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Background and Aim: Transarterial chemoembolization (TACE) is one of the standard modalities used to treat unresectable hepatocellular carcinoma (HCC), but the effectiveness of TACE for treating patients with a solitary small (≤3 cm) HCC and well-preserved liver function has not been definitively established. This study aimed to determine the therapeutic impact of TACE in patients with these characteristics., Methods: This multicenter (four university hospitals) retrospective cohort study analyzed the medical records of 250 patients with a solitary small (≤3 cm) HCC and Child-Turcotte-Pugh (CTP) class A liver function diagnosed over 10 years. Posttreatment outcomes, including overall survival (OS), recurrence-free survival (RFS), and adverse events, were assessed following TACE therapy., Results: One hundred and thirty-eight of the 250 patients (55.2%) treated with TACE achieved complete remission (CR). Overall median OS was 77.7 months, and median OS was significantly longer in the CR group than in the non-CR group (89.1 vs. 58.8 months, P = 0.001). Median RFS was 19.1 months in the CR group. Subgroup analysis identified hypertension, an elevated serum albumin level, and achieving CR as significant positive predictors of OS, whereas diabetes, hepatitis c virus infection, and tumor size (>2 cm) were poor prognostic factors of OS., Conclusions: The study demonstrates the effectiveness of TACE as a viable alternative for treating solitary small (≤3 cm) HCC in CTP class A patients., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Epithelial-mesenchymal transition (EMT) has been implicated in cancer progression, invasion, and metastasis. We aimed to evaluate the correlations between clinicopathological characteristics and EMT markers in patients with hepatocellular carcinoma (HCC) who underwent surgical resection and to identify the key regulator in EMT process. Fresh-frozen HCC tissues and adjacent nontumor liver tissues from 30 patients who underwent surgical resection were provided by the Gachon University Gil Medical Center Bio Bank. Human HCC cell lines, Hep3B, SNU449, and Huh7 cells were transfected with Rac1 siRNA and exposed to hypoxic conditions. The combined EMT markers expression (down-expression of E-cadherin and overexpression of p21-activated kinases 1 (PAK1)/Snail) by Western blot in HCC tissues when compared to adjacent nontumor liver tissues was significantly associated with macrovascular invasion ( p = 0.021), microvascular invasion ( p = 0.001), large tumor size ( p = 0.021), and advanced tumor stage ( p = 0.015). Patients with combined EMT markers expression showed early recurrence and poor overall survival. In vitro studies showed that Rac1 knockdown decreased the expression of EMT markers including PAK1 and Snail in hypoxia-induced Hep3B cells and suppressed the migration and invasion of hypoxia-induced HCC cells. Rac1 may be a potential therapeutic target for inhibition of EMT process through the inhibition of PAK1 and Snail in HCC.

Background/aims: We compared the post-treatment overall survival (OS) and recurrence-free survival (RFS) between patients with Child-Turcotte-Pugh (CTP) class-A and single small (≤3 cm) hepatocellular carcinoma (HCC) treated by surgical resection (SR) and radiofrequency ablation (RFA)., Methods: We retrospectively analyzed 391 HCC patients with CTP class-A who underwent SR (n=232) or RFA (n=159) as first-line therapy for single small (≤3 cm) HCC. Survival was compared according to the tumor size (≤2 cm/2-3 cm) and the presence of cirrhosis. Inverse probability of treatment weighting (IPW) method was used to estimate the average causal effect of treatment., Results: The median follow-up period was 64.8 months (interquartile range, 0.1-162.6). After IPW, the estimated OS was similar in the SR and RFA groups (P=0.215), and even in patients with HCC of ≤2 cm (P=0.816) and without cirrhosis (P=0.195). The estimated RFS was better in the SR group than in the RFA groups (P=0.005), also in patients without cirrhosis (P<0.001), but not in those with HCC of ≤2 cm (P=0.234). The weighted Cox proportional hazards model with IPW provided adjusted hazard ratios (95% confidence interval) for OS, and the RFS after RFA versus SR were 0.698 (0.396-1.232) (P=0.215) and 1.698 (1.777-2.448) (P=0.005), respectively., Conclusion: SR was similar for OS compared to RFA, but was better for RFS in patients with CTP class-A and single small (≤3 cm) HCC. The RFS was determined by the presence or absence of cirrhosis. Hence, SR rather than RFA should be considered in patients without cirrhosis to prolong the RFS, although there is no OS difference.

