An Immunological Perspective on the Mechanism of Drug Induced Liver Injury: Focused on Drugs for Treatment of Hepatocellular Carcinoma and Liver Transplantation.

The liver is frequently exposed to potentially toxic materials, and it is the primary site of clearance of foreign agents, along with many innate and adaptive immune cells. Subsequently, drug induced liver injury (DILI), which is caused by medications, herbs, and dietary supplements, often occurs and has become an important issue in liver diseases. Reactive metabolites or drug-protein complexes induce DILI via the activation of various innate and adaptive immune cells. There has been a revolutionary development of treatment drugs for hepatocellular carcinoma (HCC) and liver transplantation (LT), including immune checkpoint inhibitors (ICIs), that show high efficacy in patients with advanced HCC. Along with the high efficacy of novel drugs, DILI has become a pivotal issue in the use of new drugs, including ICIs. This review demonstrates the immunological mechanism of DILI, including the innate and adaptive immune systems. Moreover, it aims to provide drug treatment targets, describe the mechanisms of DILI, and detail the management of DILI caused by drugs for HCC and LT.

Sorafenib for advanced hepatocellular carcinoma provides better prognosis after liver transplantation than without liver transplantation.

BACKGROUND: Although sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), the efficacy of sorafenib in patients with recurrent HCCs after liver transplantation (LT) has not been compared with that in patients without LT (non-LT). METHODS: Between 2008 and 2019, a total of 832 consecutive HCC patients treated with sorafenib (790 in the non-LT group and 42 in the LT group) were enrolled. The primary outcome was overall survival (OS). Secondary outcomes were time-to-progression (TTP), objective response rate (ORR) and disease control rate (DCR). Treatment outcomes were assessed by multiple subgroup analyses and propensity-score matching (PSM). RESULTS: The median follow-up duration was 152.5 days. The LT group was younger and had smaller intrahepatic HCC than the non-LT group. The LT group showed significantly better OS (16.8 vs. 7.1 months, p < 0.001), TTP, ORR and DCR than the non-LT group. The superior efficacy of sorafenib in the LT group was corroborated in multiple subgroup analyses stratified by metastasis, effective sorafenib maintenance dose, or Child-Turcotte-Pugh class A. LT was identified as an independent factor for favorable OS. Intrahepatic HCC was the strongest tumor-related factor for both OS and TTP and was significantly associated with tumor response and hepatic function. Finally, subanalyses including only patients with small intrahepatic HCC or PSM modeling showed no difference in sorafenib efficacy between the LT and the non-LT groups. CONCLUSION: Sorafenib provides better outcomes in the LT setting than the non-LT setting. This benefit may be associated with the smaller intrahepatic HCC coupled with preserved hepatic function in LT recipients.

Effects of Branched-Chain Amino Acid (BCAA) Supplementation on the Progression of Advanced Liver Disease: A Korean Nationwide, Multicenter, Prospective, Observational, Cohort Study.

BACKGROUND AND AIMS: Clinical evidence for the benefits of branched-chain amino acids (BCAAs) is lacking in advanced liver disease. We evaluated the potential benefits of long-term oral BCAA supplementation in patients with advanced liver disease. METHODS: Liver cirrhosis patients with Child-Pugh (CP) scores from 8 to 10 were prospectively recruited from 13 medical centers. Patients supplemented with 12.45 g of daily BCAA granules over 6 months, and patients consuming a regular diet were assigned to the BCAA and control groups, respectively. The effects of BCAA supplementation were evaluated using the model for end-stage liver disease (MELD) score, CP score, serum albumin, serum bilirubin, incidence of cirrhosis-related events, and event-free survival for 24 months. RESULTS: A total of 124 patients was analyzed: 63 in the BCAA group and 61 in the control group. The MELD score (p = 0.009) and CP score (p = 0.011) significantly improved in the BCAA group compared to the control group over time. However, the levels of serum albumin and bilirubin in the BCAA group did not improve during the study period. The cumulative event-free survival was significantly improved in the BCAA group compared to the control group (HR = 0.389, 95% CI = 0.221-0.684, p < 0.001). CONCLUSION: Long-term supplementation with oral BCAAs can potentially improve liver function and reduce major complications of cirrhosis in patients with advanced liver disease.

Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial.

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.

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

18F-fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment.

PURPOSE: Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed to evaluate the performance of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) for predicting tumour progression during sorafenib treatment. METHODS: We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing 18F-FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured. RESULTS: Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio [HR] = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis. CONCLUSION: Pretreatment tumour metabolic activity assessed by 18F-FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment.

