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Hepatocellular carcinoma (HCC) is a common type of poorly prognosticated malignant tumor. Surgical resection is the preferred treatment method for early-stage HCC. However, at the time of the initial diagnosis, fewer than 30% of patients with liver cancer are suitable for radical therapy. Systemic therapy plays an important role in the treatment process of patients with intermediate- to advanced-stage HCC, as it can effectively extend patients' survival time. With an emphasis on the status and role of systemic therapy for comprehensive management of HCC, this article summarizes the latest progress at home and abroad in the past five years, including first-line combined immunotherapy for advanced-stage HCC, second-line therapy selection, perioperative systemic therapy application, and combined therapy of systemic and local. Currently, the treatment model combined with local therapy has already become a new research hotspot in the treatment of advanced-stage HCC. Nevertheless, in the future, individualized and precise systemic therapeutic strategies will need further exploration.

Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: This study aimed to investigate the safety of sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients., Methods: A subgroup of 345 Chinese patients from the international database of the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study was included in this analysis. Safety assessment measures were adverse events (AEs) and serious adverse events (SAEs) graded using the National Cancer Institute Common Terminology Criteria version 3.0., Results: Of 331 evaluable patients, 98% started sorafenib at 800 mg/day. The median treatment duration was 22 weeks (range, 0.1-116 weeks), and median overall survival (OS) was 322 days (10.7 months). Approximately 50% of patients had at least one adverse event, and 6% had grade 3-4 adverse events. Drug-related adverse events were experienced by 29% of patients, and 3.6% had grade 3-4 drug-related adverse events. Overall, 23% of patients (n = 77) experienced serious adverse events, among which only 1 event was drug-related (0.3%). No differences in overall adverse events, serious adverse events, and deaths were observed between Child-Pugh A and Child-Pugh B patients. The most frequent drug-related adverse events were dermatological/skin (24%), hand-foot skin reaction (20%), gastrointestinal (11%), and diarrhea (11%). The majority of adverse events occurred within 30 days of beginning sorafenib., Conclusion: Sorafenib has satisfactory efficacy and safety in Chinese Child-Pugh A and B patients with unresectable HCC using the recommended dosage of 800 mg/day, and the safety of sorafenib is not affected by liver function. Prophylaxis for gastrointestinal adverse events may help to decrease dose interruptions or discontinuation., Trial Registration: ClinicalTrials.gov ; Identifier: NCT00812175. Date of registration: December 19, 2008.

Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF-κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The purpose of this study was to examine the safety and efficacy of sorafenib in Chinese patients with unresectable hepatocellular carcinoma. Data of 338 Chinese patients from the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib study database were included. Patients were divided into those who received and did not receive sorafenib prior to surgical resection and those with and without portal vein tumor thrombosis. In the non-surgery group, the median survival was 302 days (95% confidence interval: 244-371), and the median time from diagnosis to death was 428 days (95% confidence interval: 352-556); in the surgery group, half of the patients survived for 345 days and the median time from diagnosis to death was 1000 days (95% confidence interval: 750-2816). Median progression-free survival and median time to progression were not different between the two groups. Median overall survival was 360 days (95% confidence interval: 309-435) in the non-portal vein tumor thrombosis group and 240 days (95% confidence interval: 181-296) in the portal vein tumor thrombosis group; median time between hepatocellular carcinoma diagnosis and death was 750 days (95% confidence interval: 472-1000) and 420 days (95% confidence interval: 252-567), respectively, in the two groups. Median progression-free survival was 209 days (95% confidence interval: 166-264) for patients without portal vein tumor thrombosis and 154 days (95% confidence interval: 112-202) for patients with portal vein tumor thrombosis; median time to progression was 295 days (95% confidence interval: 209-463) and 221 days, respectively. Adverse events were generally comparable regardless of prior surgery and portal vein tumor thrombosis status. We thus conclude that earlier administration of sorafenib may result in improved outcomes in patients with unresectable hepatocellular carcinoma and portal vein tumor thrombosis.

Background & Aims: Treatment approaches for hepatocellular carcinoma (HCC) vary across countries, but these differences and their potential impact on outcomes have not been comprehensively assessed. Data from the multinational GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) registry evaluated differences in patient characteristics, practice patterns and outcomes in HCC across geographical regions in patients who received sorafenib., Methods: GIDEON is a non-randomised, observational registry study conducted in 39 countries across five global regions. HCC patients in whom a decision to treat with sorafenib was made in clinical practice and according to local practices were included., Results: 3202 patients were evaluable for safety analysis: Asia-Pacific (n = 928), Japan (n = 508), Europe (n = 1113), USA (n = 563) and Latin America (n = 90). Patients in Japan had earlier-stage disease at initial diagnosis compared with patients in other regions (Barcelona Clinic Liver Cancer stage A; 43.7% vs 9.1-24.3%). Use of locoregional therapies before sorafenib, including transarterial chemoembolisation, was more common in Japan (84.4%) and Asia-Pacific (67.2%) compared with the USA (49.4%) and Europe (43.5%). Treatment patterns with respect to sorafenib also differed, with a shorter duration of treatment reported in the USA and Asia-Pacific. Time from initial diagnosis to death was longer in Japan compared with other regions (median, 79.6 months vs 14.8-25.0 months)., Conclusions: Data from GIDEON highlight regional variations in the management of HCC and patient outcomes. Greater standardisation of management may help optimise outcomes for HCC patients., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Conflicting results of the efficacy and safety of conventional transarterial chemo-embolization (cTACE) vs drug-eluting bead (DEB)-TACE have been reported. This meta-analysis aimed to update and re-evaluate the efficacy and safety of cTACE compared with those of DEB-TACE in patients with hepatocellular carcinoma (HCC)., Methods: Literature search was performed by two investigators independently in PubMed, MEDLINE and EMBASE to screen studies published from January 1990 to March 2015. Studies of parallel group designs comparing cTACE and DEB-TACE for HCC were reviewed. Complete response, partial response, objective response, disease control, overall survival and survival time were collected to evaluate the efficacy of each therapy., Results: DEB-TACE increased the complete response rate [odds ratio (OR) 1.38, 95% confidence interval (CI) 1.01-1.89], overall survival rate (OR 1.41, 95% CI 1.01-1.98) and survival time [weighted mean difference (WMD) 6.65, 95% CI 6.15-7.14) with less common adverse events (OR 0.59, 95% CI 0.41-0.84). However, DEB-TACE had a similar partial response rate (OR 1.00, 95% CI 0.67-1.49), objective response rate (OR 1.21, 95% CI 0.94-1.56), disease control rate (OR 1.14, 95% CI 0.81-1.58) and serious adverse events (OR 0.86, 95% CI 0.50-1.49) compared with cTACE., Conclusions: DEB-TACE has a higher complete response rate and a higher overall survival rate in patients with HCC than cTACE; however, the results should be interpreted with caution. Furthermore, DEB-TACE is safer and has less common adverse events than cTACE., (© 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Purpose: To evaluate transarterial chemoembolization (TACE) use prior to and concomitantly with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) across different global regions., Materials and Methods: GIDEON is an observational registry study of more than 3000 HCC patients. Patients with histologically, cytologically, or radiographically diagnosed HCC, and for whom a decision had been made to treat with sorafenib, were eligible. Patients were enrolled into the registry from 39 countries beginning in January 2009, with the last patient follow-up in April 2012. Detailed data on treatment history, treatment patterns, adverse events, and outcomes were collected. All treatment decisions were at the discretion of the treating physicians. Documented approval from local ethics committees was obtained, and all patients provided signed informed consent. Descriptive statistics, including minimum, median, and maximum, were calculated for metric data, and frequency tables for categorical data. Kaplan-Meier estimates with 95% confidence intervals were calculated for survival end points., Results: A total of 3202 patients were eligible for safety analysis, of whom 2631 (82.2%) were male. Median age was 62 years (range, 15-98 years). A total of 1511 (47.2%) patients underwent TACE prior to sorafenib; 325 (10.1%) underwent TACE concomitantly. TACE prior to sorafenib was more common in Japan and Asia-Pacific compared with all other regions (362 [71.3%] and 560 [60.3%] vs 12-209 [13.3%-37.1%]). Adverse events were reported in 2732 (85.3%) patients overall, with no notable differences in the incidence of adverse events, regardless of TACE treatment history. Overall survival was 12.7 months in prior-TACE patients, 9.2 months in non-prior-TACE patients, 21.6 months in concomitant-TACE patients, and 9.7 months in non-concomitant-TACE patients., Conclusion: Global variation exists in TACE use in sorafenib-treated HCC patients. The combination of TACE with sorafenib appears to be a well-tolerated and viable therapeutic approach., ((©) RSNA, 2016 Online supplemental material is available for this article.)

