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Objectives: To investigate the association of sarcopenia, myosteatosis, and sarcopenic obesity with survival outcomes among patients who underwent immunotherapy for advanced hepatocellular carcinoma (HCC)., Methods: In this retrospective analysis, patients who initiated immunotherapy for advanced HCC were enrolled. Sarcopenia and myosteatosis were evaluated on pretreatment CT at L3 level by skeletal muscle index and mean muscle attenuation using predefined cutoff values. Sarcopenic obesity was defined as concurrent sarcopenia and body mass index > 25 kg/m 2 . The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS)., Results: A total of 138 patients was included (discovery cohort n = 111, validation cohort n = 27). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p = 0.048) and OS (p = 0.002) than patients without sarcopenia. Patients with myosteatosis exhibited significantly poorer PFS (p < 0.001) and OS (p < 0.001) than patients without myosteatosis. Patients with sarcopenic obesity compared to patients without sarcopenic obesity exhibited significantly poorer OS (p = 0.006) but not PFS (p = 0.31). In multivariate analysis adjusting for patient demographics, tumor extent, and liver function reserve, myosteatosis remained an independent predictor of poor PFS (p = 0.014) and OS (p = 0.007); sarcopenia remained an independent predictor for poor OS (p = 0.007). The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort., Conclusions: Sarcopenia and myosteatosis are independent prognostic factors in patients who received immunotherapy for advanced HCC., Key Points: • Sarcopenia and myosteatosis can be evaluated by CT at L3 level. • Sarcopenia, myosteatosis, and sarcopenic obesity were associated with poor survival outcomes in patients who underwent immunotherapy for advanced HCC. • Myosteatosis was an independent predictor of PFS and OS, and sarcopenia was independent for OS in these patients., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials., Methods: All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records., Results: We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed., Conclusion: In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations., Competing Interests: Declaration of competing interest YYS had received honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Ipsen, Merck, Ono, and Roche. YHF had received honoraria from Roche, AbbVie, and Novartis. CJY declared no conflict of interest to disclose. TSY declared no conflict of interest to disclose. YCS had received honoraria from AstraZeneca, Bristol Myers Squibb/Ono, Roche and Eisai. YC declared no conflict of interest to disclose. JSC had received research founding from Ono Pharmaceutical, MSD Oncology, Lilly, TTY Biopharm, Merck KGaA, Roche, AstraZeneca, Janssen, Syncore, Astellas Pharma and Senhwa Biosciences. CYS, WJC, and HLH are employed by Roche. CHH has served as a consultant in advisory boards of Roche and AstraZeneca, has received honoraria from Bristol Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme, and Roche, and has received research grant from AstraZeneca, Bayer, Eli Lilly, Genentech, and Roche., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: The combination of atezolizumab and bevacizumab (Atezo-Bev) has become the standard first-line therapy for patients with advanced hepatocellular carcinoma (HCC), but the prognosis and treatment pattern after its treatment failure are unclear., Methods: We reviewed the medical records of patients who failed first-line Atezo-Bev treatment for advanced HCC from January 2018 to May 2021 in four Taiwan medical centers. Post-first-line survival (PFLS) was defined as the date from the failure of Atezo-Bev treatment to the date of death or last follow-up., Results: A total of 41 patients were included in the study. All patients had Child-Pugh A liver reserve before the initiation of Atezo-Bev treatment, but the liver reserve of 6 (15%) and 7 (17%) patients deteriorated to Child-Pugh B and C, respectively, after treatment failure. The median PFLS was 5.9 months. PFLS significantly differed among patients with various liver reserves after the failure of Atezo-Bev treatment (median 9.6 vs 3.8 vs 1.2 months, for Child-Pugh A, B, and C; p < 0.001). In total, 30 (73%) patients received second-line systemic therapy, and they exhibited significantly longer PFLS (median 8.0 vs 1.8 months, p = 0.033) than patients who did not. Deteriorated liver function and not receiving second-line therapy remained associated with inferior PFLS in multivariate analysis. The most common second-line therapies were sorafenib (n = 19, 63%) and lenvatinib (n = 9, 30%), with no significant differences in efficacies., Conclusion: Receiving second-line therapy and good liver reserve were associated with favorable PFLS after the failure of first-line Atezo-Bev treatment., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background/aim: The reimbursement criteria of sorafenib for advanced hepatocellular carcinoma (HCC) were expanded in 2016 by Taiwan's National Health Insurance (NHI) to include patients without macrovascular invasion or extrahepatic spread. This study explored sorafenib treatment outcomes before and after this expansion., Patients and Methods: The NHI database was searched for patients who initiated sorafenib treatment between January 1, 2013, and December 31, 2017. Clinical variables were retrieved from the Taiwan Cancer Registry database. Overall survival (OS) and time to treatment discontinuation (TTD) were calculated as the times from the first sorafenib prescription date until death and the final prescription date, respectively., Results: A total of 13,862 patients were included. The median age was 64 years, 78.1% of patients were male. Approximately a quarter of patients (25.1%) received sorafenib after the criteria expansion and exhibited significantly longer OS (median 7.9 vs. 6.6 months, p<0.001) and TTD (median 3.0 vs. 2.6 months, p=0.003) compared with patients who started before. These results were verified in patients with available data regarding clinical prognostic factors (n=9,378, 67.7% of the entire study population). In the multivariate analysis, sorafenib prescription after criteria expansion remained an independent predictor of longer OS [hazard ratio (HR)=0.87, p<0.001] and TTD (HR=0.93, p=0.004). In the subgroup analysis, these trends were consistently observed across different patient subgroups., Conclusion: Patients with HCC who received sorafenib treatment after the reimbursement criteria expansion exhibited longer OS and TTD., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Sorafenib is one of the standard first-line therapies for advanced hepatocellular carcinoma (HCC). Unfortunately, there are currently no appropriate biomarkers to predict the clinical efficacy of sorafenib in HCC patients. MicroRNAs (miRNAs) have been studied for their biological functions and clinical applications in human cancers., Methods: In this study, we found that miR-10b-3p expression was suppressed in sorafenib-resistant HCC cell lines through miRNA microarray analysis., Results: Sorafenib-induced apoptosis in HCC cells was significantly enhanced by miR-10b-3p overexpression and partially abrogated by miR-10b-3p depletion. Among 45 patients who received sorafenib for advanced HCC, those with high miR-10b-3p levels, compared to those with low levels, exhibited significantly longer overall survival (OS) (median, 13.9 vs. 3.5 months, p = 0.021), suggesting that high serum miR-10b-3p level in patients treated with sorafenib for advanced HCC serves as a biomarker for predicting sorafenib efficacy. Furthermore, we confirmed that cyclin E1, a known promoter of sorafenib resistance reported by our previous study, is the downstream target for miR-10b-3p in HCC cells., Conclusions: This study not only identified the molecular target for miR-10b-3p, but also provided evidence that circulating miR-10b-3p may be used as a biomarker for predicting sorafenib sensitivity in patients with HCC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Vascular endothelial growth factor (VEGF) plays a role in the tumor microenvironment. Sorafenib, which inhibits the VEGF pathway, has an immune-modulation function but lacks substantial clinical data. This study aims to explore the efficacy of anti-PD-1 combined sorafenib in advanced hepatocellular carcinoma (HCC)., Methods: HCC patients who underwent anti-PD-1 treatment at Taipei Veterans General Hospital (Taipei, Taiwan) between January 2016 and February 2019 were reviewed. The efficacy was compared between groups after propensity-score matching., Results: There were 173 HCC patients receiving anti-PD-1. After excluding unsuitable cases, 140 patients were analyzed, of which 58 received combination therapy and 82 received anti-PD-1 alone. The combination therapy had a trend of higher CR rate (8.6% vs. 4.9%, ns.), ORR (22.4% vs. 19.5%, ns.) and significantly higher DCR (69.0% vs. 37.8%, p < 0.05) comparing to anti-PD-1 alone. After matching, combination group achieved longer progression-free survival (3.87 vs. 2.43 months, p < 0.05) and overall survival (not reached vs. 7.17 months, p < 0.05) than anti-PD-1 alone, without higher grade 3/4 AE (10.3% vs. 7.1%, p = 0.73). The tumor response varied among different metastatic sites, with high responses in adrenal glands, peritoneum and lungs. The more AFP declined (> 10, > 50 and > 66%), the higher the ORR (70, 80 and 92%) and CR rates (30, 35 and 58%) were achieved at day 28., Conclusions: This is the first study to demonstrate the combination of anti-PD-1 and sorafenib had better efficacy and survival benefit. A prospective randomized study is needed to confirm this finding., (© 2022. The Author(s).)

