirrhosis, and excessive alcohol intake did not affect circulating HBV positivity. Genomic mutations with amino acid substitutions were detected in the polymerase and the precore regions from one of the five cases, and in the core region from four of the five cases. PCR-based HBV screening is necessary in patients suffering from liver diseases of unknown etiology, although its etiological importance and benefit of viral elimination have not been established. Genomic mutations in the precore/core and the polymerase region detected in this study might be involved in the lack of HBsAg in NBNC HCC cases.