Objectives: Liver-specific MRI is a fast-growing field, with technological and protocol advancements providing more robust imaging and allowing a greater depth of information per examination. This article reports the evidence for, and expert thinking on, current challenges in liver-specific MRI, as discussed at the 7th International Forum for Liver MRI, which was held in Shanghai, China, in October 2013., Methods: Topics discussed included the role of gadoxetic acid-enhanced MRI in the differentiation of focal nodular hyperplasia from hepatocellular adenoma and small hepatocellular carcinoma (HCC) from small intrahepatic cholangiocarcinoma (in patients with chronic liver disease), the differentiation of low-grade dysplastic nodule (DN) from pre-malignant high-grade DN and early HCC, and treatment planning and assessment of treatment response for patients with HCC and colorectal liver metastasis. Optimization of the gadoxetic acid-enhanced MRI protocol to gain robust arterial and hepatobiliary phase images was also discussed., Results and Conclusions: Gadoxetic acid-enhanced MRI demonstrates added value for the detection and characterization of focal liver lesions and shows promise in a number of new indications, including regional liver functional assessment and patient monitoring after therapy; however, more data are needed in some areas, and further developments are needed to translate cutting-edge techniques into clinical practice., Key Points: Liver-specific MRI is a fast-growing field, with many technological and protocol advancements. Gadoxetic acid-enhanced MRI demonstrates value for detecting and characterizing focal liver lesions. Gadoxetic acid-enhanced MRI shows promise in regional functional assessment and patient monitoring. Further developments are needed to translate cutting-edge techniques into clinical practice.

We report data from the final analysis of the Chinese subset of the GIDEON (the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study, which evaluated the safety and efficacy of sorafenib in Child-Pugh A, B and C patients with unresectable hepatocellular carcinoma (uHCC) in real-life clinical practice. Patient demographics, disease characteristics and treatment history were recorded at enrollment; dose, adverse events (AEs) and efficacy were recorded at follow-up. Of the 338 evaluable patients, 98.5% started on 800 mg/day sorafenib, regardless of their Child-Pugh status. The median treatment duration (21.1 vs. 18.8 weeks) and median overall survival (322 vs 240 days) were longer in patients with Child-Pugh A compared with the Child-Pugh B, progression-free survival were 183 vs. 208 days, respectively). AEs (all grades) were comparable in the Child-Pugh B vs A group (56.3% vs. 50.4%, respectively), moreover, the Child-Pugh B group also had comparable rates of drug-related AEs (35.4% vs. 27.2%, respectively) and serious AEs (25.0% vs. 23.0%, respectively) compared with the Child-Pugh A group. The overall dosing strategy was consistent in Chinese patients across Child-Pugh subgroups. Tolerability and safety data suggest that Child-Pugh B patients might be safely treated with sorafenib. The findings from our study showed that safety profile of sorafenib in terms of rate and type of AEs is similar to the global international GIDEON study as well as other pivotal studies.

Background and Aim: Radiofrequency ablation (RFA) is recommended as one of the standard treatments for early hepatocellular carcinoma (HCC). Because of high-risk tumor locations unfit for RFA, transarterial chemoembolization (TACE) is served as an alternative option in these settings. To define the role of TACE on early HCC, we retrospectively compared the efficacies of TACE with RFA in patients with unresectable Barcelona Clinic Liver Cancer (BCLC) stage 0/A HCC., Materials and Methods: Treatment-naïve patients with unresectable BCLC stage 0/A HCC who underwent TACE or RFA were recruited from 2007 to 2011. In all, 208 patients who underwent TACE and 235 patients who underwent RFA were included in the final analysis. Using the propensity model to correct selection bias, 103 patients were selected from each treatment arm. Cumulative overall survival (OS) as the primary end point was compared after adjustment with propensity score matching., Results: In all patients, the OS rate was significantly higher in patients treated with RFA than that in those who received TACE (1-, 3-, and 5-year OS rates, 93.7%, 72.6%, and 58.1% vs 88.1%, 50.3%, and 30.4%, respectively; P < 0.001). However, adjustment with propensity score matching yielded comparable OS between the two groups (P = 0.207). Subgroup analysis showed that RFA provided better OS than TACE in patients with serum γ-glutamyltranspeptidase < 75 IU/L (P = 0.035). Univariate and subsequent multivariate analyses revealed that Child-Pugh class B (hazard ratio = 1.805; 95% confidence interval, 1.805-3.003; P = 0.023) and hepatitis C virus positivity (hazard ratio = 2.478; 95% confidence interval, 1.136-5.404; P = 0.023) were independent predictors of poor prognosis., Conclusion: Transarterial chemoembolization is an effective alternative treatment for unresectable BCLC stage 0/A HCC when RFA is not feasible., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Radiofrequency ablation (RFA) is related to a high intrahepatic distant recurrence (IDR) rate, and the associations between IDR and relevant imaging features have not yet been fully investigated. This study aimed to determine both clinical and imaging risk factors of IDR after complete RFA for HBV-related small hepatocellular carcinoma (HCC) (≤ 3 cm)., Methods: Thirty-five patients (29 men and 6 women; mean age 60.7 years) with 40 HBV-related small HCCs who underwent complete RFA were included in our study. The incidence and potential clinical and MR imaging risk factors for IDR after RFA were assessed using the Kaplan-Meier method, the log-rank test and a stepwise Cox hazard model., Results: The median follow-up period was 25 (4-45) months, and IDR was observed in 20 (57.1%) patients. The 12- and 24-month cumulative IDR-free survival rates were 76.7% and 61.3%, respectively. Univariate analysis revealed that pretreatment albumin < 3.5 g/dL (P = 0.026), multinodular tumor (P = 0.032), ablative margin < 3 mm (P = 0.007), no or disrupted periablational enhancement within 24 hours (P = 0.001) and at 1 month (P = 0.043) after RFA, and hyperintensity of the central ablative zone on T1-weighted images (T1WI) at 1 month after RFA (P = 0.004) were related to IDR. Multivariate analysis showed that pretreatment albumin < 3.5 g/dL (P = 0.032), multinodular tumor (P = 0.012), no or disrupted periablational enhancement within 24 hours after RFA (P = 0.001), and hyperintensity of the central ablative zone on T1WI at 1 month after RFA (P = 0.003) were independent risk factors for IDR. During the 1-month follow-up, the apparent diffusion coefficient exhibited an up-and-down evolution without significant value in the prediction of IDR following RFA., Conclusions: Patients with HBV-related small HCC had a high IDR rate after RFA. The risk factors included low serum albumin, multiple nodules, lesions with no or disrupted periablational enhancement and persistent hyperintensity in the central ablative zone on T1WI within 1 month after RFA.