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.Clinical trials registration: ClinicalTrials.gov (NCT02865369)., (© 2022. The Author(s).)

Background/aims: : The clinical significance of partial virological response (PVR) in patients undergoing antiviral therapy is not well known. This study investigated whether PVR after 2 years of entecavir (ETV) therapy is associated with hepatocellular carcinoma (HCC) development in cirrhotic patients., Methods: A total of 472 naïve patients with hepatitis B virus (HBV)-associated cirrhosis who were treated with ETV for at least 2 years were retrospectively enrolled. Clinical characteristics, laboratory data, PVR, and noninvasive fibrosis markers (aspartate aminotransferase to platelet ratio and FIB-4 index) at 2 years after ETV commencement were analyzed for HCC risk., Results: After excluding those who developed HCC within 2 years of ETV therapy, 359 patients (mean age, 51±10 years; male 64.3%) were examined. During a median follow-up of 82 months, 80 patients developed HCC. In the univariate analysis, older age (hazard ratio [HR], 1.056; p<0.001), PVR (HR, 2.536; p=0.002), higher aspartate aminotransferase (HR, 1.018; p=0.005), lower albumin level (HR, 0.463; p<0.001), lower platelet count (HR, 0.993; p=0.01), and higher FIB-4 index (HR, 1.141; p<0.001) at 2 years after ETV commencement were risk factors for HCC. In the multivariate analysis, older age (HR, 1.046; 95% confidence interval [CI], 1.022 to 1.072; p<0.001), PVR (HR, 2.358; 95% CI, 1.310 to 4.245; p=0.004), and higher FIB-4 index (HR, 1.103; 95% CI, 1.035 to 1.177; p=0.003) were independent risk factors., Conclusions: PVR and higher FIB-4 index after 2 years of ETV therapy were independent risk factors for HCC. Therefore, efforts to accomplish a complete virological response and reduce the FIB-4 index should be made.

Background & Aims: Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC., Methods: In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, n = 169) or in combination with cTACE on demand (Arm C, n = 170). Sorafenib was started within 3 days and cTACE within 7-21 days of randomization. The primary endpoint was overall survival (OS)., Results: For Arms C and S, the median OS was 12.8 vs. 10.8 months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; p = 0.290); median time to progression, 5.3 vs. 3.5 months (HR 0.67; 90% CI 0.53-0.85; p = 0.003); median progression-free survival, 5.2 vs. 3.6 months (HR 0.73; 90% CI 0.59-0.91; p = 0.01); and tumor response rate, 60.6% vs. 47.3% (p = 0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (p = 0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8 months; HR 0.58; 95% CI 0.40-0.82; p = 0.006)., Conclusion: Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC., Lay Summary: For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Contrast-enhanced ultrasound (CEUS) is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to verify the characteristics of CEUS in distinguishing small (≤3 cm) hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC).A total of 65 patients with a liver nodule (HCC, n = 58; ICC, n = 7) smaller than 3 cm who underwent liver CEUS and pathologic confirmation were retrospectively reviewed. CEUS findings were compared with histopathologic and clinical data.Arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS were observed in 77.6% (45/58) of HCCs and 85.7% (6/7) of ICCs. Time of arterial-phase hyperenhancement (11 seconds [6-20] vs 16 seconds [14-19], P = .008), time of portal-delayed-phase wash-out (65 seconds (15-260) vs 35 secconds (27-54), P = .002), and time interval between arterial-phase hyperenhancement and portal-delayed-phase wash-out (50 seconds [5-249] vs 19 seconds [13-35], P < .001) on CEUS were significantly different between HCCs and ICCs showing arterial-phase hyperenhancement and portal-delayed-phase wash-out. The sensitivity, specificity, positive predictive value, and negative predictive value of time interval more than 25 seconds between arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS for the differentiation of HCCs and ICCs were 91.1%, 83.3%, 97.6%, and 55.6%, respectively.The time interval between arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS was the most sensitive indicator in distinguishing small HCC from ICC showing arterial-phase hyperenhancement and portal-delayed-phase wash-out.