Introduction: Inducible co-stimulator (ICOS), an important co-stimulatory receptor on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC)., Methods: Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center. Dual immunohistochemistry was performed to evaluate the expression of ICOS and Foxp3. The cell densities and proximities between stained cells in regions of interest were measured by digital pathology and the associations with clinical outcome were analyzed., Results: A total of 142 patients (male:female = 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus infection and 33 (23.2%) had chronic hepatitis C infection. Low α-fetoprotein level (<20 ng/mL) and early-stage were significantly associated with improved overall survival (OS). The density of ICOS+Foxp3+ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p < 0.001) in the tumor center than in the peritumor area. Patients with a high density of ICOS+Foxp3+ cells or a high ratio of ICOS+Foxp3+/total Foxp3+ cells in the tumor center trended to have a shorter OS. A shorter distance between ICOS+Foxp3+ cells and ICOS+Foxp3- cells (likely Teffs) in the tumor center was significantly associated with a shorter OS (p = 0.030), suggesting active immunosuppression of ICOS+ Tregs on ICOS+ Teffs., Conclusion: An increased abundance of ICOS+ Tregs in the tumor center in comparison to the peritumor area indicates a strong immunosuppressive tumor microenvironment of HCC. A high proportion of ICOS+Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells were associated with a poor OS, suggesting that depleting ICOS+ Tregs might provide clinical benefit for patients with HCC., (© 2022 S. Karger AG, Basel.)

Purpose: Composite cyclin-dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC., Methods: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition., Results: CDK9 inhibitors exhibited potent antiproliferative activities in HCC cells regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1 and survivin. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited significantly slower tumor growth than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving a CDK9 inhibitor also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Knockdown of CDK9 expression reduced the proliferative activities of HCC cells., Conclusion: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC., (© 2022 S. Karger AG, Basel.)

Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC.

Background/purpose: Recent progress in cancer immunology provides more insight in immune evasion of cancer cells. Cancer cells may achieve immune evasion through several ways including ineffective antigen presentation, T cell checkpoint utilization, immunosuppressive cytokines secretion and immunosuppressive cells recruitment. However, few literatures mentioned about the change of peripheral blood immune cells in advanced hepatocellular carcinoma (HCC) patients. To answer this question, we initiated a pilot study through detailed flow cytometry., Methods: We enrolled patients with advanced HCC patients who had informed consent to the collection of their peripheral blood. We also recruited healthy individuals for the control group. Using flow cytometry, we analyzed lymphocyte subclasses and the PD-1 or PD-L1 positivity of immune cells in peripheral blood from HCC patients and healthy individuals., Results: Twenty-four HCC patients were enrolled and twenty healthy individuals were enrolled. Most of the HCC patients were HBV carrier (58.3%), and the mean age was 61 years old. Among 55 immune cell parameters we examined in peripheral blood, 16 were significantly different between advanced HCC patients and healthy individuals by univariate analysis. Multivariate analysis was then conducted by fitting logistic regression model and showed that CD69 - CD25 - Naïve CD4αβT cell percentage and dendritic cell percentage can reasonably predict the advanced HCC status from peripheral blood. By our regression model, the adjusted generalized R2 = 0.918 and the estimated area under the Receiver Operating Characteristic (ROC) curve was 0.99., Conclusion: CD69 - CD25 - Naïve CD4αβT cell percentage and dendritic cell percentage in peripheral blood are highly correlated with the advanced HCC status. The change may result from immune evasion initiated by hepatocellular carcinoma cells and further investigation is warranted. Validation study is ongoing and this mechanism may be utilized to treat advanced HCC patient in the future., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

Background: The kinesin Eg5 , a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in hepatocellular carcinoma (HCC)., Methods: HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model., Results: A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS ( p < 0.001) or DFS remained ( p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control., Conclusion: High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.