Inflammation plays a critical role in tumor metastasis. However, few inflammation-related biomarkers are currently available to predict the risk of metastasis for advanced hepatocellular carcinoma (HCC). Using huge tumors (diameter >10 cm) as a model, we evaluated the potential risk of pre- and post-treatment inflammatory responses in the development of metastasis of HCC patients undergoing transarterial chemoembolization (TACE). A logistic regression model was used to analyze the risk factors. One hundred and sixty-five patients with huge HCC were enrolled in the study. Metastases were identified in 25.5% (42/165) patients by imaging evaluation post-TACE. Neutrophils increased, whereas lymphocytes decreased significantly post-TACE. Univariate analysis showed that high post-treatment neutrophil-to-lymphocyte ratio (NLR; p = 0.003), low post-treatment lymphocyte count (p = 0.047), and high baseline NLR (p = 0.100) were potential risk factors for metastasis. Further, multivariate analysis showed that high post-treatment NLR, but not pre-treatment NLR, was an independent risk factor for metastasis; this was confirmed by receiver operating characteristic curve analysis. Post-treatment NLR, however, had no correlation to tumor response and overall survival of patients. In conclusion, post-treatment NLR but not pre-treatment NLR independently increases the risk of metastasis in huge HCC. Our findings suggest the potential contribution of treatment-related inflammation to metastasis in advanced HCC.

Inflammation is particularly strong in huge hepatocellular carcinoma (HCC). However, it is unclear whether the platelet-to-lymphocyte ratio (PLR), as an inflammatory-related marker, can predict survival of patients with huge HCC. In this study, we enrolled 291 patients with huge HCC (diameter over 10 cm) who were undergoing repeated transarterial chemoembolization (TACE) at our institute. The baseline PLR was calculated from complete serum blood counts before the first chemoembolization. We found that a baseline PLR cutoff value over 150 best predicted huge HCC survival. The 12, 24, and 36 months survival rates in the high PLR group (22.6, 8.1, and 4.1 %, respectively) were significantly lower than in the low PLR group (35.6, 22.4, and 14 %, respectively). Thus, a significant difference was found in overall survival (log-rank test, p < 0.0001). Univariate analyses indicated a high PLR (p < 0.0001) was predictor of poor survival, and multivariate Cox analyses further showed that a high PLR (p = 0.002) was an independent factor that predicted worse survival. In conclusion, for patients with huge HCC, a high baseline PLR is a useful predictor of poor survival in patients undergoing chemoembolization. Additional anti-inflammatory or anti-platelet treatments, in combination with TACE, may improve survival in HCC patients with high PLR.

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are common primary liver cancers worldwide. However, the survival and prognosis of ICC are much poorer than those of HCC, indicating the different molecular characteristics and mechanisms between ICC and HCC. To identify differentially expressed (DE) genes between ICC and HCC or combined hepatocellular-cholangiocarcinoma (CHC), we performed integrated analysis of publicly available microarray Gene Expression Omnibus (GEO) datasets by MetaOmics. Three GEO datasets comprising 32 ICC biochips, 77 HCC biochips, and 34 CHC biochips were available for the data integration. We identified 7313 DE genes between ICC and HCC, including 3650 upregulated genes and 3663 downregulated genes. The S100 family members on chromosome 1q21 were extensively upregulated in ICC, and S100A11 had the greatest degree of upregulation in ICC. Based on the DE genes, combined gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed the enhanced pathways of local adhesion, ECM-receptor interaction, and regulation of action cytoskeleton, suggesting the enhanced communication between ICC and the microenvironment. Additionally, development-related genes and development-related pathways, including the Notch, Wnt, and TGF-β signaling pathways, were shown to be active prominently in ICC. Taken together, we identified the characteristically upregulated or downregulated DE genes and pathways in ICC compared with HCC or CHC. These DE genes and pathways supply new transcriptomics evidence for ICC and could help identify new therapeutic targets.

Aim: To investigate transarterial chemoembolization (TACE) with hepatic infusion of oxaliplatin and 5-fluorouracil and Lipiodol chemoembolization in large hepatocellular carcinoma (HCC)., Methods: In this retrospective study, 132 patients with unresectable HCCs larger than 10 cm were treated with hepatic infusion of oxaliplatin and 5-fluorouracil followed by Lipiodol chemoembolization. The primary endpoint was overall survival (OS). Sixteen-week disease-control rate, time to progression (TTP), and major complications were also studied. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP., Results: A total of 319 procedures were performed in the 132 patients. Eleven (8.3%) patients received radical resection following TACE treatment (median time to initial TACE 4.3 ± 2.3 mo). The median OS and TTP were 10.3 and 3.0 mo respectively, with a 50.0% 16-wk disease-control rate. Major complications were encountered in 6.0% (8/132) of patients following TACE and included serious jaundice in 1.5% (2/132) patients, aleukia in 1.5% (2/132), and hepatic failure in 3.0% (4/132). One patient died within one month due to serious hepatic failure and severe sepsis after receiving the second TACE. The risk factor associated with TTP was baseline alpha-fetoprotein level, and vascular invasion was an independent factor related to OS., Conclusion: Hepatic infusion of oxaliplatin and 5-fluorouracil followed by lipiodolized-chemoembolization is a safe and promising treatment for patients with HCCs larger than 10 cm in diameter.

Purpose: To assess whether urea-based cream (UBC) has prophylactic benefits on sorafenib-induced hand-foot skin reaction (HFSR) in patients with advanced hepatocellular carcinoma (HCC)., Patients and Methods: In this randomized, open-label trial, 871 patients with advanced HCC throughout China were treated with 10% UBC three times per day plus best supportive care (BSC; n = 439) or BSC alone excluding all creams (n = 432), starting on day 1 of sorafenib treatment, for up to 12 weeks. HFSR was assessed every 2 weeks and at 14 weeks for patients completing the study. Once HFSR occurred, patients were allowed any cream, including a UBC., Results: The 12-week incidence of any grade HFSR was significantly lower in the UBC group versus the BSC-alone group (56.0% v 73.6%, respectively; odds ratio [OR], 0.457; 95% CI, 0.344 to 0.608; P < .001), as was the incidence of grade ≥ 2 HFSR (20.7% v 29.2%, respectively; OR, 0.635; 95% CI, 0.466 to 0.866; P = .004). Median time to first occurrence of HFSR was significantly longer in the UBC group than the BSC-alone group (84 v 34 days, respectively; hazard ratio, 0.658; 95% CI, 0.541 to 0.799; P < .001). Elevated AST was associated with increased risk of HFSR but did not alter the treatment effect of UBC. UBC plus BSC, compared with BSC alone, did not affect the sorafenib dose reduction or interruption rate (9.1% v 11.8%, respectively; P = .1937), response rate (11.1% v 10.1%, respectively; P = .6674), or disease control rate (98.8% v 98.2%, respectively; P = .5350) at week 12., Conclusion: UBC prophylaxis in patients with advanced HCC starting sorafenib reduced HFSR rates, extended the time to first occurrence of HFSR, and improved patient quality of life compared with BSC. Blinded, randomized, placebo-controlled trials to determine the role of UBC on the incidence and severity of HFSR are warranted., (© 2015 by American Society of Clinical Oncology.)