Background/aims: B-mode ultrasound (US) has difficulty targeting small hepatocellular carcinomas (HCCs) with poor conspicuity during radiofrequency ablation (RFA). Contrast-enhanced ultrasound (CEUS) can improve visualization of small or inconspicuous HCCs. This study was conducted to evaluate the effectiveness of CEUS-guided RFA electrode insertion during the arterial phase in inconspicuous HCCs., Materials and Methods: Ninety-three treatment-naïve HCCs from 80 patients treated with RFA from August 2012 to December 2014 were retrospectively reviewed. Seventy-five HCCs from 65 patients underwent B-mode US-guided RFA, and 15 HCCs from 14 patients that were inconspicuous on B-mode US underwent CEUS-guided RFA during the arterial phase after injection of sulfur hexafluoride microbubbles (SonoVue®). Technical success was assessed by contrast-enhanced computed tomography within 1 week and 3 months after the procedure., Results: The mean size of HCCs treated with CEUS-guided RFA was smaller than that of HCCs treated with B-mode US-guided RFA (1.17±0.36 vs. 1.63±0.55 cm, p=0.003). Technical success rates of CEUS-guided RFA within 1 week and 3 months were 100% (15/15) and 93.3% (14/15), respectively. Technical success rates of B-mode US-guided RFA were 97.3% (73/75) and 94.5% (69/73), respectively., Conclusion: CEUS-guided RFA is highly efficacious for ablation of very small and inconspicuous HCCs.

Recently, it has been suggested that peritumoral decreased uptake area (PDUA) in the hepatobiliary phase (HBP) of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) was associated with vascular invasion in hepatocellular carcinoma (HCC). We aimed to investigate correlations between microvascular invasion and PDUA, and elucidate the predictability of PDUA for tumor recurrence after resection.We retrospectively analyzed clinicopathological and radiological data from 126 consecutive patients with single HCC ≤5 cm without macrovascular invasion who underwent preoperative Gd-EOB-DTPA-enhanced MRI and surgical resection. The presence of a faint and hypointense area around the tumor in the HBP was defined as PDUA.Among 126 patients with HCCs, microvascular invasion was observed in 29 (23.0%) patients and PDUA was observed in 15 (11.9%) patients. PDUA [odds ratio (OR) 20.06, confidence interval (CI) 4.74-84.96, P < .001] was an independent risk factor for microvascular invasion. In multivariate survival analysis using Cox regression, PDUA [hazard ratio (HR) 4.51, CI 2.17-9.38, P < .001], pathologically confirmed satellite nodules (HR 5.18, CI 1.50-17.88, P = .009), and AFP (≥100 ng/mL, HR 2.28, CI 1.04-5.01, P = .040) were independent risk factors for recurrence after resection. Recurrence-free survival in the group with PDUA was significantly lower than that in the group without PDUA according to analysis using the Kaplan-Meier method with the log-rank test (P < .001).PDUA in the HBP of Gd-EOB-DTPA-enhanced MRI could be a useful preoperative predictor of microvascular invasion and independent prognostic factor after surgical resection in patients with single HCC ≤5 cm without macrovascular invasion.

Non-alcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). NAFLD-related HCCs (NAFLD-HCCs) have the following clinical features: high body mass index, deranged lipid profiles, diabetes mellitus, hypertension, and metabolic syndrome. Among them, obesity, diabetes mellitus, and high Fe contents in the liver are risk factors of developing HCC in patients with NAFLD. Inflammatory cytokines, adipokines, insulin like growth factor-I, and lipotoxicity are intermingled and may cross react with each other to develop HCC. Because there is no guideline for early detection of HCC in patients with NAFLD, NAFLD-HCCs tend to be greater in size and in advanced stages when detected compared with hepatitis virus-related HCCs. Therefore, there is an urgent need of a surveillance program for the early detection of HCC. Treatment of NAFLD-HCCs is not different from other causes-related HCCs. However, patients with NAFLD-HCCs have cardiovascular disease and other metabolic problems, which may complicate treatment.

Background: Sustained abnormal serum alanine aminotransferase (ALT) levels can increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B., Aim: This study is aimed to confirm the impact of rapid ALT normalization (≤30 IU/L) on HCC risk in patients with hepatitis B virus (HBV)-associated cirrhosis after entecavir (ETV) commencement., Methods: A total of 578 treatment-naïve patients with HBV-associated cirrhosis (mean age 51 ± 9 years, male sex 63.3%) were treated with ETV for more than 1 year. Serum ALT and HBV DNA levels were measured at three time points (baseline, 6, and 12 months after ETV commencement) and subjected to risk factor analysis., Results: Median follow-up after ETV commencement was 43 (12-98) months. Cumulative incidences of HCC at 1, 3, 5, and 7 years were 0.3, 8.5, 19.5, and 30.6%, respectively. Univariate Cox regression analysis showed that older age, abnormal ALT at 6 months or 12 months, and lower platelet count were significant risk factors for HCC. However, gender, HBeAg positivity, abnormal ALT levels or HBV DNA levels at baseline, and detectable HBV DNA at 6 or 12 months were not risk factors. Multivariate analysis showed that older age (P < 0.001), abnormal ALT at 12 months (P = 0.006), and lower platelet count (P = 0.034) were the risk factors for HCC., Conclusions: Abnormal serum ALT levels after ETV commencement are significant risk factor for HCC. Therefore, ALT should be rapidly normalized to minimize the risk of HCC development in patients with HBV-associated cirrhosis.