Background: Many systemic therapies for advanced hepatocellular carcinoma (HCC) may cause hypothyroidism; however, in these patients, hypothyroidism prevalence before therapy and its prognostic impact remain unclear., Materials and Methods: We previously established a prospective cohort of patients who received sorafenib as first-line therapy for advanced HCC. No patients had been clinically diagnosed with hypothyroidism before or during sorafenib treatment. We retrospectively determined the levels of thyrotropin and free thyroxine before initiation of systemic therapy. Hypothyroidism was defined as thyrotropin level higher than the upper limit of the normal range. Among patients with hypothyroidism, free thyroxine level less than the lower normal range was defined as overt hypothyroidism, and free thyroxine level within the normal range was defined as subclinical hypothyroidism., Results: In total, 79 patients were enrolled; of them, 16 (20%) had hypothyroidism (overt hypothyroidism, 10; subclinical hypothyroidism, 6). Patients with hypothyroidism, compared with those without hypothyroidism, were more likely to be older than 65 years (56% vs. 29%, p = .037), have a serum α-fetoprotein level of >400 ng/mL (81% vs. 52%, p = .037), and have a significantly poorer overall survival (OS; median, 5.5 vs. 11.6 months, p = .043). After adjusting for other potential prognostic factors, hypothyroidism remained an independent predictor for poorer OS (hazard ratio, 2.53, p = .018). Patients with overt hypothyroidism and subclinical hypothyroidism exhibited similarly poor OS (p = .768)., Conclusion: Underdiagnosis of hypothyroidism in patients with advanced HCC was common. Hypothyroidism, whether overt or subclinical, is associated with poor prognosis of advanced HCC., Implications for Practice: The results of this study showed the underdiagnosis of hypothyroidism in patients with advanced hepatocellular carcinoma (HCC) and its influence on prognosis. These findings implied the importance of thyroid function check before initiation of systemic therapy for patients with advanced HCC., (© 2021 AlphaMed Press.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan had established a management consensus guideline in 2016. The current recommendations focus on updating critical issues regarding the management of HCC, including surveillance, diagnosis, and systemic treatment. For surveillance, the updated guideline suggests the role of dynamic computed tomography or magnetic resonance imaging and contrast-enhanced ultrasound (CEUS) in selected patients. For diagnosis, this update incorporates CEUS and recognizes the role of gadoxetic acid-enhanced magnetic resonance imaging. For systemic therapy, the updated guideline summarizes the multiple choices of targeted therapy, immune checkpoint inhibitors, and the combination of both. Through this update of the management consensus guideline, patients with HCC can benefit from receiving optimal diagnostic and therapeutic modalities., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

Background: Remarkable progress has been made in immunotherapy, specifically antibodies for programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), for treating advanced cancers. In this study, we explored whether circulating immune cells can be used as biomarkers of the efficacy of such therapy., Methods: We enrolled patients who received nivolumab, an anti-PD-1 antibody, for advanced hepatocellular carcinoma (HCC) in clinical trials and who consented to the collection of their peripheral blood. Using flow cytometry, we analyzed lymphocyte subclasses and the PD-1 or PD-L1 positivity of immune cells. These results were compared between patients with disease control (complete response, partial response, or stable disease) and those with disease progression., Results: This study included 16 patients. The objective response rate was 19%, and the disease control rate was 75%. The hemogram results and the percentage of total αβ T cells or CD4 T cells did not significantly change after nivolumab treatment; moreover, they were not associated with treatment outcomes. The number of CD8 T cells significantly increased after 4 weeks (p = 0.016); however, this change was not associated with treatment outcomes. Patients with disease control exhibited peripheral B cells with significantly lower pretreatment PD-1 positivity than did patients with disease progression (p = 0.042). Patients with disease progression were more likely to exhibit monocytes with increased PD-L1 positivity after 28 (p = 0.020) or 42 (p = 0.008) days of treatment., Conclusion: The low pretreatment PD-1 positivity of peripheral B cells and the constant posttreatment PD-L1 positivity of monocytes were associated with disease control after nivolumab treatment for advanced HCC., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2020, the Chinese Medical Association.)

Competing Interests: Declaration of competing interest Dr. Chih-Hung Hsu reports receiving honoraria from BMS, MSD, ONO Pharmaceutical Company, and Roche; serving in a consulting role for BMS, MSD, ONO Pharmaceutical Company, and Roche; and receiving research funding from MSD. Dr. Yu-Yun Shao and Dr. Tsung-Hao Liu report no conflicts of interest.

Purpose: We investigated whether low skeletal muscle mass (LSMM) defined according to different muscle groups on computed tomography (CT) scans are predictive factors of survival for advanced hepatocellular carcinoma (HCC)., Methods: In this retrospective study, we analyzed patients who received sorafenib therapy for advanced HCC in a prospective patient cohort between 2007 and 2012. The total skeletal muscle (TSM), paraspinal muscle (PS), psoas muscle (PM), rectus abdominis (RA), and abdominal wall (AW) muscle areas were evaluated using a single CT slice at the third lumbar vertebra before treatment. LSMM was determined according to the TSM, PS, PM, RA and AW indices, which was calculated as the parameters divided by the square of the body height., Results: We enrolled 137 patients. Women had significantly lower TSM index than men did (p < .001). Among men, the optimal cut points of the TSM, PM and RA indices for LSMM diagnosis were 39.1, 8.3 and 2.9 cm 2 /m 2 , respectively. Patients with LSMM defined by TSM (median 5.1 vs. 8.0 months, p = .007), PM (5.8 vs. 11.8 months, p < .001), and RA (7.2 vs. 8.1 months, p = .003) indices exhibited poorer overall survival than patients without LSMM. After adjusting for clinical variables, TSM (hazard ratio [HR]: 2.122, 95% confidence interval [CI]: 1.134-3.971) and PM (HR: 1.730, 95% CI: 1.058-2.828) indices-defined LSMM remained independent predictors for poor OS, but RA index-defined LSMM did not., Conclusion: LSMM defined by TSM and PM indices are independent predictors of poor prognosis for advanced HCC., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