Radiofrequency ablation (RFA) has been used as a curative therapy for small hepatocellular carcinoma (HCC). However, relatively little is known about the long-term outcome of RFA for small HCC in a background of hepatitis B infection, which is common among the Chinese population. Between May 2001 and May 2012, 837 patients with HCC nodules ≤3 cm treated with RFA were enrolled in this study. We evaluated long-term survival rates, local tumor progression rates, complications and the prognostic factors. Among 1020 tumor nodules in 837 patients, complete ablation was achieved in 98.8% (1008/1020) and the 1-, 3-,5-, and 10-year overall survival rates were 91, 71, 54, and 33%, respectively. Multivariate analysis revealed that tumor number [P = 0.003, hazard ratio (HR) 1.523, 95% confidence interval (CI) 1.158-2.004], Child-Pugh grade (P = 0.001, HR 3.089, 95% CI 2.238-4.266), and serum-glutamyltranspeptidase level (P = 0.002, HR 1.576, 95% CI 1.251-1.985) were independent predictors of overall survival. The 1-, 3-, 5-, and 10-year recurrence-free survival rates were 74, 44, 30, and 15%, respectively. Multivariate analysis revealed that serum α-fetoprotein level (P = 0.041, HR 1.249, 95% CI 1.028-1.517) and tumor number (P = 0002, HR 1.449, 95% CI 1.143-1.836) were independent predictors of recurrence-free survival. There were no procedure-related patient deaths and major complications occurred in 0.59% (5/837) of patients. RFA achieved comparable long-term overall survival rates to those of surgical resection with fewer major complications and could therefore be considered as an alternative option for curative treatment of patients with small liver cancer.

Background: Gender disparity is well known in hepatocellular carcinoma (HCC). SRY is a critical sex-determination gene involved in embryonic development., Aim: The potential relevance of SRY to HCC progression was evaluated., Methods: SRY expression in HCC cell lines and tissues was evaluated. Invasion and wound healing assays were used to evaluate the role of SRY in HCC cell migration. The prognostic value of SRY for HCC patient survival was evaluated., Results: SRY was highly expressed in HCC cell lines and tumor tissues. Downregulation of SRY expression decreased migration and invasion potential of HCC cells. High SRY levels correlated with poor HCC patient survival. Additionally, neither spatial position nor expression intensity of SRY was correlated with HCC gender disparity., Conclusions: High levels of SRY expression correlated with cancer progression and poor HCC patient survival. However, high SRY levels are not significantly correlated with HCC sex bias.

Background: Hairy and enhancer of split 1 (Hes-1) protein is a downstream target of Notch signaling and is a basic helix-loop-helix transcriptional repressor. However, definitive evidence for a role in hepatocellular carcinoma (HCC) cells has not been reported. Here, Hes-1 was revealed to an important component of the Notch signaling cascade in HCC cell lines possessing different potential for lung metastasis., Materials and Methods: RNAi mediated by plasmid constructs was used to analyze the role of Hes-1 in MHCC-97L HCC cells by assessing proliferation, apoptosis, cell migration and matrigel invasion following transfection. Hes-1 protein expression analysis in HCC tissue was also conducted by immunohistochemistry., Results: Our studies revealed that Hes-1 was decreased in HCC cell lines with higher lung metastasis potential at both the mRNA and protein levels. Down-regulation of the Hes-1 gene in MHCC-97L cells resulted in increased cell proliferation, reduced apoptosis and increased migration and invasion., Conclusions: Hes-1 has potential prognostic value in post-surgical HCC patients and may be an independent prognostic indicator for overall survival and tumor recurrence. These findings have important implications for understanding the mechanisms by which Hes-1 participates in tumor proliferation and invasion.

The model of Notch-driven carcinogenesis and development of hepatocellular carcinoma remains controversial and is based on observations of developmental stage- and dose-dependent Notch activation. In this study, the relevance of the spatial distribution of Notch cascade members to the promotion of hepatocellular carcinoma metastasis was evaluated. The spatial expression patterns of the members of the Jagged1 (JAG1)/Notch1 cascade in HCC were evaluated in a tissue microarray of 112 tumors and 46 peri-tumors. Regulation of JAG1/Notch1 on osteopontin (OPN) was evaluated by RNA interference. Tumor cells with JAG1 expressed on the membrane (JAG1(Mem)) were more likely to undergo extrahepatic metastasis [p<0.001; hazard ratio (HR), 0.166; 95% CI, 0.068-0.402], and JAG1(Mem) was a strong independent prognostic factor for metastasis (HR, 0.467; 95% CI, 0.271-0.806; p=0.006). JAG1(Mem) also showed a strong positive correlation with Notch1(Mem). In addition, tumors with JAG1(Mem) expression had more poorly encapsulated membranes (p=0.014). Furthermore, Notch1(Mem) expression correlated with HCC metastasis and was the strongest predictive factor for metastasis. However, in peri-tumoral tissues, most JAG1 (45/46) and Notch1 (41/46) was localized to the cytoplasm. The expression of OPN, one of the main targets of JAG1/Notch1 signaling and a crucial metastasis-related gene in HCC, correlated significantly with JAG1(Mem) expression. Knockdown of JAG1 expression or Notch1 expression induced the downregulation of OPN in HCC cells. Taken together, protein localization is a critical factor affecting the activity of the Notch cascade in the development of hepatocellular carcinoma. Furthermore, our results suggest that the JAG1/Notch1/OPN cascade represents a potential therapeutic target for hepatocellular carcinoma metastasis.

The homeobox gene, goosecoid (GSC), is a transcription factor that participates in cell migration during embryonic development. Because cell migration during development has characteristics similar to cell invasion during metastasis, we evaluated the potential role of GSC in the metastasis of hepatocellular carcinoma (HCC). GSC expression in HCC cell lines and tissues was evaluated, and its effects on the migration potential of HCC cells were determined by GSC knock-down and overexpression methods. In addition, the prognostic role of GSC expression in the metastasis of cancer cells in HCC patients was determined. Our data showed that GSC was highly expressed in several HCC cell lines, particularly in a highly metastatic HCC cell line. Overexpression of GSC promoted cell migration and invasion of HCC cells in vitro. Gain-of-function induced the epithelial-mesenchymal transition but not collective cell migration, whereas loss-of-function induced the reverse change. High-level expression of GSC correlated closely with poor survival and lung metastasis in HCC patients; lung metastases showed more upregulated GSC expression than the primary tumor. We conclude that GSC promotes metastasis of HCC potentially through initiating the epithelial-mesenchymal transition. GSC is also a prognostic factor for poor survival and metastasis of HCC, which suggests its potential as a therapeutic target for metastatic HCC.