Background/aims: We analyzed the incidence of change of Barcelona Clinic Liver Cancer (BCLC) stage after add-on Primovist-enhanced magnetic resonance imaging (MRI) in hepatocellular carcinoma (HCC) patients with Barcelona Clinic Liver Cancer stage 0 or A as determined by liver dynamic computed tomography (LDCT)., Methods: A total of 166 patients enrolled prospectively between August 2012 and December 2014 were retrospectively analyzed. The rates of stage change after Primovist-enhanced MRI and the treatment finally adopted in patients with stage change were evaluated., Results: Of the 166 patients, 24 (18.6%) had truly new HCCs. Forty-six (27.7%) and 120 (72.3%) patients had BCLC stages 0 and A, respectively, before Primovist-enhanced MRI, but after Primovist-enhanced MRI, 28 (16.9%), 134 (80.7%), and 4 (2.4%) patients had BCLC stages 0, A, and B, respectively. Tumor stage changed in 22 (13.3%) patients, from 0 to A (18, 39.1%) or A to B (4, 3.3%)., Conclusions: Add-on Primovist-enhanced magnetic resonance imaging can change BCLC stage with 13.3% in patients with BCLC 0 or A staged HCC, as determined by LDCT. J. Surg. Oncol. 2016;114:106-111. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Inflammation is one of the most prominent characteristic features of chronic liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most of HCC cases develop in patients with cirrhosis and cirrhosis develops in patients with chronic liver inflammation. Therefore, there is no doubt that there exist some strong connection among inflammation, fibrosis, and cancer. In fact, chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. This review will discuss the common mechanism of inflammation and fibrosis in chronic liver diseases, and then demonstrate why HCC develops in inflammatory and fibrotic conditions.

Background: Contrast-enhanced ultrasound is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to evaluate the usefulness of contrast-enhanced ultrasound for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules showing atypical or not coincidental typical vascular pattern on two dynamic imaging techniques (computed tomography and magnetic resonance imaging)., Methods: A total of 46 patients with cirrhosis and a liver nodule smaller than 3cm showing an atypical or non-coincident typical vascular pattern on two dynamic imaging techniques, who underwent liver contrast-enhanced ultrasound and ultrasound-guided liver biopsy, were retrospectively reviewed. Contrast-enhanced ultrasound findings were compared with histopathological and clinical data, and with the two dynamic imaging findings., Results: Significantly different contrast-enhanced ultrasound enhancement patterns were observed among dysplastic nodules, Edmondson grade I and grade II-III hepatocellular carcinomas. Ten out of 11 (90.9%) non-hypervascular hepatocellular carcinomas on two dynamic imaging techniques showed a hypervascular pattern on contrast-enhanced ultrasound, and these made it possible to distinguish hepatocellular carcinomas from dysplastic nodules., Conclusion: Contrast-enhanced ultrasound is useful for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background/aims: Nonalcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether patients with cryptogenic HCC share clinical features similar to that of NAFLD., Methods: Cryptogenic HCC was defined as HCC that occurs in patients with the following conditions: HBsAg(-), anti-HCV(-), and alcohol ingestion of less than 20 g/day. All patients diagnosed with cryptogenic HCC from 2005 to 2012 (cryptogenic HCC group), and all patients diagnosed with HBV associated HCC between 2008 and 2012 (HBV-HCC group) were enrolled in the present study. Clinical features, BMI, lipid profiles, presence of diabetes mellitus, hypertension, and metabolic syndrome were compared between the two groups., Results: Cryptogenic HCC group was composed of 35 patients (19 males and 16 females) with a mean age of 70 ± 11 years. HBV-HCC group was composed of 406 patients (318 males and 88 females) with a mean age of 56 ± 7 years. Patients in the cryptogenic HCC group were older (p=0.001) and female dominant (p=0.042) than those in the HBV-HCC group. There were no differences in the laboratory test results including lipid profiles and Child-Turcotte-Pugh class between the two groups. Patients in the cryptogenic HCC group had higher prevalence of diabetes (37% vs. 17%, p=0.015), hypertension (49% vs.27%, p=0.051), metabolic syndrome (37% vs. 16%, p=0.001), and higher BMI (25.3 kg/m(2) vs. 24.1 kg/m(2), p=0.042) than those in the HBV- HCC group. The tumor stage was more advanced (stage III and IV) at diagnosis in the cryptogenic HCC group than in the HBV-HCC group (60% vs. 37%, p=0.007)., Conclusions: Cryptogenic HCC has clinical features similar to that of NAFLD and is diagnosed at a more advanced tumor stage.

