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Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab. [ABSTRACT FROM AUTHOR]

Purpose: We investigated whether spleen volume (SV) changes were associated with treatment outcomes in advanced hepatocellular carcinoma (HCC) patients who received immunotherapy or first-line sorafenib. Patients and Methods: Patients with advanced HCC who underwent immunotherapy or first-line sorafenib at our institute were retrospectively analyzed. CT was used to measure SV before and within 3 months of treatment initiation. Tumor assessment followed Response Evaluation Criteria in Solid Tumors version 1.1. The association between SV change and tumor response or progression-free survival (PFS) was analyzed. The inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics. Results: The immunotherapy group comprised 143 patients (124 men, mean age, 59.8 years ± 11.2 [standard deviation]), while the sorafenib group had 57 (47 men, mean age, 59.6 years ± 9.9). SV increased in 108 (75.5%) immunotherapy and 21 (36.8%) sorafenib patients. In the immunotherapy group, patients with increased SV were more likely than those with decreased SV to have a higher disease control rate (76.9% vs 57.1%, p = 0.024) and durable clinical benefit (52.8% vs 25.7%, p = 0.005). It was also associated with extended PFS in the immunotherapy group in both the univariate (p = 0.028) and multivariate (p = 0.014) analysis. By contrast, in the sorafenib group, an increased in SV was not associated with treatment response but was presumably associated with reduced PFS (p = 0.072) in the multivariate analysis. After IPTW adjustment, the increase in SV remained a significant predictor for DCB and PFS in the immunotherapy group. Conclusion: Most patients exhibited an increase in SV after the initiation of immunotherapy, which may be used to predict response and prognosis. However, this association was not observed in patients who received sorafenib. Plain Language Summary: The study provides significant evidence that an increase in spleen volume is associated with better treatment outcomes in advanced hepatocellular carcinoma patients undergoing immunotherapy. These findings offer oncologists a new potential biomarker for optimizing treatment strategies. Specifically, increased spleen volume could be used to predict higher rates of disease control and durable clinical benefits, allowing for more personalized care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Systemic therapies for advanced hepatocellular carcinoma (HCC) can cause hypothyroidism. This study examined the prevalence and prognostic impact of hypothyroidism in patients with HCC before receiving any systemic therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 cm2/m2, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 124I 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 AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124I 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). [ABSTRACT FROM AUTHOR]

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 R2 (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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 4.0months. 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. 1.0month, 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 7.8–8.6months. 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 &y& Elsevier]

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 [ABSTRACT FROM AUTHOR]

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/m2 cisplatin on Day 2, and 500 mg/m2/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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

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/m2 (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 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Total tumor-infiltrating CD8 T cells inconsistently correlate with the efficacy of immune checkpoint blockade (ICB) in hepatocellular carcinoma. Tumor-infiltrating CD8 tissue-resident memory T cells (TRM) are considered a surrogate of tumor-specific T cells and correlated better with survival in patients with melanoma, non–small-cell lung cancer, head and neck cancer or bladder cancer who received ICB. However, in this study, compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 TRM cells failed to provide additional advantages in predicting the efficacy of ICB-based immunotherapy in patients with hepatocellular carcinoma. Purpose: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 TRM; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 TRM and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 TRM, and CD39+ or PD-L1+ subsets of CD8 TRM were correlated with tumor response and overall survival (OS). Results: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0–92.6%) of tumor-infiltrating CD8 T cells were TRM. In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 TRM cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 TRM-high, CD39+ CD8 TRM-high, and PD-L1+ CD8 TRM-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 TRM-high, CD39+ CD8 TRM-high, or PD-L1+ CD8 TRM-high, tumors, had significantly prolonged OS (p = 0.0429). Conclusions: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 TRM or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: In patients with advanced hepatocellular carcinoma, systemic therapy is recommended by most treatment guidelines. Sorafenib and lenvatinib are both 1st-line treatments for inoperable advanced HCC. Regorafenib, cabozantinib, and ramucirumab have been approved as 2nd-line targeted therapy in patients who show progression or do not tolerate sorafenib. However, there is a lack of imaging biomarkers for predicting survival outcomes in patients receiving 2nd-line targeted therapy after sorafenib failure. In this paper, we try to predict survival outcomes via early changes in the DCE-MRI biomarkers in participants with advanced HCC after 2nd-line targeted therapy following sorafenib failure, taking data from two different prospective clinical trials. We found that an early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict survival outcomes in these participants. For the further clinical development of anti-angiogenic therapies, optimal participant selection with predictive biomarkers, such as DCE-MRI, is essential in order to improve treatment outcomes. In this paper, our main objective was to predict survival outcomes using DCE-MRI biomarkers in patients with advanced hepatocellular carcinoma (HCC) after progression from 1st-line sorafenib treatment in two prospective phase II trials. This study included 74 participants (men/women = 64/10, mean age 60 ± 11.8 years) with advanced HCC who received 2nd-line targeted therapy (n = 41 with lenalidomide in one clinical trial; n = 33 with axitinib in another clinical trial) after sorafenib failure from two prospective phase II studies. Among them, all patients underwent DCE-MRI at baseline, and on days 3 and 14 of treatment. The relative changes (Δ) in the DCE-MRI parameters, including ΔPeak, ΔAUC, and ΔKtrans, were derived from the largest hepatic tumor. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The Cox model was used to investigate the associations of the clinical variables and DCE-MRI biomarkers with progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was 10.8% (8/74) and the disease control rate (DCR) was 58.1% (43/74). The median PFS and OS values were 1.9 and 7.8 months, respectively. On day 3 (D3), participants with high reductions in ΔPeak_D3 (hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.17–0.93, p = 0.017) or ΔAUC_D3 (HR 0.51, 95% CI 0.25–1.04, p = 0.043) were associated with better PFS. On day 14, participants with high reductions in ΔPeak_D14 (HR 0.51, 95% CI 0.26–1.01, p = 0.032), ΔAUC_D14 (HR 0.54, 95% CI 0.33–0.9, p = 0.009), or ΔKtrans_D14 (HR 0.26, 95% CI 0.12–0.56, p < 0.001) had a higher PFS than those with lower reduction values. In addition, high reductions in ΔAUC_D14 (HR 0.53, 95% CI 0.32–0.9, p = 0.016) or ΔKtrans_D14 (HR 0.47, 95% CI 0.23–0.98, p = 0.038) were associated with a better OS. Among the clinical variables, ORR was associated with both PFS (p = 0.001) and OS (p = 0.005). DCR was associated with PFS (p = 0.002), but not OS (p = 0.089). Cox multivariable analysis revealed that ΔKtrans_D14 (p = 0.002) remained an independent predictor of PFS after controlling for ORR and DCR. An early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict favorable survival outcomes in participants with HCC receiving 2nd-line targeted therapy after sorafenib failure. [ABSTRACT FROM AUTHOR]