Lessons Learned: For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers., Background: Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC., Methods: Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control., Results: From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib., Conclusion: Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background: Post-treatment decline in serum alpha-foetoprotein (AFP) levels has been shown to predict the treatment efficacy of antiangiogenic therapy for advanced hepatocellular carcinoma (HCC). We explored whether a decline in AFP levels was also associated with treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with advanced HCC., Methods: We reviewed all patients who received ICI therapy for advanced HCC. AFP response was evaluated in patients with the pretreatment AFP level of >20 ng/mL. We defined early AFP response as a >20% decline in serum AFP levels within the first 4 weeks of treatment initiation relative to pretreatment levels. We then studied whether early AFP response was associated with treatment outcomes., Results: Sixty patients were enrolled in this study; 43 of them were evaluable for early AFP response. The objective response rate of early AFP responders was significantly higher than that of early AFP nonresponders (73% vs. 14%, P < .001). Early AFP responders, compared with early AFP nonresponders, exhibited significantly longer overall survival (OS) (median, 28.0 vs 11.2 months, P = .048) and progression-free survival (PFS) (median, 15.2 vs 2.7 months, P = .002). After adjusting for other clinicopathological variables and treatments, early AFP response remained an independent predictor for longer OS (hazard ratio [HR] = 0.089, 95% confidence interval [CI] = 0.018-0.441; P = .003) and PFS (HR = 0.128, 95% CI = 0.041-0.399; P < .001)., Conclusion: Early AFP response was associated with higher treatment efficacy of ICIs for advanced HCC. Additional validation studies are nonetheless warranted., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction : Clinical trials in hepatocellular carcinoma (HCC) exhibit a high degree of heterogeneity. These heterogeneities may lead to unexpected results among clinical trials. Area covered : In this review, we address the heterogeneity noted in early phase HCC trials, trials involving transarterial chemoembolization, and advanced HCC trials. Furthermore, we discuss possible methods to attenuate the detrimental effects of heterogeneity when conducting clinical trials. Expert opinion : Clinical trials in HCC exhibit an inherently high degree of heterogeneity because of various reasons: tumor heterogeneity, different cirrhotic backgrounds, various etiologies of cirrhosis, and geographical differences in practice and expertise. Such heterogeneity may cause imbalance among the enrolled patient population, premature withdrawal from the clinical trial, and variable response to the treatment. In addition, methodological heterogeneity also exists in designing trial protocol and response evaluation. All these factors may eventually lead to conflicting results among clinical trials. Accounting for these heterogeneities is important to foster the success of future trials. In recent years, significant progress with molecular targeted agents and immune checkpoint inhibitors was made in advanced HCC. These new agents are also being tested in clinical trials involving earlier stage HCC and will also face the challenge of these issues.

Purpose: Antiangiogenic therapy is crucial for advanced hepatocellular carcinoma (HCC) treatment. Interleukin (IL)-6 is an inflammatory response mediator that can promote angiogenesis. We explored its prognostic role in patients with advanced HCC., Methods: We had two patient cohorts, both comprising patients who received sorafenib-containing therapy as the first-line treatment for advanced HCC. We explored the best cut point for pretreatment plasma IL-6 levels in the exploration cohort and then confirmed it in the validation cohort., Results: In total, 55 and 73 patients constituted the exploration and validation cohorts, respectively. In the exploration cohort, a cut point of 4.28 pg/ml was the best for defining high and low IL-6 levels because it could most effectively differentiate overall survival (OS). On application of this cut point to the validation cohort, patients with high plasma IL-6 levels, compared with patients with low IL-6 levels, exhibited significantly poorer OS (median, 8.0 vs 13.9 months, P = 0.031) but similar progression-free survival or treatment response. After adjusting for patient demographics and tumor characteristics, a high plasma IL-6 level remained an independent predictor of poor OS (hazard ratio 2.594, P = 0.005)., Conclusion: High pretreatment plasma IL-6 levels were associated with poor prognosis of patients with advanced HCC., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC). We analyzed national prescription patterns and treatment outcomes of patients who received sorafenib for advanced HCC., Patients and Methods: We established a nation-wide cohort of patients who started receiving treatment with sorafenib for advanced HCC between August 2012 and July 2013 from the National Health Insurance Research Database of Taiwan and also retrieved demographic and prescription data. The databases of National Death Registry and Taiwan Cancer Registry were used for survival outcomes and cancer diagnosis information, respectively., Results: A total of 3,293 patients were enrolled. The median overall survival (OS) and time to treatment discontinuation (TTD) of all patients were 6.8 and 2.6 months, respectively. Upon the first prescription of sorafenib, 58.4% of patients received the standard dose (800 mg/day). Among them, 61.9% had subsequent dose reduction. A total of 41.6% of patients initially received lower than standard doses; 36.1% of them had subsequent dose escalation to 800 mg/day. Being male (odds ratio=1.41; p<0.001) and treatment year of 2012 (odds ratio=1.28; p=0.002) were associated with the standard initial dose. Patients who received standard initial dose of sorafenib, compared to patients who received lower initial doses, exhibited longer OS (median of 7.8 vs. 6.6 months, p<0.001) but similar TTD (median of 2.6 vs. 2.9 months, p=0.840)., Conclusion: A considerable number of patients with advanced HCC received less than the standard dose of sorafenib. The treatment outcomes in the general population were consistent with those reported in clinical trials., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC., Patients and Methods: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy 124 I radiolabeled codrituzumab PET scan imaging were performed., Results: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUC t of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124 I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed., Conclusion: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).

Sorafenib, a multikinase inhibitor, is currently the only approved drug for advanced hepatocellular carcinoma (HCC). The current study tested the hypothesis whether inhibition of the Wnt/β-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC. ICG-001, a small molecule which blocks the interaction of β-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth-suppressive and apoptosis-induction effects of sorafenib in multiple HCC cell lines. Downregulation of β-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of β-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was attenuated by β-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA-mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. Our data indicate that inhibition of the Wnt/β-catenin signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aim: The Cancer of the Liver Italian Program (CLIP) score is a commonly used staging system for hepatocellular carcinoma (HCC) helpful with predicting prognosis of advanced HCC. CLIP uses the Child-Turcotte-Pugh (CTP) score to evaluate liver reserve. A new scoring system, the albumin-bilirubin (ALBI) grade, has been proposed as they objectively evaluate liver reserve. We examined whether the modification of CLIP with ALBI retained its prognosis prediction for patients with advanced HCC., Methods: We included patients who received first-line antiangiogenic therapy for advanced HCC. Liver reserve was assessed using CTP and ALBI scores, which were then incorporated into CLIP and ALBI-CLIP, respectively. To assess their efficacies of prognostic prediction, the Cox's proportional hazard model and concordance indexes were used., Results: A total of 142 patients were included; 137 of them were classified CTP A and 5 patients CTP B. Patients could be divided into four or five groups with different prognosis according to CLIP and ALBI-CLIP, respectively. Higher R(2) (0.249 vs 0.216) and lower Akaike information criterion (995.0 vs 1001.1) were observed for ALBI-CLIP than for CLIP in the Cox's model predicting overall survival. ALBI-CLIP remained an independent predictor for overall survival when CLIP and ALBI-CLIP were simultaneously incorporated in Cox's models allowing variable selection with adjustment for hepatitis etiology, treatment, and performance status. The concordance index was also higher for ALBI-CLIP than for CLIP (0.724 vs 0.703)., Conclusions: Modification of CLIP scoring with ALBI, which objectively assesses liver reserve, retains and might have improved prognosis prediction for advanced HCC., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclin-dependent kinase (CDK) inhibition in therapy., Experimental Design: The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenib-sensitive (Huh-7 and HepG2, IC50 5-6 μmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC50 14-15 μmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosis-related proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments., Results: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect., Conclusions: The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma. Clin Cancer Res; 22(10); 2555-64. ©2015 AACR., (©2015 American Association for Cancer Research.)

Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC.

Background: The TGF-β signaling pathway is crucial in the progression and metastasis of malignancies. We investigated whether the serum TGF-β1 level was related to the outcomes of patients treated with sorafenib for advanced hepatocellular carcinoma (HCC)., Experimental Design: We selected patients who had received sorafenib-containing regimens as first-line therapy for advanced HCC between 2007 and 2012. Serum TGF-β1 levels were measured and correlated with the treatment outcomes. The expression TGF-β1 and the sensitivity to sorafenib were examined in HCC cell lines., Results: Ninety-one patients were included; 62 (68%) were hepatitis B virus surface antigen (+), and 11 (12%) were anti-hepatitis C virus (+). High (≥ median) pretreatment serum TGF-β1 levels (median 13.7 ng/mL; range, 3.0-41.8) were associated with high α-fetoprotein levels, but not with age, gender, or disease stage. Patients with high pretreatment serum TGF-β1 levels exhibited significantly shorter progression-free survival (median, 2.5 vs. 4.3 months; P = 0.022) and overall survival (median 5.6 vs. 11.6 months; P = 0.029) than did patients with low serum TGF-β1 levels. Compared with pretreatment levels, the serum TGF-β1 levels were significantly increased at disease progression (n = 29, P = 0.010). In preclinical models of HCC, higher TGF-β1 expression levels were associated with poorer sensitivity to sorafenib., Conclusions: High pretreatment serum TGF-β1 levels were associated with poor prognoses, and increased serum TGF-β1 levels were associated with the disease progression of advanced HCC patients. TGF-β pathway may be explored as a therapeutic target for advanced HCC., (©2015 American Association for Cancer Research.)

Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7(R)) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7(R) tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7(R) cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1α signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objectives: Hepatocellular carcinoma (HCC) is a heterogeneous disease. We explored whether any specific subgroups of patients may gain more survival benefits from sorafenib as the first-line therapy for advanced HCC., Methods: PubMed and the Cochrane library were searched for phase III clinical trials that compared sorafenib with other treatments as first-line therapy for advanced HCC. We retrieved data from the published articles and then calculated synthesized hazard ratios (HRs) of overall mortality for patients of different subgroups, using patients who received other treatments as the reference., Results: Four phase III clinical trials comparing sorafenib with other treatments were included in this study. The HRs were not significantly different between patients from various geographic regions (p = 0.183), patients with different Eastern Cooperative Oncology Group performance statuses (p = 0.699), or patients with different tumor involvement (p = 0.221). By contrast, the synthesized HR for hepatitis C virus (HCV)+ patients was 0.65 [95% confidence interval (CI) 0.53-0.80], which was significantly lower than that for HCV- patients (0.87, 95% CI 0.79-0.96, p = 0.013)., Conclusions: As the first-line therapy for advanced HCC, sorafenib might provide more survival benefits to HCV+ patients than to HCV- patients., (© 2015 S. Karger AG, Basel.)

Background: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor despite treatment with sorafenib or other anti-angiogenic targeted-therapies. Patients with advanced HCC with prolonged survival may exhibit unique clinical characteristics., Patients and Methods: We reviewed patients with Barcelona Clinic Liver Cancer stage C HCC, who were enrolled in six clinical trials for first-line anti-angiogenic targeted-therapy between May 2005 and December 2010 in a single Institute. Patients with prolonged survival were identified as those who exhibited overall survival (OS) of more than two years; their clinical variables were analyzed., Results: Of the 189 enrolled patients, 22 (11.6%) patients with prolonged survival were identified. Their median OS was 58.7 (range=24.6-88.4) months, compared to an OS of 7.1 months for the overall patient cohort. A multivariate analysis showed that the patients with prolonged survival were less likely to have chronic hepatitis B virus infection, α-fetoprotein level >400 ng/ml, and liver involvement than were the remaining patients. In addition, the patients with prolonged survival experienced significantly higher response rates (50.0%) and disease control rates (86.4%) to the first-line targeted-therapy, and received more additional therapies than did the other patients. Seven patients remained disease-free for a median of 27.0 (range, 4.5-64.6) months after receiving additional locoregional therapies., Conclusion: Patients with advanced HCC who experienced prolonged survival exhibited certain clinical features and strong treatment responses to first-line anti-angiogenic targeted-therapies. Additional locoregional therapies could contribute to the long-term disease-free status in selected patients.

Background & Aims: No approved therapy is available for patients with advanced hepatocellular carcinoma (HCC) who fail first-line therapy. The prognosis of these patients, especially those eligible for clinical trials of second-line therapy, is unclear., Methods: All patients who participated in clinical trials of first-line systemic therapy for metastatic or locally advanced HCC in a referral center of Taiwan between 2005 and 2011 were included. Their clinicopathologic characteristics, when the first-line treatment failed, were analyzed and correlated with the overall survival (OS) from the date of first-line treatment failure., Results: A total of 192 patients were included. Before the start of the first-line therapy, all patients had Child-Pugh class A liver reserves and Cancer of the Liver Italian Program (CLIP) scores ≤4. After the failure of the first-line therapy, the median OS of the entire group was 4.0 months. Patients with Child-Pugh class A liver reserves, when the first-line treatment failed, had significantly better OS than patients with Child-Pugh class B or C liver reserves (median, A vs. B vs. C=7.5 vs. 1.3 vs. 1.0 month, p<0.001). According to the key eligibility criteria of 3 published clinical trials for second-line therapy, 41%-56% of patients were potentially eligible. Compared to patients who were ineligible for clinical trials, potentially eligible patients had longer OS with a median of 7.8-8.6 months., Conclusions: Patients with advanced HCC who failed first-line therapy could have substantially improved prognosis if they had Child-Pugh A liver reserves or were potentially eligible for clinical trials., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: Mutation of the exon 3 of CTNNB1, the coding gene of β-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/β-catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of CTNNB1 mutations in advanced HCC remain unclear., Methods: Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of CTNNB1 was performed to detect somatic mutations. The associations between CTNNB1 mutations and clinicopathologic features were analyzed., Results: A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have CTNNB1 mutations, all of which were missense mutations. The CTNNB1 mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have CTNNB1 mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features., Conclusion: In patients with advanced HCC, CTNNB1 mutations were not prognostically significant. No apparent increase of CTNNB1 mutations occurred during the progression of HCC., (© 2014 S. Karger AG, Basel.)