The neutrophil-to-lymphocyte ratio (NLR) is a useful biomarker that reflects systemic inflammation responses. However, the prognostic value of the NLR in patients with primary liver cancer (PLC) remains controversial. We performed a meta-analysis of 26 studies (comprising 4,461 patients) to evaluate the association between the pre-treatment NLR and clinical outcomes of overall survival (OS) and disease-free survival (DFS) in patients with PLC. The correlation between NLR and tumor characteristics or other inflammation-related parameters was also assessed. Data were synthesized using the random-effects model of DerSimonian and Laird, and the hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was used to estimate effect size. Our analysis indicated that a high NLR predicted poor OS (HR, 2.102; 95% CI: 1.741-2.538) and DFS (HR, 2.474; 95% CI: 1.855-3.300) for PLC. A high NLR was associated with the presence of tumor vascular invasion (OR: 1.889, 95% CI: 1.487-2.400; p<0.001) and an elevated alpha-fetoprotein level (OR: 1.536; 95% CI: 1.152-2.048; p = 0.003). Thus, we conclude that a high NLR indicates a poor prognosis for patients with PLC and may also be predictive for PLC invasion and metastasis. Subgroup analysis suggested that the predictive role of NLR in cholangiocarcinoma is limited, and a further large study to confirm these findings is warranted.

Background: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials., Methods: Patients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when ~1500 treated patients were followed up for ≥ 4 months., Results: Of the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800 mg initial sorafenib dose, regardless of Child-Pugh status; however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population., Conclusions: Consistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in > 3000 patients are ongoing., (© 2013 The Authors. International Journal of Clinical Practice Published by John Wiley & Sons Ltd.)

Background: Recent studies suggest that a combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) may have theoretical advantages over TACE alone for treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the effectiveness and safety of radiofrequency ablation following first-line TACE treatment in the management of HCC beyond the Milan Criteria., Methods: Forty-five patients who consecutively underwent RFA following first-line TACE treatment for HCC beyond the Milan criteria were enrolled in this study. RFA was performed within 1-2 months after TACE treatment in patients who had incomplete necrotic tumor nodules. Primary effectiveness, complications, survival rates, and prognostic factors were evaluated retrospectively., Results: Complete ablation was achieved in 76.2% of the lesions according to 1-month follow-up computed tomography/magnetic resonance imaging evaluation. The mean follow-up period was 30.9 months (range 3-94 months). There were no major complications after RFA therapy. The median overall survival was 29 months (range 20-38 months), with 1-, 2-, and 3-year survival of 89%, 61%, and 43%, respectively. Multivariate analysis revealed that tumor diameter (P = 0.045, hazard ratio [HR] = 0.228, 95% confidence interval [CI]: 0.054-0.968) and pretreatment serum alpha-fetoprotein level (P = 0.024, HR = 2.239, 95% CI: 1.114-4.500) were independent predictors for long-term survival., Conclusions: HCC beyond the Milan criteria can be completely and safely ablated by radiofrequency ablation following first-line TACE treatment with a low rate of complications and favorable survival outcome. Further assessment of the survival benefits of combination treatment for HCCs beyond the Milan Criteria is warranted.

Profound T cell inhibitory activity of hepatic stellate cells (HSCs) in vitro has recently been described in hepatocellular carcinoma (HCC). In the present study, we investigated the immune inhibitory activity of HSCs in vivo in an orthotopic rat HCC model with lung metastasis. Rats (n=24) were randomly sacrificed on days 7, 14, 21 and 28 (n=4 each). Lung tissues were stained with hematoxylin and eosin. Liver sections were stained for immunofluorescence analysis. T-cell apoptosis was detected using double staining for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Staining revealed marked and continuous accumulation of α-smooth muscle actin with tumor progression after orthotopic tumor implantation in rat liver. T lymphocyte numbers gradually increased following tumor progression, and subset analysis revealed an increase in the distribution of liver CD8+ and CD4+ T cells. Double staining for CD3 and TUNEL demonstrated T-cell apoptosis. Apoptotic T cells were more frequent in the HCC livers compared to the normal livers, and were spatially associated with intratumoral activated HSCs (tHSCs), suggesting a direct interaction. T-cell apoptosis was more frequently induced in the co-cultures of activated splenic T cells(aT)/tHSCs compared to aT/quiescent (q) HSCs or qT/tHSCs. tHSCs were positively correlated with T-cell apoptosis, and the percentage of T-cells undergoing apoptosis was positively correlated with the number of lung metastasis nodules. T-cell apoptosis may be promoted via an interaction with tHSCs, suggesting that tHSCs regulate T cells and contribute to lung metastasis in HCC.

Recurrence and metastasis are the main obstacles to improving the survival of patients with post-resective hepato-cellular carcinoma (HCC). Our previous study suggests a critical role of CXCR7 in the metastasis of HCC. In the present study, the effect of CXCR7 as a risk factor for metastasis of HCC was evaluated. Immunohistochemical assay was performed on tissue microarrays based on HCC with extrahepatic metastases after hepatectomy. Two categories based on staining scores were used to evaluate the risk effect of CXCR7, respectively. The effect of CXCR7 on osteopontin (OPN) was explored by RNA interference. Based on the results, in both categories, highly expressed CXCR7 was a dependent risk factor for extrahepatic metastasis because of the potential association with relatively good cell differentiation. Stratification analyses indicated that CXCR7 was a strong independent risk factor (OR, 3.40; 95% CI, 1.07-18.84; P=0.038 in category 1 and OR, 6.40; 95% CI, 1.64-24.92; P=0.007 in category 2, respectively) in patients with Edmondson grade 1/2. Furthermore, CXCR7 correlated well and positively with expression of OPN (P=0.019 and P<0.001 in two categories, respectively) in HCC cases with Edmondson grade 1/2. Immunocytochemistry and RT-PCR demonstrated downregulation of OPN in a highly metastatic HCC cell line following knockdown of CXCR7. Taken together, these findings suggest that high expression of CXCR7 increases the risk of metastasis in post-resective HCC patients with relatively good differentiated tumors, potentially through upregulation of OPN. This group of patients may acquire a survival benefit from early detection and treatment of recurrence and metastasis.

Aims: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON), a global, non-interventional, surveillance study, aims to evaluate the safety of sorafenib in all patients with unresectable hepatocellular carcinoma (uHCC) under real-life practice conditions, particularly Child-Pugh B patients, who were not well represented in clinical trials., Methods: Treatment decisions are determined by each physician according to local prescribing guidelines and clinical practice. Patients with uHCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Demographic data and medical and disease history are recorded at entry. Sorafenib dosing and adverse events (AEs) are collected throughout the study., Results: From January 2009 to April 2011, >3000 patients from 39 countries were enrolled. The prespecified first interim analysis was conducted when the initial approximately 500 treated patients had been followed up for ≥4 months; 479 were valid for safety evaluation. Preplanned subgroup analyses indicate differences in patient characteristics, disease aetiology and previous treatments by region. Variation in sorafenib dosing by specialty are also observed; Child-Pugh status did not appear to influence the starting dose of sorafenib. The type and incidence of AEs was consistent with findings from previous clinical studies. AE profiles were comparable between Child-Pugh subgroups., Discussion: The GIDEON study is generating a large, robust database from a broad population of patients with uHCC. First interim analyses have shown global and regional differences in patient characteristics, disease aetiology and practice patterns. Subsequent planned analyses will allow further evaluation of early trends., (© 2012 Blackwell Publishing Ltd.)