Dexamethasone Prophylaxis to Alleviate Postembolization Syndrome after Transarterial Chemoembolization for Hepatocellular Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled Study.

PURPOSE: To test the hypothesis that prophylactic administration of dexamethasone alleviates postembolization syndrome (PES) after transarterial chemoembolization for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This prospective, randomized, double-blinded, placebo-controlled trial was conducted in a single center from August 2015 to June 2016. A total of 88 patients with intermediate-stage HCC were enrolled. After randomization, 44 patients were assigned to the dexamethasone group and the other 44 to the control group. In the dexamethasone group, 12 mg of intravenous dexamethasone was administered before chemoembolization. Nausea, vomiting, fever, pain, and alanine aminotransferase level elevation were evaluated after chemoembolization had been performed with the use of Lipiodol and doxorubicin. RESULTS: The incidences of PES were 78.0% in the dexamethasone group and 97.5% in the control group (P = .008). Mean hospitalization times after chemoembolization were 2.7 days ± 1.44 in the dexamethasone group and 2.9 days ± 1.83 in the control group (P = .553). Mean doses of antiemetic and analgesic agents were lower in the dexamethasone group than the control group (0.2 ± 0.58 vs 1.0 ± 1.89 [P = .029] and 0.6 ± 0.97 vs 1.92 ± 2.54 [P = .006], respectively). Prophylactic administration of dexamethasone was a significant factor that influences PES occurrence after chemoembolization (odds ratio = 10.969, P = .027). CONCLUSIONS: This study demonstrates that the prophylactic administration of dexamethasone before chemoembolization is an effective way to reduce PES.

Effects of branched-chain amino acids (BCAAs) on the progression of advanced liver disease: A Korean nationwide, multicenter, retrospective, observational, cohort study.

Evidence of the potential benefits of long-term oral branched-chain amino acid (BCAA) supplementation in reducing the severity of liver disease is limited.Patients who were diagnosed with liver cirrhosis with a Child-Pugh (CP) score of 8-10 were included. The BCAA group consumed BCAAs daily for at least 6 months, and the control group consumed a diet without BCAA. We analyzed the improvements based on the model for end-stage liver disease (MELD) score, CP score, incidence of cirrhosis-related complications, and event-free survival over 2 years. Among the 867 recruited patients, 307 (166 in the BCAA group and 141 in the control group) were analyzed. The BCAA group was divided into 3 subgroups, whose patients consumed 4.15 g, 8.3 g, or 12.45 g of BCAAs daily for the analysis. There were significant differences in the CP score, albumin, and hepatic encephalopathy between the 2 groups at baseline. After matching the propensity scores, we analyzed patients in the BCAA-12.45 g group (12.45 g of BCAAs daily, n = 41) and matched control group (n = 41). The MELD score significantly improved in the BCCA-12.45 g group compared to the matched control group (P = .004). The changes in the serum bilirubin level (P = .014) and CP score (P = .033) over time also differed significantly between the 2 groups. The incidence rates of cirrhosis-related complications (P = .973) and development of hepatocellular carcinoma (2 cases each) did not differ significantly between the 2 groups.Long-term oral BCAA supplementation has beneficial effects in patients with advanced liver cirrhosis. A further large-scale prospective study is needed to delineate these beneficial effects.

A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function.

BACKGROUND/AIMS: Metronomic chemotherapy (MET) is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS) of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). METHODS: A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. RESULTS: The median number of MET cycles was two (1-15). The OS values for the MET group and sorafenib group were 158 days (132-184) and 117 days (92-142), respectively (P=0.029). The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014) and Child-Pugh class B (HR=1.856, P=0.008). CONCLUSIONS: MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

Radioembolization Is a Safe and Effective Treatment for Hepatocellular Carcinoma with Portal Vein Thrombosis: A Propensity Score Analysis.