Background: Randomized trials suggest that radiofrequency ablation (RFA) may be more effective than percutaneous ethanol injection (PEI) in the treatment of hepatocellular carcinoma (HCC). However, the survival advantage of RFA needs confirmation in daily practice., Methods: We conducted a population-based cohort study using the Taiwan Cancer Registry, National Health Insurance claim database and National Death Registry data from 2004 through 2009. Patients receiving PEI or RFA as first-line treatment for newly-diagnosed stage I-II HCC were enrolled., Results: A total of 658 patients receiving RFA and 378 patients receiving PEI treatment were included for final analysis. The overall survival (OS) rates of patients in the RFA and PEI groups at 5-year were 55% and 42%, respectively (p < 0.01). Compared to patients that received PEI, those that received RFA had lower risks of overall mortality and first-line treatment failure (FTF), with adjusted hazard ratios (HRs) [95% confidence interval (CI)] of 0.60 (0.50-0.73) for OS and 0.54 (0.46-0.64) for FTF. The favorable outcomes for the RFA group were consistently significant for patients with tumors > 2 cm as well as for those with tumors < 2 cm. Consistent results were also observed in other subgroup analyses defined by gender, age, tumor stage, and co-morbidity status., Conclusion: RFA provides better survival benefits than PEI for patients with unresectable stage I-II HCC, irrespective of tumors > 2 cm or ≤ 2 cm, in contemporary clinical practice.

Background & Aims: For patients with advanced hepatocellular carcinoma (HCC) who have failed first-line anti-angiogenic therapy, there is no salvage treatment. Hepatic arterial infusion of chemotherapy (HAIC) has been reported to achieve substantial treatment responses in HCC patients. We aimed to explore the feasibility of using HAIC as second-line therapy for advanced HCC., Methods: We retrospectively reviewed all consecutive patients who received HAIC for advanced HCC after failure of first-line anti-angiogenic therapy at a single institute. Patients received HAIC with 60 mg/m(2) cisplatin on Day 2, and 500 mg/m(2) /d dose of 5-fluorouracil on Days 1-3. The treatment was repeated every 21 days and continued until disease progression or the occurrence of intolerable toxicities. Tumour assessment was performed after every 3 cycles of HAIC following RECIST criteria, version 1.0., Results: A total of 23 patients were included. Eleven (48%) patients had main portal vein thrombosis. Liver reserve was classified as Child-Pugh A in 19 (83%) patients and B in 4 (17%) patients. No complete response was observed, although 6 (26%) patients showed partial responses. The median progression-free survival was 4.4 months, and the median overall survival was 7.5 months. Common toxicities included bone marrow suppression, elevated transaminase levels, neutropenia, nausea and malaise. Only 7 (30%) patients experienced grade 3 or 4 toxicities, and no patients withdrew from the therapy because of intolerable or life-threatening toxicities., Conclusion: HAIC is a feasible second-line therapy for patients with advanced HCC who have failed anti-angiogenic therapy., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Hospital volume for several major operations is associated with treatment outcomes. In this study, the authors explored the influence of hospital radiofrequency ablation (RFA) volume on the prognosis of patients who received RFA for hepatocellular carcinoma (HCC)., Methods: The authors searched for all patients who were diagnosed with stage I or stage II HCC from 2004 to 2006 and who received RFA as first-line therapy in a population-based cohort. Overall survival (OS) and liver cancer-specific survival (CSS) were compared according to hospital volume. A Cox proportional hazards model was used for multivariate analysis., Results: In total, 661 patients received first-line RFA for stage I and II HCC in 28 hospitals. Among these, there were 480 patients (72.6%) in the high-volume group (those who received RFA at hospitals that treated >10 first-line patients per year), and there were 181 patients (27.4%) in the low-volume group (those who received RFA at hospitals that treated ≤ 10 first-line patients per year). The sex, age, stage, tumor size, and year of diagnosis for patients in the 2 groups did not differ significantly. Patients in the high-volume group demonstrated significantly longer OS and CSS than those in the low-volume group (5-year OS rate, 58.7% vs 47.2%; P = .001; 5-year CSS rate, 67.1% vs 57.1%; P = .009). After adjusting for covariates, high-volume hospitals remained an independent predictor of longer OS (hazard ratio, 0.57; P < .001) and CSS (hazard ratio, 0.57; P = .003)., Conclusions: Patients who received first-line RFA for HCC in high-volume hospitals demonstrated better survival outcomes., (Copyright © 2012 American Cancer Society.)

Objectives: A germline BIM deletion polymorphism has been proposed to predict a poor treatment efficacy of certain kinase inhibitors. The current study aimed to explore whether the BIM deletion polymorphism predicts the treatment efficacy of sorafenib for advanced hepatocellular carcinoma (HCC)., Methods: All patients who were enrolled in clinical trials to receive sorafenib-containing regimens as first-line therapy for advanced HCC and consented to providing peripheral blood samples were included. Polymerase chain reaction followed by gel electrophoresis was used to detect the germline BIM deletion polymorphism., Results: A total of 89 patients were enrolled; 69 (77%) patients had chronic hepatitis B infection, and 18 (20%) had chronic hepatitis C infection. The heterozygous BIM deletion polymorphism was identified in 9 (10%) patients. Patients with and without the BIM deletion polymorphism had similar response rates (11 vs. 6%) and disease control rates (56 vs. 61%). The time to progression, progression-free survival, and overall survival were similar between patients with and without the BIM deletion polymorphism. After adjusting for basic clinicopathologic variables and treatment regimens, the BIM polymorphism still could not predict treatment outcomes., Conclusions: The BIM deletion polymorphism was not associated with the treatment efficacy of sorafenib for advanced HCC., (© 2013 S. Karger AG, Basel.)