Background: Hepatocellular carcinoma (HCC) is a common and aggressive form of cancer. Due to a high rate of postoperative recurrence, the prognosis for HCC is poor. Subclinical metastasis is the major cause of tumor recurrence and patient mortality. Currently, there is no reliable prognostic method of invasion., Aim: To investigate the feasibility of fingerprints of volatile organic compounds (VOCs) for the in-vitro prediction of metastasis., Methods: Headspace gases were collected from 36 cell cultures (HCC with high and low metastatic potential and normal cells) and analyzed using nanomaterial-based sensors. Predictive models were built by employing discriminant factor analysis pattern recognition, and the classification success was determined using leave-one-out cross-validation. The chemical composition of each headspace sample was studied using gas chromatography coupled with mass spectrometry (GC-MS)., Results: Excellent discrimination was achieved using the nanomaterial-based sensors between (i) all HCC and normal controls; (ii) low metastatic HCC and normal controls; (iii) high metastatic HCC and normal controls; and (iv) high and low HCC. Several HCC-related VOCs that could be associated with biochemical cellular processes were identified through GC-MS analysis., Conclusion: The presented results constitute a proof-of-concept for the in-vitro prediction of the metastatic potential of HCC from VOC fingerprints using nanotechnology. Further studies on a larger number of more diverse cell cultures are needed to evaluate the robustness of the VOC patterns. These findings could benefit the development of a fast and potentially inexpensive laboratory test for subclinical HCC metastasis.

Background: Liver cancer is both common and burdensome in Asia. Effective liver cancer control, however, is hindered by a complex etiology and a lack of coordination across clinical disciplines. We sought to identify strategies for inclusion in a comprehensive liver cancer control for Asia and to compare qualitative and quantitative methods for prioritization., Methods: Qualitative interviews (N = 20) with international liver cancer experts were used to identify strategies using Interpretative Phenomenological Analysis and to formulate an initial prioritization through frequency analysis. Conjoint analysis, a quantitative stated-preference method, was then applied among Asian liver cancer experts (N = 20) who completed 12 choice tasks that divided these strategies into two mutually exclusive and exhaustive subsets. Respondents' preferred plan was the primary outcome in a choice model, estimated using ordinary least squares (OLS) and logistic regression. Priorities were then compared using Spearman's Rho., Results: Eleven strategies were identified: Access to treatments; Centers of excellence; Clinical education; Measuring social burden; Monitoring of at-risk populations; Multidisciplinary management; National guidelines; Public awareness; Research infrastructure; Risk-assessment and referral; and Transplantation infrastructure. Qualitative frequency analysis indicated that Risk-assessment and referral (85%), National guidelines (80%) and Monitoring of at-risk populations (80%) received the highest priority, while conjoint analysis pointed to Monitoring of at-risk populations (p < 0.001), Centers of excellence (p = 0.002), and Access to treatments (p = 0.004) as priorities, while Risk-assessment and referral was the lowest priority (p = 0.645). We find moderate concordance between the qualitative and quantitative methods (rho = 0.20), albeit insignificant (p = 0.554), and a strong concordance between the OLS and logistic regressions (rho = 0.979; p < 0.0001)., Conclusions: Identified strategies can be conceptualized as the ABCs of comprehensive liver cancer control as they focus on Antecedents, Better care and Connections within a national strategy. Some concordance was found between the qualitative and quantitative methods (e.g. Monitoring of at-risk populations), but substantial differences were also identified (e.g. qualitative methods gave highest priority to risk-assessment and referral, but it was the lowest for the quantitative methods), which may be attributed to differences between the methods and study populations, and potential framing effects in choice tasks. Continued research will provide more generalizable estimates of priorities and account for variation across stakeholders and countries.

The stroma of hepatocellular carcinoma (HCC) is markedly infiltrated with activated hepatic stellate cells (HSCs), and associated invasion and metastasis of HCC. However, little is known of the role of HSCs in immune responses in HCC. The Buffalo rat HCC model was established. Quiescent HSCs (qHSCs) and intratumoral HSCs (tHSCs) were isolated. Surface molecules of tHSC were detected by flow cytometry, and gene expression was analyzed by fluorescence quantitative RT-PCR. T cell proliferation was monitored by [(3)H]-thymidine ((3)H-TdR) incorporation into DNA, and cytotoxic activity was assessed by measuring the release of (51)Cr. The level of cytokine expression by T cells was measured by enzyme-linked immunosorbent assay. T cell apoptosis was detected by double-stained terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and anti-CD3 antibodies. The migration and invasion of HCC was observed by transwell experiments. tHSCs express low levels of major histocompatibility complex (MHC) class I, MHC class II, and costimulatory molecules, and produce varying levels of cytokines. Addition of the tHSCs suppressed thymidine uptake by T cells that were stimulated by alloantigens or by anti-CD3-mediated T-cell receptor ligation. The tHSC-induced T-cell hyporesponsiveness was associated with enhanced T-cell apoptosis, and contributed to the migration and invasion of hepatoma cell. tHSCs was associated with markedly enhanced expression of B7-H1. Blockade of B7-H1/PD-1 ligation significantly reduced HSC immunomodulatory activity, and hepatoma cell migration and invasion. tHSCs can induce T cell apoptosis, suggesting an important role for B7-H1. The interactions between tHSCs and T cells may contribute to hepatic immune tolerance and invasion and migration of HCC.

Objectives: Not every unresectable hepatocellular carcinoma (HCC) could receive survival benefits from transcatheter arterial chemoembolization (TACE), even for intermediate HCC (Barcelona Clinic Liver Cancer stage B). The aim of this study was to investigate prognostic significance of serum γ-glutamyl transferase (GGT) in patients with intermediate HCC treated with TACE., Methods: A total of 277 patients with intermediate HCC were consecutively treated with TACE and overall survival (OS) was evaluated with the Kaplan-Meier method. Significant difference was estimated with the Log rank method according to GGT value before treatment. Univariate and multivariate analyses were used for the study of significance of prognostic factor., Results: The median follow-up period was 18.7 months. The 1-year and 3-year OS rates were 71.6 and 38.5% in patients with normal GGT and 48.8 and 16.9% in patients with high GGT (P=0.002). High GGT, correlating with higher tumor size, α-fetoprotein (AFP), and alanine aminotrasferase, was an independent prognostic factor for OS (P=0.009). Others included tumor size and ascites. Furthermore, in small HCC and normal AFP subgroup, serum GGT was also correlated with OS (P=0.013 and 0.041, respectively). The combination of GGT and AFP had a better power to predict the TACE effects., Conclusion: GGT level was an important prognostic factor to predict prognosis of patients with intermediate HCC treated with TACE.

Osteopontin (OPN) is over-expressed in a variety of cancers, but its role in hepatocellular carcinoma (HCC) progression has not been clarified. In this study, weakly tumorigenic, non-metastastic human HCC cell line SMMC-7721 cells were forced to over-express OPN via stable transfection. A series of functional assays were performed to assess the effects of OPN on tumor cell behaviors and cDNA microarray was used to identify the genes regulated by OPN. The results showed that OPN significantly enhanced the migration and invasion of SMMC-7721 cells in vitro. In addition, CD44v6 antibody could significantly inhibit the invasion of OPN over-expressing SMMC-7721 cells. Moreover, MMP-2 and uPA expressions were significantly up-regulated in OPN over-expressing SMMC-7721 cells. Together, these findings indicate that OPN enhanced HCC cells invasion through interaction with its receptor CD44v6 and increased MMP-2 and uPA expressions, providing at least one mechanism for OPN-mediated HCC progression and metastasis.