BACKGROUND/AIMS: Limited treatment options are available for patients with hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). Transarterial radioembolization using Yttrium-90 microspheres is a new treatment modality for HCC with PVT. For this analysis, we compared responses to treatment with radioembolization and with sorafenib. METHODS: We evaluated 32 patients who were part of a multicenter retrospective cohort. All patients had PVT without extrahepatic metastasis and were treated with radioembolization in one of six tertiary referral hospitals in Korea. We retrospectively enrolled another 31 consecutive PVT patients without extrahepatic metastasis from a single center who received sorafenib treatment to serve as the control group. We used inverse probability weighting (IPW) using propensity scores to adjust for the between-group differences in baseline characteristics. RESULTS: At 3 months, the response rate and disease control rate were 32.1% (9/32) and 57.1% (16/32), respectively, in the radioembolization group and 3.2% (1/31) and 41.9% (13/31) in the sorafenib group. Median overall survival (OS) and time to progression (TTP) were not significantly different between the radioembolization group and the sorafenib group (13.8 months and 10.0 months, P = 0.22; and 6.0 months and 6.0 months, P = 0.08; respectively). No differences in OS (P = 0.97) or TTP (P = 0.34) were observed after IPW was applied to balance the population characteristics. The sorafenib group showed significantly more grade 3/4 adverse effects than the radioembolization group (P < 0.01). CONCLUSION: HCC patients with PVT who underwent radioembolization achieved comparable survival to patients who received sorafenib, even after application of IPW. The radioembolization group also experienced fewer severe adverse effects. Radioembolization can be considered a new treatment option for patients with HCC with PVT.

A comparative study between sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND: The aim of this study was to compare the efficacy of hepatic arterial infusion chemotherapy (HAIC) and sorafenib in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). METHODS: A total of 110 patients were observed between February 2008 and May 2013 in seven Korean centers. Fifty patients were treated with HAIC, and 60 patients were treated with sorafenib. RESULTS: The disease control rate in the HAIC was significantly higher than that in the sorafenib group (p < 0.001), although there was no significant difference in the objective response rate (p = 0.214). The median overall survival (OS) was significantly longer in the HAIC group than in the sorafenib group (7.1 vs. 5.5 months, p = 0.011). The median time to-progression (TTP) was also significantly longer in the HAIC group than in the sorafenib group (3.3 vs. 2.1 months, p = 0.034). In the multivariate analysis, tumor diameter (≥ 10 cm) and the absence of combined loco-regional treatment were significant prognostic factors influencing OS (p = 0.002 and p = 0.010, respectively) and TTP (p = 0.017 and p = 0.006, respectively). The treatment modality tended to be a significant prognostic factor for survival (p = 0.052), but not for tumor progression (p = 0.121). CONCLUSIONS: HAIC is comparable with sorafenib in terms of OS and TTP in advanced HCC patients with PVTT. HAIC shows more favorable treatment responses compared with sorafenib. Therefore, HAIC might be an alternative treatment modality to sorafenib in advanced HCC patients with PVTT.

Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice.

BACKGROUND & AIMS: Here, we evaluated the safety and immunogenicity of hepatitis B virus (HBV) DNA vaccine, HB-110, in mice and Korean patients with chronic hepatitis B (CHB) undergoing adefovir dipivoxil (ADV) treatment. METHODS: For animal study, mice (BALB/c or HBV transgenic) were immunized with mHB-110, and T-cell and antibody responses were evaluated. For clinical study, 27 patients randomly received either ADV alone or ADV in combination with HB-110. Liver function tests, serum HBV DNA levels and the presence of HBeAg/anti-HBe were analysed. T-cell responses were estimated by ELISPOT and FACS analysis. RESULTS: mHB-110 induced higher T-cell and antibody responses than mHB-100 in mice. No adverse effects were observed by HB-110 cotreated with ADV. HBV-specific T-cell responses were induced in a portion of patients in medium to high dose of HB-110. Interestingly, HB-110 exhibited positive effects on ALT normalization and maintenance of HBeAg seroconversion. One patient, who received high dose of HB-110 exhibited HBeAg seroconversion during vaccination, which correlated with vaccine-induced T-cell responses without ALT elevation. CONCLUSIONS: HB-110 was safe and tolerable in CHB patients. In contrast to results in animal models, HB-110 in Korean patients exhibited weaker capability of inducing HBV-specific T-cell responses and HBeAg seroconversion than HB-100 in Caucasian patients. As Asian patients, who are generally infected via vertical transmission, appeared to have higher level of immune tolerance than Caucasian, novel approaches for breaking immune tolerance rather than enhancing immunogenicity may be more urgently demanded to develop effective therapeutic HBV DNA vaccines.

Newer treatments for advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The only curative treatment modalities for HCC are surgery, percutaneous ablation, and liver transplantation. Unfortunately, the majority of patients have unresectable disease at diagnosis. Therefore, effective treatment options are needed for patients with advanced HCC. The current standard treatment for patients with advanced HCC, according to the Barcelona Clinic Liver Cancer staging system, is the multikinase inhibitor sorafenib. Other alternative therapies are required, due to the limited treatment response to, and tolerance of, this molecular target agent. Clinical trials of hepatic artery infusion chemotherapy, radioembolization, and multimodal treatments have shown favorable results in advanced HCC patients. This article introduces new treatment modalities for advanced HCC and discusses future therapeutic possibilities.