Hepatocellular carcinoma (HCC) is a critical global health issue and the third most common cause of cancer-related deaths worldwide. The majority of patients who present HCC are already at an advanced stage and their tumors are unresectable. Sorafenib is a multi-kinase inhibitor of the vascular endothelial growth factor pathway and was recently introduced as a therapy for advanced HCC. Furthermore, studies have shown that oral sorafenib has beneficial effects on survival. However, many patients experience diverse side effects, and some of these are severe. Liver abscess development has not been previously documented to be associated with sorafenib administration in HCC. Here, we report the case of a HCC patient that developed a liver abscess while being treated with sorafenib.

Many studies have suggested that occult HBV infection has a substantial clinical relevance to hepatocellular carcinoma (HCC). Occult HBV infection is an important risk factor for the development of cirrhosis and HCC in patients without HBsAg. As a matter of fact, occult HBV infection is one of the most common causes of crytogenic HCC in endemic areas of HBV. However, there still are controversial issues about the association between occult HBV infection and HCC according to the underlying liver disease. In alcoholic cirrhosis, occult HBV infection may exert synergistic effect on the development of HCC. However, there is insufficient evidence to relate occult HBV infection to hepatocarcinogenesis in non-alcoholic fatty liver disease. In cryptogenic HCC, occult HBV infection may play a direct role in the development of HCC. In order to elucidate the assocciation between occult HBV infection and HCC, underlying liver disease must be specified and larger number of cases must be included in future studies.

Background/aims: Recurrence after hepatic resection is one of the most important factors impacting the prognosis and survival of patients with hepatocellular carcinoma (HCC). We identified prognostic factors affecting overall survival (OS) and disease-free survival (DFS) in patients with HCC after hepatic resection., Methods: This study was of a retrospective cohort design, and 126 patients who underwent hepatic resection for HCC at Gachon University Gil Medical Center between January 2005 and December 2010 were enrolled. Various clinical, laboratory, and pathological data were evaluated to determine the prognostic factors affecting OS and DFS., Results: Two- and 4-year OS and 2- and 4-year DFS were 78.1% and 65% and 51.1% and 26.6%, respectively. In a multivariate analysis, preoperative α-fetoprotein (> 400 ng/mL), tumor size (≥ 5 cm), multiple tumors (two or more nodules), presence of portal vein invasion, modified Union for International Cancer Control (UICC) stage III/IV, and Barcelona Clinic Liver Cancer (BCLC) stage B/C were independent prognostic factors affecting a shorter OS. In the multivariate analysis, presence of microvascular invasion, modified UICC stage III/IV, and BCLC stage B/C were independent prognostic factors for a shorter DFS., Conclusions: The presence of vascular invasion was an independent poor prognostic factor for OS and DFS in patients with HCC after hepatic resection. Thus, close postoperative surveillance for early detection of recurrence and additional treatments are urgently needed in patients with vascular invasion after hepatic resection.