Osteopontin (OPN) has an important role in hepatocellular carcinoma (HCC) progression and metastasis. This study was to investigate the therapeutic potential of inhibition of OPN expression. A 2'-O-methoxyethylribose-modified phosphorothioate antisense oligonucleotides (ASO) was used to knock-down OPN expression in the human metastatic HCC cell line HCCLM6 and in nude mice orthotopically implanted with HCCLM6 showing highly spontaneous lung metastasis. Furthermore, we assessed the metastatic potential of HCCLM6 cells in vitro and in vivo after ASO treatment. Treatment of HCCLM6 cells with OPN ASO inhibited OPN mRNA expression in a dose- and time-dependent manner, whereas the control oligonucleotides had no effect. OPN ASO significantly suppressed migration and invasion of HCCLM6 cells in vitro. Specific suppression of OPN also inhibited matrix metalloproteinase 2 (MMP-2) and urokinase-type plasminogen activator (uPA) expression in HCCLM6 cells. In mice bearing orthotopical xenografts with HCCLM6, OPN inhibition following therapeutic treatment with OPN ASO significantly decreased lung metastases although tumor weight did not appear to be reduced. These findings suggest that OPN-targeted therapy may be a promising strategy for the treatment of HCC metastases.

Background: Hepatocellular carcinoma (HCC) is particularly burdensome in the Asia-Pacific region, however, cross-country comparisons have been limited to somewhat unreliable epidemiological measures. We conducted a comparative needs assessment for HCC control policy to inform HCC control efforts in the Asia-Pacific region. The aims were to identify regional needs, to compare overall competence across the region, and to identify which needs were concordant across the region., Method: Using the self-explicated method, a stated-preference approach, clinical experts from Australia, China, Japan, Korea, Taiwan, and the United States valued ten previously identified dimensions of HCC control: clinical education; risk assessment; HBV strategy; HCV strategy; life-style risk factors; national statistics; funding for screening; funding for treatment; political awareness; and public awareness. Results were normalized and analyzed using Z-scores and ANOVA, with concordance of need across the region tested via the F-test., Results: Seventy-two respondents, equally drawn from the study sites, completed the survey (response rate: 36%). Respondents were hepatologists (39%), oncologists (21%), radiologists (17%), surgeons (17%), and other specialists (7%) who were involved in liver cancer control at local/regional (35%) national (44%) or international (21%) levels. In aggregate, the most significant needs were political awareness, public awareness, and life-style risk factors (all p<0.001). Significant differences in aggregate competence were observed across the region (p<0.001), with better than expected competence reported by respondents from Taiwan (p<0.001), Japan (p=0.006), and Korea (0.041), and close to expected competence reported by respondents from Australia, China, and USA (all p>0.05). There were differences in the extent of needs across the region (p<0.05) on all dimensions except funding for screening, clinical education and life style risk factors., Conclusions: As the first comparative needs assessment for HCC for the Asia-Pacific region, our results can inform national and cross-national priorities for intervention and facilitate the identification of best practices. Regional efforts to control HCC should adopt as objectives the needs for greater political and public awareness and improved management of lifestyle risk factors because these are the most significant needs, and are shared concerns across the region.

The lung is the most frequent metastatic site of hepatocellular carcinoma (HCC), negatively impacting on survival rates. In this study, we evaluated the prognostic role of the chemokine receptor CXCR7 in lung metastasis of HCC after hepatectomy, using immunohistochemical detection on tissue microarrays of HCCs, with and without lung metastasis. Using three categories based on staining characteristics, patients with high CXCR7 expression demonstrated a shorter time to development of lung metastasis compared with patients with low CXCR7 expression (log-rank test) with no effet on overall survival. Analysis of tissue adjacent to tumor showed patients with microvascular invasion to have higher CXCR7. Stratification based on alpha fetoprotein level >20 ng/ml also showed high expression of CXCR7 to be a strong independent prognostic factor. These findings suggest that high expression of CXCR7 in HCCs with elevated alpha fetoprotein levels correlates with metastasis to lung and poor survival after hepatectomy, indicating potential use as a prognostic factor.

Background: Specific gene expression is tightly regulated by various transcription factors. Osteopontin (OPN) is a phosphoprotein that mediates hepatocellular carcinoma (HCC) progression and metastasis. However, the mechanism of OPN up-regulation in HCC metastasis remains to be clarified., Methods: Oligonucleotide array-based transcription factor assays were applied to compare different activities of transcription factors in two human HCC cell lines with different OPN expression levels. The effects of one selected transcription factor on OPN expression were further evaluated., Results: Eleven transcription factors were over-expressed in metastatic HCC cell line HCCLM6 cells whereas twelve transcription factors were down-regulated. Electrophoretic mobility shift assays (EMSA) and reporter gene assays showed that one of up-regulated transcription factors c-Myb could bind the OPN promoter and increase its transcription activity. In addition, small interfering RNA targeting c-Myb could inhibit OPN expression and significantly decrease migration and invasion of HCCLM6 cells in vitro., Conclusion: Our data first demonstrate that c-Myb has a functionally important role in the regulation of OPN expression in HCC cells, suggesting that c-Myb might be a new target to control HCC metastasis.

The largest burden of hepatocellular carcinoma (HCC) lies in Asia, secondary to hepatitis B virus (HBV) infection. Improved survival with sorafenib has fostered new research but many challenges remain in designing clinical trials. The disease, its management, and populations affected by it are heterogeneous worldwide and within Asia. An expert conference of Eastern Asian oncologists and hepatologists was convened to foster consensus in clinical trial design. The panel identified key areas that need to be addressed to facilitate clinical trials in Asia. Stratification by viral etiology is desirable within Asia and by region in global trials. Antiviral therapy should also be considered as a stratification factor and incorporated into HCC management in trials. The panel agreed that histological diagnosis is not required for trial entry and that Barcelona-Clinic Liver Cancer (BCLC) staging is acceptable for trials as long as portal hypertension can be better defined with standardized methodology. Consensus in treatment must be sought to allow multi-national trials and it must be recognized that first-line sorafenib is not largely feasible in Asia. Finally, Asian nations must be urged to participate in clinical trials, many of which are ongoing, to advance new treatment options in this challenging disease.

Asia has a disproportionate share of the world's burden of hepatocellular carcinoma (HCC). However, the highly regarded clinical practice guidelines and recommendations for the design and conduct of clinical trials for HCC largely reflect Western practice. In order to design mutually beneficial international clinical trials of promising targeted therapies, it is imperative to understand how the aetiology, staging and treatment of HCC differ between Asian and Western countries. Our group, comprising experts in oncology and hepatology from countries that constitute the Eastern Asian region, convened to compare and contrast our current practices, evaluate potential compliance with the clinical trial recommendations, and offer suggestions for modifications that would enhance international collaboration. Here, we describe the results of our discussions, including recommendations for appropriate patient stratification based on potentially important differences in HCC aetiology, identification of practices that may confound interpretation of clinical trial outcomes (traditional Chinese medicine; antivirals that target hepatitis B virus; heterogeneous embolization procedures), suggestions for utilizing a common staging system in study protocols, recognition that sorafenib usage is limited by financial constraints and potentially increased toxicity in Asian patients, and expansion of patient populations that should be eligible for initial clinical trials with new agents., (© 2010 John Wiley & Sons A/S.)