Epirubicin, cisplatin, 5-FU combination chemotherapy in sorafenib-refractory metastatic hepatocellular carcinoma.

AIM: To evaluate the clinical efficacy and safety of epirubicin, cisplatin, and 5-FU combination chemotherapy for the sorafenib-refractory metastatic hepatocellular carcinoma (HCC). METHODS: From April 2009 to June 2012, 31 patients who were diagnosed with metastatic and progressive HCC after sorafenib treatment were retrospectively reviewed. Patients were treated with the combination of epirubicin (50 mg/m(2) IV; day 1), cisplatin (60 mg/m(2) IV; day 1), and 5-FU (1000 mg/m(2) IV; day 1-3) [Epirubicin, cisplatin, 5-FU combination (ECF)], repeated every 4 wk. RESULTS: The overall response rate was 12.9%. Patients who responded to ECF chemotherapy showed a longer overall survival (OS) and time to progression (TTP) relative to those in the non-responder group (OS: 20.4 mo vs 4.9 mo, P < 0.001, TTP: 9.4 mo vs 2.2 mo, P < 0.001). Patients with a stable primary liver mass also exhibited a longer OS and TTP relative to those with progressive disease (OS: 13.4 mo vs 5.3 mo, P = 0.003; TTP: 9.4 mo vs 2.3 mo, P = 0.003). The most common hematologic toxicity was thrombocytopenia (87.2%), and the incidence of grade 3-4 neutropenia was 53.9%. Age older than 60, a stable primary mass, and a good response to chemotherapy were prognostic factors for OS and TTP. CONCLUSION: This combination cytotoxic chemotherapy can serve as another treatment option after sorafenib failure for the subset of patients with advanced metastatic HCC.

Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.

PURPOSE: Recent studies have revealed that branched-chain amino acids (BCAA) reduce the development of hepatocellular carcinoma (HCC) in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR). The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN)-induced HCC and liver cirrhosis in a rat model. METHODS: Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight) for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. RESULTS: The mean area and number of dysplastic nodules (DNs) and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-ß-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. CONCLUSIONS: BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level.

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand-foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib-induced HFSR and genetic polymorphisms in Korean patients with HCC. METHODS: For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were measured using enzyme-linked immunosorbent assays before therapy and 1 month after therapy. RESULTS: During a median treatment period of 18 months, 55 patients (93%) developed sorafenib-induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF-α -308GG, VEGF -94GG, VEGF 1991CC, VEGF IVS3-28CC, and uridine diphosphate glucuronosyltransferase 1 family-polypeptide A9 (UGT1A9) IVS1-37431AA were associated significantly with the development of high-grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF-α -308GG (odds ratio, 44.1), and UGT1A9 IVS1-37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high-grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF-α level measured 1 month after sorafenib therapy was correlated significantly with the development of high-grade HFSR (odds ratio, 3.56; P = .026). CONCLUSIONS: Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF-α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF-α after sorafenib therapy.

Oleuropein reduces free fatty acid-induced lipogenesis via lowered extracellular signal-regulated kinase activation in hepatocytes.

Oleuropein, a bitter glucoside found in green olive leaves, and its metabolite hydroxytyrosol display powerful antioxidant activity both in vivo and in vitro. In this study, we hypothesized that the antioxidant activity of oleuropein could attenuate hepatic steatosis. To test this hypothesis, we established steatotic hepatocytes using HepG2 and FL83B cells treated with free fatty acids (FFAs) (oleate:palmitate, 2:1). To confirm hepatic steatosis, the intracellular lipid levels were quantitatively measured by Nile Red staining, and the sizes and distributions of lipid droplets were visualized by transmission electron microscopy. The expression of PAT family proteins as well as of adipose differentiation-related protein and tail interacting protein (TIP47) was evaluated by reverse transcriptase polymerase chain reaction and immunoblotting. To examine the cellular and molecular events associated with oleuropein, annexin V/propidium iodide staining and immunoblotting were performed. Oleuropein decreased the number and size of lipid droplets in FFA-treated cells and reduced intracellular triglyceride accumulation. However, it did not affect the expression of lipid droplets-associated PAT family proteins, including adipose differentiation-related protein and TIP47. In addition, oleuropein reduced FFA-induced extracellular signal-regulated kinase activation but had no effect on c-Jun N-terminal kinase or AKT activation. Given its protective effects against FFA-induced hepatocellular steatosis, oleuropein may be a lipid-lowering agent.

Serum selenium levels in Korean hepatoma patients.