Objective: This study assessed dynamic contrast-enhanced (DCE)-MRI and intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) parameters to prospectively predict survival outcomes in participants with advanced hepatocellular carcinoma (HCC) who received lenalidomide, a dual antiangiogenic and immunomodulatory agent, as second-line therapy in a Phase II clinical trial. Materials and methods: Forty-four participants with advanced HCC who had progression after sorafenib as first-line treatment were prospectively enrolled. Pretreatment MRI parameters—obtained from DCE-MRI (peak, slope, AUC, Ktrans, Kep, and Ve), apparent diffusion coefficient (ADC), and IVIM DWI (pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f))—were derived from the largest hepatic tumor. The Cox model was used to investigate the associations of the parameters with progression-free survival (PFS) and overall survival (OS). Results: Median PFS and OS were 2.3 and 8.0 months, respectively. Univariate analysis showed that participants with a high slope (p = 0.024), Kep (p < 0.001), and ADC (p = 0.018) values had longer PFS than those with low values; participants with a small tumor size (p = 0.006), high slope (p = 0.01), ADC (p = 0.015), and f (p = 0.012) values had longer OS than those with low values did. Cox multivariable analysis revealed that Kep (p < 0.001) and ADC (p = 0.009) remained independent predictors of PFS; slope (p = 0.003) and ADC (p = 0.009) remained independent predictors of OS. Moreover, Kep and slope were still significant after Bonferroni correction was performed (p < 0.005). Conclusion: Both pretreatment DCE-MRI and IVIM DWI parameters, especially slope and ADC, may predict PFS and OS in participants with HCC receiving lenalidomide as second-line therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alterations in cell cycle regulators are common in hepatocellular carcinoma (HCC). We tested the efficacy of composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib on HCC. In vitro, dinaciclib exhibited potent antiproliferative activities in HCC cell lines regardless of Rb or c-myc expression levels. Dinaciclib significantly downregulated the phosphorylation of Rb (target of CDKs 1 and 2), ataxia telangiectasia mutated kinase (target of CDK5), and RNA polymerase II (target of CDK9) in the HCC cells. In xenograft studies, mice receiving dinaciclib tolerated the treatment well without significant body weight changes and exhibited a significantly slower tumor growth rate than the mice receiving vehicles. RNA interference (RNAi) of CDKs 1 and 9 was more effective in inhibiting the cell proliferation of HCC cells than RNAi of CDKs 2 and 5. Overexpression of CDK9 significantly reduced the efficacy of dinaciclib in HCC cells, but overexpression of CDK1 did not. In conclusion, composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib exhibited potent in vitro and in vivo activity against HCC. CDK9 inhibition might be the crucial mechanism. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (4:1molar 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 (125mg/m2 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 3.7months (95% C.I., 1.9–5.5) and the median overall survival was 7.4months (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 &y& Elsevier]