Objectives: The bevacizumab/erlotinib combination was reported with high clinical activity for advanced hepatocellular carcinoma (HCC) by a phase II study conducted in the USA. This multicenter study across several Asian countries was to evaluate the safety and efficacy of the combination in this population., Methods: Patients with histology-proven HCC, advanced disease and Child-Pugh class A liver function received bevacizumab 5 mg/kg intravenously every 2 weeks and erlotinib 150 mg/day orally as first-line therapy. The primary end point was progression-free survival at 16 weeks (PFS-16W). The expression of epidermal growth factor receptor (EGFR), phospho-AKT and vascular endothelial growth factor, the microvessel density and the EGFR gene copy number in HCC tissues were correlated with treatment efficacy., Results: Fifty-one patients were enrolled. The PFS-16W was 35.3% (95% CI 22.4-49.9), the median PFS was 2.9 months (95% CI, 1.3-4.4) and the median overall survival was 10.7 months (95% CI, 6.2-15.2). Grade 3/4 toxicities were uncommon, including rash, acne (10% each), diarrhea (6%) and gastrointestinal bleeding (4%). None of the evaluated biomarkers correlated with disease control or PFS., Conclusions: Bevacizumab plus erlotinib showed good tolerability and modest activity in this Asian cohort. Further studies are warranted to identify the predictive biomarkers of this combination., (Copyright © 2013 S. Karger AG, Basel.)

Background/aim: Biomarker studies using immunohistochemical (IHC) staining have not been successful for advanced hepatocellular carcinoma (HCC). We aimed to examine whether the tissue procurement process influences the protein expression levels detected by IHC., Materials and Methods: Forty-two tissue pairs of HCC that had been both preoperatively biopsied and then surgically resected were included in the study. IHC staining was used to determine expression of target molecules, all of which were graded according to the percentage of positively stained tumor cells. The expression of beta-catenin was analyzed according to the localization of positive staining., Results: Biopsied and surgically resected tissues exhibited dissimilar phosphorylated extracellular signal regulated kinase (p-ERK) and phosphorylated AKT expression levels (kappa=0.025 and 0.153, respectively). On the contrary, p53 exhibited similar expression levels, and beta-catenin exhibited similar staining localization patterns in biopsied and surgically resected tissues (kappa=0.729 and 0.654, respectively)., Conclusion: Biopsied HCC tissues and their corresponding resected HCC tissues have inconsistent IHC-detected ERK and AKT expressions.

Purpose: Patients with liver cirrhosis or hepatocellular carcinoma (HCC) have decreased serum insulin-like growth factor (IGF)-1 levels. We evaluated whether IGF-1 levels were associated with the outcomes of patients with advanced HCC treated with systemic antiangiogenic therapy., Experimental Design: The study was based on patients with advanced HCC who were enrolled in two clinical trials evaluating first-line combination antiangiogenic therapy. Serum samples were collected before treatment and four to six weeks after the start of treatment. The levels of IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP3) were analyzed for their associations with treatment outcomes., Results: A total of 83 patients were included in the study. Patients who had high (≥the median level) baseline IGF-1 levels had significantly higher disease control rate (DCR) than patients who had low (

Background: Diabetes mellitus (DM) is closely associated with hepatocarcinogenesis. This study explores the prognostic impact of DM in patients who received curative therapy for localized hepatocellular carcinoma (HCC)., Methods: Patients who had been diagnosed with stage I or II HCC in 2003 and 2004 and received surgical resection or local ablation therapy were identified from the population-based Taiwan National Cancer Registry. Data pertaining to DM and other comorbidities were retrieved from the Taiwan National Health Insurance database. Liver cancer-specific survival (LCS), liver disease-related survival (LDS) and overall survival (OS) rates were compared between patients with and without DM. The presence of other comorbidities and tumor status were adjusted using multivariate analysis., Results: A total of 931 patients who fulfilled the study criteria were analyzed; 185 (20%) of them had DM (type 1 or type 2). The LCS, LDS, and OS rates were significantly worse for patients with DM than patients without DM (all p < .001). After adjusting for age, sex, tumor stage, treatment, and the presence of other comorbidities, DM remained an independent predictor of poorer LCS (hazard ratio [HR] = 1.57; p < .001), LDS (HR = 1.70; p < .001), and OS (HR = 1.69; p < .001). The associations between DM and mortality were consistent among subgroups, irrespective of tumor size, stage, treatment modality, and liver cirrhosis., Conclusions: DM is an independent factor for poorer prognosis in patients who received curative therapy for localized HCC.

Objectives: Thalidomide has been shown to have antitumor activity in some patients with advanced hepatocellular carcinoma (HCC). We initiated a phase II study to determine the safety and efficacy of adding metronomic chemotherapy to thalidomide as first-line therapy., Methods: This open- labeled, single-arm, multicentered, investigator-initiated study enrolled patients with treatment-naïve advanced HCC not amenable to locoregional therapies. Treatment included oral thalidomide (100 mg twice daily) and tegafur/uracil [125 mg/m(2) (based on tegafur) twice daily]. Tumor assessment was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Pretreatment plasma levels of angiogenesis factors were correlated with patient outcomes., Results: Forty-three patients were included. Sixteen (37%) patients had a Cancer of the Liver Italian Program (CLIP) score of 4, and 31 (72%) patients had chronic hepatitis B virus infection. The objective response rate was 9%, and the disease stabilization rate was 33%. The median progression-free survival was 1.9 months (95% CI 1.7-2.1 months), and the median OS was 4.6 months (95% CI 2.3-6.9 months). Treatment was generally tolerable. High baseline plasma levels of interleukin (IL)-6 and IL-8 were adversely correlated with patient survivals., Conclusions: The combination of thalidomide and tegafur/uracil was safe and demonstrated modest activity in patients with advanced HCC., (Copyright © 2012 S. Karger AG, Basel.)

Background: The purpose of this study was to determine the prognostic significance of clinical factors and staging systems for survival of hepatocellular carcinoma (HCC) patients who are candidates for therapeutic clinical trials., Methods: From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into six published phase II trials assessing various therapeutic regimens. Of these, 156 chemotherapy-naive patients with Child-Pugh class A and Barcelona Clinic Liver Cancer stage C disease were included in this analysis. Twenty-seven relevant clinical characteristics were analyzed to identify prognostic factors of survival. Beyond these prognosticators, the predictive ability of eight staging systems (the tumor-node-metastasis, Okuda, Cancer of the Liver Italian Program [CLIP], Chinese University Prognostic Index, Japanese Integrated Staging, Tokyo, National Taiwan University Risk Estimation, and Advanced Liver Cancer Prognostic System [ALCPS] score) were compared using the Akaike information criteria., Results: The median overall survival time was 129 days (95% confidence interval, 111-147 days). Significant predictors of a shorter overall survival time were an Eastern Cooperative Oncology Group performance status score ≥2, the presence of symptoms, ascites, an aspartate transaminase level more than two times the upper limit of normal, and regional lymph node involvement. The ALCPS and CLIP scores were superior to the other systems for predicting survival., Conclusions: The prognosis of patients with advanced HCC who are candidates for therapeutic clinical trials is affected by several factors related to the patient, liver function, and the tumor. The ALCPS and CLIP scores appear to be superior to the other systems for predicting survival.