The aim of this study was to determine serum selenium (Se) levels during the development of liver disease as well as the possible Se supplementation benefits in liver disease patients. Serum was collected from 187 patients with liver diseases and 120 normal healthy people living in Seoul. The samples were collected at the Kangnam St. Mary's Hospital College of Medicines, The Catholic University of Korea, in accordance with procedures approved by the Institutional Review Board of the Catholic University of Korea. Serum Se levels were quantified by inductively coupled plasma mass spectrometry and were compared between healthy and liver diseases patients. Se levels were 92.65 ± 32.50 µg/l in hepatitis infection, 92.33 ± 30.66 µg/l in hepatitis B virus infection and 96.41 ± 51.50 µg/l in hepatitis C virus infection, 96.42 ± 32.80 µg/l in cirrhosis, and 67.47 ± 14.30 µg/l in hepatoma patients. Findings were significantly lower in hepatitis and hepatoma as compared with the healthy participants (P < 0.001). The Se level of the healthy population was 108.38 ± 29.50, 119.37 ± 28.31 for males and 97.87 ± 26.99 µg/l for females. Our data shows the same parallelism between liver disease progression and decrease of Se levels except in the case of liver cirrhosis. And also, our study confirms the previous findings of significantly lower Se levels in Korean hepatoma patients. Se levels that decrease parallel to liver disease progression should be further integrated and analyzed with liver function blood biomarkers.

Drug-eluting bead loaded with doxorubicin versus conventional Lipiodol-based transarterial chemoembolization in the treatment of hepatocellular carcinoma: a case-control study of Asian patients.

OBJECTIVE: Lipiodol transcatheter arterial chemoembolization (TACE) is widely used to treat hepatocellular carcinoma (HCC). Recently, a drug-eluting bead (DEB) has been developed to enhance drug delivery to the tumor and reduce its systemic availability. The purpose of this study was to compare the efficacy and safety of intra-arterial injection of DEB loaded with doxorubicin versus conventional, Lipiodol-based TACE regimens in Asian patients with HCC. METHODS: The study was designed as a case-control, single-institution clinical trial. Twenty patients with HCC who received DEB loaded with 50 mg doxorubicin ('cases') were matched with 20 patients who had undergone conventional TACE ('controls'). The primary efficacy endpoint was tumor response at 1 month according to modified Response Evaluation Criteria in Solid Tumors. The primary safety endpoint was liver toxicity. RESULTS: The rate of objective response by modified Response Evaluation Criteria in Solid Tumors was 85% (17 of 20 patients) in the DEB arm versus 30% (six of 20 patients) in the conventional TACE arm (P=0.001). Subgroup analyses conducted in patients with large (>5 cm) or multinodular tumor confirmed significantly higher objective response rates in patients receiving DEB as compared with those treated with conventional TACE (P=0.003 and P=0.005, respectively). At the dose of 50 mg doxorubicin, there was no statistically significant difference in liver toxicity between DEB and conventional TACE (P>0.05). CONCLUSION: In Asian patients with HCC, transcatheter treatment with DEB loaded with doxorubicin offers a distinct advantage in objective tumor response rate as compared with conventional, Lipiodol-based TACE regimens.

Acute hepatitis C in Korea: different modes of infection, high rate of spontaneous recovery, and low rate of seroconversion.

The epidemiology and clinical outcomes of acute hepatitis C are different geographically. This study aimed to investigate the mode of infection, clinical characteristics, and outcomes of acute hepatitis C in Korea. Forty-seven patients with acute hepatitis C were enrolled consecutively in a study conducted in seven medical centers. The patients with the mean age of 45.8 years had mostly mild symptoms. A healthcare-related procedure was the most common exposure history (42.5%): acupuncture (17%), surgery (10.6%), needle-stick injury (8.5%), and other medical procedures (6.4%). There was no case of intravenous drug use. Twenty-one patients (44.7%) recovered spontaneously. Among the 16 patients who received antiviral therapy (34%), all of the 12 evaluable patients had a sustained virologic response, while 10 patients (21.3%) who did not receive antiviral therapy progressed to chronic infection. The overall seroconversion rate of anti-HCV antibody was 61.7%. The patients who recovered spontaneously had significantly lower rate of seroconversion compared with the patients who did not clear spontaneously the infection. In conclusion, acute hepatitis C in Korea was related to various healthcare procedures, including acupuncture, characterized by high rates of spontaneous recovery and low rates of seroconversion, which may be associated with different modes of infection and ethnic differences. The characteristics of acute hepatitis C in Asian countries warrants further study.