The purpose of this report is to summarize the roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma (HCC). Chronic heavy alcohol exposure is a major risk factor for HCC, which is the most frequent type of liver cancer. Alcohol ingestion may initiate and or promote the development of HCC by: 1) acetaldehyde-DNA adduct formation; 2) cytochrome P4502E1-associated reactive oxygen species (ROS) generation , lipid peroxidation, p53 mutation, and conversion of pro-carcinogens to carcinogens; 3) iron accumulation that leads to ROS generation, lipid peroxidation, p53 mutation, and initiation of inflammatory cascade via nuclear factor-KappaB (NF-kB) activation; 4) glutathione depletion leading to oxidative stress; 5) s-adenosylmethionine (SAM) depletion and associated DNA hypomethylation of oncogenes ; 6) retinoic acid depletion and resultant hepatocyte proliferation via up-regulation of activator protein-1 (AP-1); 7) initiating an inflammatory cascade through increased transfer of endotoxin from intestine to liver, Kupffer cell activation via CD14/toll-like receptor-4 (TLR-4), oxidative stress, NF-kB or early growth response-1(Egr-1) activation, and generation of inflammatory cytokines and chemokines; 8) induction of liver fibrosis; and 9) decreasing the number and/or function of natural killer cells. Tobacco exposure is also a risk factor for HCC. It may contribute to the initiation and promotion of HCC due the presence of mutagenic and carcinogenic compounds as well as by causing oxidative stress due to generation of ROS and depletion of endogenous antioxidants. Simultaneous exposure to alcohol and tobacco is expected to promote the development of HCC in an additive and/or synergistic manner., (Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) is occasionally developed in patients with alcoholic cirrhosis. Old age, male gender, lifetime quantity of alcohol, and presence of hepatitis C virus (HCV) infection are risk factors for HCC in alcoholic cirrhosis. In this study, we investigated whether anti-hepatitis B core (HBc) positivity or occult hepatitis B virus (HBV) infection is a risk factor for HCC in patients with alcoholic cirrhosis. Between January 2006 and August 2008, a total of 72 cirrhotic male patients with an initial diagnosis of HCC, hospitalized in three major hospitals in the Incheon area, were enrolled as cases. Another 72 cirrhotic male patients without HCC, who matched the cases by age (±3 years), were enrolled as controls. All cases and controls were negative for hepatitis B surface antigen and anti-HCV, but had history of chronic alcohol intake over 80 g per day. The clinical characteristics including presence of anti-HBc or serum HBV DNA (identified by nested polymerase chain reaction) were investigated. The mean age of both the cases and controls was 62 ± 10 years. The basal laboratory data, Child-Pugh scores, total lifetime alcohol intake (1459 ± 1364 versus 1641 ± 1045 kg), and detection rates of serum HBV DNA [31.7% (20/63) versus 29.9% (20/67)] of the cases and controls were not significantly different. However, the anti-HBc positivity rate was higher among the cases [86.1% (62/72)] than in the controls [66.7% (48/72); p=0.005] and was the only significant risk factor for HCC (odds ratio; 3.1, 95% confidence interval; 1.354-7.098, p=0.007). Anti-HBc positivity was identified as a risk factor for the development of HCC in patients with alcoholic cirrhosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background/aims: Whether alcohol intake increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection remains controversial. The aim of this study was to determine the effect of alcohol intake on the development of HCC., Methods: Between January 2006 and August 2008, 146 patients with an initial diagnosis of HCC who were hospitalized in 3 major hospitals in the Incheon area were enrolled as cases. Another 146 cirrhotic patients, who matched the cases by age and sex, were enrolled as controls. All cases and controls were HBsAg positive, and had a history of lifetime alcohol intake., Results: The cases and controls were aged 53±8 and 53±9 years (mean±SD), respectively, with each group comprising 118 males and 28 females. The basal laboratory data, distribution of Child-Pugh class, HBeAg positivity (31.5% vs. 37.7%), HBV DNA level (5.74±2.35 vs. 5.98±2.29 log10 copies/mL), and proportion with a lifetime alcohol intake of more than 292 kg (30.8% vs. 34.9%) did not differ between cases and controls. The cumulative alcohol intake and the proportion of heavy drinkers did not differ between the two groups in male patients., Conclusions: Alcohol intake might not increase the risk of HCC in patients with HBV infection.

Primary hepatic epithelioid hemangioendothelioma is a rare neoplasm of endothelial origin. The clinical manifestations are nonspecific, ranging from complete absence of symptoms to hepatic failure and death. Spontaneous rupture of a hepatic epithelioid hemangioendothelioma is an extremely rare presentation. We present a case of primary hepatic epithelioid hemangioendothelioma in a 65-year-old male patient with alcoholic liver cirrhosis. He was hospitalized due to epigastric pain and multiple liver masses on abdominal ultrasound. Dynamic liver CT imaging revealed multiple peripheral nodular enhanced mass lesions with delayed centripetal enhancement, and the adjacent collection of high-attenuation fluid along the liver capsule. Abdominal tapping revealed blood in the peritoneal cavity. Primary hepatic epithelioid hemangioendothelioma with spontaneous rupture was finally diagnosed based on a histopathologic examination revealing positive immunohistochemical staining for CD34.