Background/aims: The metastasis of hepatic carcinoma is correlated with the body's immune status. T lymphocytes play a big part role in tumor immune. The aim of the present study is to investigate the inhibition effects of metastatsis in nude mice bearing hepatic carcinoma after T lymphocytes reconstitution., Methodology: An immune reconstitution model was established in nude mice. Then, 42 nude mice were distributed into 4 groups for T lymphocytes reconstitution. The lymph nodes of each group were obtained to investigate the tumor metastasis. And the secretion of cytokines and the apoptosis of tumor cells in each group were also detected., Results: The ratio of CD3, CD4, CD8, CD4/CD8 in reconstituted groups were higher than controlled groups. The average time of tumor formation in Balb/c nu/nu mice was 7.7 +/- 0.6 days and in Balb/c mice was 11.5 +/- 1.3 days. After active T lymphocytes reconstitution, the extent lymph nodes metastasis in reconstitution groups was lower than control groups (p < 0.05), but proximal metastasis has no significant difference. The level of serum IL-10 in nude mice after immune reconstitution was significantly lower and VEGF was significantly higher than that of the control group (p < 0.05). Apoptosis of the hepatic carcinoma cells was increased significantly after immune reconstitution (p < 0.05)., Conclusions: The metastasis of hepatic carcinoma can be inhibited by reconstitution of actived T lymphocytes in nude mice, which indicated that tumor metastasis can be affected by the immune status in host body.

Objective: To identify the effect of postoperative adjuvant transarterial chemoembolization (TACE) on late recurrence of hepatocellular carcinoma (HCC) patients after radical resection., Methods: From year 2001 to 2007, 2436 HCC patients underwent radical resection were retrospectively selected. Patients underwent resection only were classified into control group, while those received adjuvant TACE within 2 months after operation were classified into intervention group. Patients were further stratified into those with tumor5 cm and presenting low or high risk factors for recurrence. Patients with single tumor and without microscopic tumor thrombus were defined as low risk for recurrence; otherwise they were defined as high risk. The effect of adjuvant TACE on late (>2 years) recurrence was evaluated., Results: Recurrence rates of tumor5 cm and presenting low, high risk factors for recurrence at 2-year after resection were 20.38%, 33.06%, 30.54% and 50.82%, respectively in the control group, compared with 25.41%, 39.61%, 40.55% and 51.57%, respectively in the intervention group; there were no significant differences between intervention group and control group in each stratum. For patients recurred or died within the first 2 years after resection, the median survival of tumor>5 cm and presenting high risk factors for recurrence was 24 months in the intervention group and 12 months in the Control group. Only in this subgroup, the survival curve of the intervention group was significantly higher than that compared to the control group. For patients who remained recurrence free and survived within the first 2 years after resection, there were no significant differences in the recurrence curves between the intervention group and control group in each stratum; while cumulative survival rates in the subgroup of patients with tumor size is less than or equal to 5 cm and presenting low risk factors for recurrence were 93.95%, 91.50% and 88.42% respectively in the control group, compared with 91.70%, 81.32% and 78.19% respectively in the intervention group at 3-, 4- and 5-year after resection (P=0.0062); for other subgroups, there were no significant differences in the survival curves between the intervention group and the control group in each stratum. Cox regression model suggested adjuvant TACE was not an independent risk factor for late recurrence; however, it might have negative effect on survival [hazard ratio (HR)=1.50, P=0.062] for those patients (especially patients with tumor is less than or equal to 5 cm and presenting low risk factors for recurrence)., Conclusions: The value of adjuvant TACE was mainly due to its therapeutic actions on residual tumor or early recurrence. It had no effect on postponing or eliminating late recurrence; moreover, it could be a risk rather than a benefit in patients at low risk for recurrence (especially those with tumor is less than or equal to 5 cm and presenting low risk factors for recurrence).

Objective: To evaluate the efficacy and analyze the prognostic factors of sorafenib treatment in patient with unresectable primary hepatocellular carcinoma (HCC)., Methods: During the period from December 2005 to March 2009, 50 patients with unresectable primary HCC of Child-Pugh status A were treated with sorafenib (400 mg, Bid). The tumor response was evaluated with CT or MRI imaging every 6 - 8 weeks according to the RECIST criteria. The overall survival (OS) and time to progression (TTP) were defined as the time from administration of sorafenib to the death or the last follow up and were evaluated by Kaplan-Meier method., Results: There was no PR or CR, but 28 patients (56.0%) achieved stable disease. The median follow up time was 15 months with a median OS of 14 months and median TTP of 4 months. The common adverse events were dermal reaction (68.0%, 34/50), diarrhea (52.0%, 26/50), hypertension (4.0%, 2/50), hair loss (14.0%, 7/50), myelosuppression (16.0%, 8/50), and liver dysfunction (20.0%, 10/50). However, most of the drug-related adverse events were grade I-II and reversible. The patients with lower tumor burden and without distant metastasis had better prognosis., Conclusion: Soafenib is effective for unresectable primary HCC with tolerable toxicity. Tumor stage is a predominant prognostic factor.

Background and Aim: Osteopontin (OPN) has been linked to clinical outcomes in several solid tumors. However, it has not been fully evaluated whether OPN could be used as a single marker for the prognosis of patients with hepatocellular carcinoma (HCC), particularly in patients of the tumor-node-metastasis (TNM) stage I., Methods: A total of 151 patients with HCC who underwent surgical resection were enrolled, including 112 patients of the TNM stage I. OPN expression was evaluated using immunohistochemistry in the tissue microarrays derived from these patients. Immunoreactivity was classified according to the percentage and intensity of staining: negative (-), weak (+) and strong (++). The impact of OPN expression on survival of patients was analyzed., Results: In total, 65.6% (99 of 151) of HCC tissues expressed OPN. Overall survival in patients of OPN (-) group was significantly higher than those of OPN (+) or OPN (++) group (P = 0.049 and P = 0.001). Interestingly, in patients of the TNM stage I, OPN expression was correlated with the early recurrence after surgical resection (P = 0.001). Multivariate analysis showed that OPN expression was an independent prognostic factor for overall survival and disease-free survival in patients with the TNM stage I HCC (hazard ratio, 2.272, P = 0.014 and 1.982, P = 0.037)., Conclusions: These results suggest that OPN is commonly expressed in HCC and is a useful marker for predicting the prognosis of patients with the TNM stage I HCC, contributing to determining which individual patient needs adjuvant therapy to prevent the early recurrence after surgical resection.

Background: Hepatocellular carcinoma (HCC) is a complicated condition influenced by multiple confounding factors, making optimum patient management extremely challenging. Ethnicity, stage at diagnosis, comorbidities and tumour morphology affect outcomes and vary from region to region, and there is no common language to assess patient prognosis and make treatment recommendations. Despite recent efforts to reduce the incidence of HCC, most patients present with unresectable disease. Non-surgical treatments include ablation, transarterial chemoembolisation and the multikinase inhibitor, sorafenib, but their effects in all patient subgroups are not known and further information is needed to optimise the use of these treatments., Aims: The Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with SorafeNib (GIDEON) study (ClinicalTrials.gov identifier NCT00812175; http://clinicaltrials.gov/) is an ongoing global, prospective, non-interventional study of patients with unresectable HCC who are eligible for systemic therapy and for whom the decision has been taken to treat with sorafenib under real-life practice conditions. The aim of this study is to evaluate the safety and efficacy of sorafenib in different subgroups, especially Child-Pugh B where data are limited., Discussion: This study will recruit 3000 patients from > 40 countries and follow them for approximately 5 years to compile a large and robust database of information that will be used to analyse local, regional and global differences in baseline characteristics, disease aetiology, treatment practice patterns and treatment outcomes, with a view to improve the knowledge base used to guide physician treatment decisions and to improve patient outcomes.