Background: Hepatitis B virus (HBV) infection is one of the main etiologies of hepatocellular carcinoma (HCC). We explored the impact of HBV DNA levels on the prognosis of patients with advanced HCC., Patients and Methods: The study was based on patients with advanced HCC and chronic HBV infection enrolled into three phase II trials evaluating first-line antiangiogenic therapy. Pre-treatment HBV DNA levels were measured by real-time quantitative polymerase chain reaction., Results: Seventy-two patients were included. Patients with detectable HBV DNA levels had poorer median overall survival (OS) compared to patients without detectable levels (4.8 vs. 9.3 months, p=0.037). After adjusting for other clinicopathologic variables, the baseline HBV DNA level was an independent predictor of poor OS (p=0.014). Baseline HBV DNA levels were not correlated with progression-free survival or disease control rate., Conclusion: Baseline HBV DNA levels were associated with the prognosis of patients with chronic HBV infection receiving antiangiogenic therapy for advanced HCC.

Objectives: We examined whether circulating endothelial progenitor (CEP) and circulating endothelial cell (CEC) levels had associations with the survival of patients who received antiangiogenic therapy for advanced hepatocellular carcinoma (HCC)., Methods: Patients with advanced HCC were enrolled into a phase II trial evaluating a combination of sorafenib and metronomic chemotherapy with tegafur/uracil as first-line systemic therapy. CEPs and CECs were enumerated with six-color flow cytometry at baseline, 2 weeks, and 4 weeks after treatment and analyzed for their associations with treatment outcomes along with other clinicopathologic factors., Results: Forty patients were enrolled. Baseline CEP and CEC levels were not associated with tumor stages, α-fetoprotein levels, or macrovascular invasion. By univariate analysis, a high baseline CEP level was a significant predictor of poor progression-free survival (PFS) and overall survival (OS) (p = 0.02 and p = 0.004, respectively). The high baseline CEP level remained an independent, significant predictor of poor PFS [hazard ratio (HR) 1.953, p = 0.049] and OS (HR 2.512, p = 0.004) in multivariate analysis. On the other hand, the baseline or posttreatment CEC levels were not associated with PFS or OS., Conclusion: High baseline CEP levels were associated with poor survival in patients with advanced HCC receiving sorafenib-based antiangiogenic combination therapy., (Copyright © 2011 S. Karger AG, Basel.)

Aim: Brain metastasis was regarded, until recently, as a rare and late-stage event in patients with hepatocellular carcinoma (HCC). With the prolongation of survival in patients with advanced HCC by molecular targeted agents, this may have changed. We aimed to examine whether or not the incidence of brain metastasis in these patients has increased., Methods: Between June 2005 and May 2009, 158 advanced HCC patients in total with either metastatic or locally advanced disease untreatable by locoregional therapies were enrolled in clinical trials of first-line antiangiogenic therapies. The clinicopathologic features and survival times of those who developed brain metastasis were analyzed., Results: Eleven (7%) of 158 advanced HCC patients, with a median follow-up of 26.6 months, were diagnosed with brain metastasis as a result of compatible symptoms, confirmed by brain imaging. All 11 patients had extrahepatic metastasis upon enrollment, and 10 of them had lung metastasis. The median time to brain metastasis was 9.6 months (range, 0.6-19.6 months). The median overall survival (OS) time after diagnosis of brain metastasis was 4.6 months (range, 0.7-12.6 months). Four patients received brain tumor excision, and their survival duration after brain metastasis tended to be longer than that of those who did not (median OS time, 6.1 months versus 3.1 months)., Conclusions: In the era of antiangiogenic targeted therapy, the importance of brain metastasis for advanced HCC patients may have increased.

Background: Antiangiogenic therapy has become the most important treatment modality for patients with advanced hepatocellular carcinoma (HCC). In this study, the authors investigated levels of alpha-fetoprotein (AFP) as a potential biomarker for treatment efficacy of antiangiogenic therapy., Methods: Patients with advanced HCC who had been enrolled in 3 prospective phase 2 clinical trials that evaluated either sorafenib, bevacizumab, or thalidomide in combination with a potentially antiangiogenic, metronomic, oral 5-fluoropyrimidine as first-line systemic therapy were included. An early AFP response was defined as a decline >20% from baseline after 2 to 4 weeks of treatment. AFP response was analyzed for its association with treatment efficacy and survival outcome., Results: Seventy-two patients were included for early AFP response evaluation, and 12 of those patients (17%) were classified as early AFP responders. Early AFP responders, compared with nonresponders, had a significantly improved overall response rate (33% vs 8%; P=.037) and a significantly improved disease control rate (83% vs 35%; P=.002), which was defined as the percentage of patients who had an objective response plus stable disease for a minimum of 8 weeks. AFP responders, compared with nonresponders, also had longer median progression-free survival (PFS) (7.5 months vs 1.9 months; P=.001) and longer median overall survival (OS) (15.3 months vs 4.1 months; P=.019). In a multivariate analysis, AFP response remained a significant independent predictor of better PFS and OS., Conclusions: The current results indicated that an early AFP response is a useful surrogate marker to predict treatment response and prognosis in patients with advanced HCC who receive antiangiogenic therapy., (Copyright © 2010 American Cancer Society.)

Background & Aims: Sorafenib, a multi-kinase inhibitor with anti-angiogenic activity, was recently approved for the treatment of advanced hepatocellular carcinoma (HCC). Metronomic chemotherapy using tegafur/uracil (4:1 molar ratio), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in preclinical models. This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC., Methods: Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib (400mg twice daily) and tegafur/uracil (125 mg/m(2) based on tegafur twice daily) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies. The primary endpoint was progression-free survival (PFS)., Results: The study enrolled 53 patients. Thirty-eight patients (72%) were hepatitis B surface antigen-positive. The median PFS was 3.7 months (95% C.I., 1.9-5.5) and the median overall survival was 7.4 months (95% C.I., 3.4-11.4). According to RECIST criteria, 4 patients (8%) had a partial response and 26 patients (49%) had a stable disease. Major grade 3/4 toxicities included fatigue (15%), abnormal liver function (13%), elevated serum lipase (10%) hand-foot skin reaction (HFSR) (9%), and bleeding (8%). HFSR was the major adverse event resulting in dose reduction (19%) or treatment delay (21%)., Conclusions: Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients., (Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)