Background/aims: Alcohol and the hepatitis B virus (HBV) exert synergistic effects in hepatocelluar carcinogenesis. We aimed to elucidate the clinical significance of the antibody to hepatitis B core antigen (anti-HBc) and occult HBV infection on the development of hepatocellular carcinoma (HCC) in patients with alcoholic liver cirrhosis (LC)., Methods: Patients with alcoholic LC alone (n=193) or combined with HCC (n=36), who did not have HBsAg or antibody to hepatitis C virus were enrolled. Clinical data and laboratory data including anti-HBc were investigated at enrollment. The polymerase chain reaction was applied to HBV DNA using sera of patients with HCC or LC after age and sex matching., Results: Patients with HCC were older (60+/-11 years vs. 53+/-10 years, mean+/-SD, P<0.001), more likely to be male (100% vs. 89%, P=0.03), and had a higher positive rate of anti-HBc (91.2% vs. 77.3%, P=0.067), and a higher alcohol intake (739+/-448 kg vs. 603+/-409 kg, P=0.076) than those with LC. Age was the only significant risk factor for HCC revealed by multiple logistic regression analysis (odds ratio, 1.056; P=0.003). The positive rate of anti-HBc and alcohol intake did not differ in age- and sex-matched subjects between the LC (n=32) and HCC (n=31) groups. However, the detection rate of serum HBV DNA was higher in the HCC group (48.4%) than in the LC group (0%, P<0.001)., Conclusions: Anti-HBc positivity is not a risk factor for HCC. However, occult HBV infection may be a risk factor for HCC in patients with alcoholic LC.

Background/aims: Alcohol may be a cocarcinogen in patients with chronic viral hepatitis. We investigated the effect of alcohol on the development of hepatocellular carcinoma (HCC) in liver cirrhosis (LC) caused by hepatitis B virus (HBV)., Methods: All patients with LC or HCC associated with HBV or alcohol, admitted between March 2001 and June 2005, were included. Patients were divided into three groups according to the etiology of LC: Alcohol (AL), HBV, or HBV alcohol (HBV AL). Age and laboratory data at the enrollment of study were analyzed. The logistic regression coefficiency for the prevalence of HCC was calculated by using variables such as age, gender, serologic markers, and etiology of LC., Results: In LC patients (n=342), the proportions of AL, HBV, and HBV AL groups were 44%, 39%, and 17%, respectively. The proportions of HCC in AL, HBV and HBV AL groups were 17%, 55%, and 76%, respectively. Age at the diagnosis of HCC was younger in HBV AL than in AL group (p=0.036). In logistic regression analysis for the risk factor of HCC, odds ratio of age was 1.056 (p0.001). Odds ratios of HBV and HBV AL group comparing AL were 8.449 (p0.001) and 17.609 (p0.001), respectively. Therefore, old age and chronic alcohol intake in patients with HBsAg were the risk factors of HCC., Conclusions: Chronic alcohol intake may be an additive factor for the development of HCC in patient with LC caused by HBV. However, a prospective cohort study is needed to confirm these findings.

Background: Thalidomide has been reported to have antitumor activity for treating metastatic hepatocellular carcinoma (HCC). We evaluated the safety and efficacy of using thalidomide for treating selected patients with unresectable or metastatic HCC, and their disease was refractory to systemic chemotherapy., Methods: Eight patients with measurable and metastatic HCC that had progressed with prior systemic chemotherapy and who desired further active therapy were enrolled in this study. Thalidomide was given orally at bedtime and it was started at 200 mg/day with no further dose escalation. The response was measured at 2-month intervals., Results: The median age was 44 years (range: 34-52 years) and all the patients had received doxorubicin-based systemic chemotherapy prior to their enrollment. Each patient received thalidomide for a median of 152 days (range: 5-422 days). One partial response was observed (12.5%, 95% CI; 0-42%) along with 4 cases of stable diseases. The most commonly encountered toxicity was somnolence; grade 3 somnolence was noted for one patient, which led to treatment discontinuation. Skin rash was observed in one responding patient., Conclusions: The results indicate that thalidomide may feasibly offer disease stabilization to metastatic HCC patients. Further dose escalation of thalidomide, or its combination with other chemotherapeutic agents, may be of interest and this should be investigated for treating patients with metastatic HCC.

Background: Although numerous chemotherapeutic agents have been tested, the role of systemic chemotherapy for hepatocellular carcinoma (HCC) has not been clarified. New therapeutic strategies are thus needed to improve outcomes, and we designed this study with new effective drug combination., Methods: Twenty-nine patients with histologically-confirmed, metastatic HCC received a combination chemotherapy with doxorubicin 60 mg/m2 and cisplatin 60 mg/m2 on day 1, plus capecitabine 2000 mg/m2/day as an intermittent regimen of 2 weeks of treatment followed by a 1-week rest., Results: The median age was 49 years (range, 32-64) and 19 patients were hepatitis B virus seropositive. Child-Pugh class was A in all patients and 4 had Zubrod performance status of 2. The objective response rate was 24% (95% CI 9-40) with 6 stable diseases. The chemotherapy was generally well tolerated despite one treatment-related death., Conclusion: Combination chemotherapy with doxorubicin, cisplatin and capecitabine produced modest antitumor activity with tolerable adverse effects in patients with metastatic HCC.

Background/aims: Gelatinase (matrix metalloproteinase (MMP) -2 and 9) has an important role in the pathogenesis of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In this study, we evaluated the relationship of gelatinase to chronic liver disease., Methods: Four groups of subjects were examined; healthy control (10 cases), chronic hepatitis (18 cases), LC (15 cases), and HCC (28 cases). The plasma of each subject was obtained, and the equal quantification of plasma protein was done. The plasma activities of MMP-2 and 9 were measured by zymography., Results: The activities of plasma MMP-2 in patients with LC were significantly higher than those in controls (p=0.009) and in patients with chronic hepatitis (p=0.011), but not different from those in patients with HCC. The activities of plasma MMP-9 in patients with LC were significantly higher than those in controls, but not different from those in patients with chronic hepatitis or HCC. In patients with LC (regardless of having HCC), the activities of MMP-2 correlated with total bilirubin (r=0.323, p=0.048) and Child-Pugh score (r=0.414, p=0.012). The activities of MMP-2 and 9 were higher in patients with LC (regardless of having HCC) caused by alcohol than caused by HBV (p=0.009 and 0.002 for each one)., Conclusions: The plasma activity of MMP-2 may be a useful marker for the diagnosis and determination of the severity of LC. The plasma activity of MMP-9 was not useful for HCC, but may be a marker for alcoholic LC. Further study is needed to determine why the plasma activity of gelatinase was higher in patients with LC caused by alcohol than by HBV.

Background/aims: The genetic polymorphism of transforming growth factor-beta1 (TGF-beta1) at codons 10 and 25 which influences the production of TGF-beta1 is related to fibrogenesis in the lung and liver. We evaluated the genetic polymorphism at codons 10 and 25 in controls and in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC)., Methods: Blood samples were collected from controls (n=35), patients with LC (n=64), and HCC (n=49). Genomic DNA was isolated and polymerase chain reaction (PCR) was done for a segment including codons 10 and 25. The results of direct sequencing for PCR products were compared between the controls and the patients., Results: There was no genetic polymorphism at codon 25 and three types of genetic polymorphism at codon 10. The leucine homozygous genotype (CTG/CTG) at codon 10 was more common in patients with LC than the controls (p=0.01) and especially in patients with LC caused by HBV (p=0.004). The polymorphism at codons 10 in patients with HCC was similar to the controls. However, leucine homozygous genotype was more common in patients with HCC of uninodular morphology than those of massive morphology (p=0.007)., Conclusions: The genetic polymorphism of TGF-beta1 at codon 10 might be associated with LC and morphology of HCC. The potential usefulness of TGF-beta1 genotyping needs further studies in large scale.

Primary adenosquamous carcinoma of the liver is a very rare type of cholangiocarcinoma and is defined as a cancer containing both squamous and adenomatous components in the same lesion. Recently, we experienced a primary adenosquamous carcinoma of the liver presented as liver abscess. A 63-year-old man was presented with a 4-day history of fever and chill. The radiologic study showed a 4 cm-sized, central hypoattenuated mass with peripheral rim enhancement in the left lobe of the liver. Ultrasonography-guided aspiration and biopsy suggested an adenocarcinoma with abscess in the liver. At laparotomy, the tumor occupied the left lobe of the liver and invaded the right diaphragm. An extended left lobectomy and a partial excision of the involved diaphragm were done. Grossly, the tumor was 6 x 5 x 5 cm in size and had an eccentric necrosis. Microscopically, the tumor was composed of adenocarcinoma and squamous cell carcinoma with a transitional area.