Potential candidates for liver resection in liver-confined advanced HCC: a Chinese multicenter observational study.

Background: Advanced hepatocellular carcinoma (HCC) is characterized as symptomatic tumors [performance status (PS) score of 1-2], vascular invasion and extrahepatic spread, but patients with PS1 alone may be eliminated from this stage. Although liver resection is used for liver-confined HCC, its role in patients with PS1 alone remains controversial. Therefore, we aimed to explore its application in such patients and identify potential candidates. Methods: Eligible liver-confined HCC patients undergoing liver resection were retrospectively screened in 15 Chinese tertiary hospitals, with limited tumor burden, liver function and PS scores. Cox-regression survival analysis was used to investigate the prognostic factors and develop a risk-scoring system, according to which patients were substratified using fitting curves and the predictive values of PS were explored in each stratification. Results: From January 2010 to October 2021, 1535 consecutive patients were selected. In the whole cohort, PS, AFP, tumor size and albumin were correlated with survival (adjusted P<0.05), based on which risk scores of every patient were calculated and ranged from 0 to 18. Fitting curve analysis demonstrated that the prognostic abilities of PS varied with risk scores and that the patients should be divided into three risk stratifications. Importantly, in the low-risk stratification, PS lost its prognostic value, and patients with PS1 alone achieved a satisfactory 5-year survival rate of 78.0%, which was comparable with that PS0 patients (84.6%). Conclusion: Selected patients with PS1 alone and an ideal baseline condition may benefit from liver resection and may migrate forward to BCLC stage A.

Lenvatinib with or without Concurrent Drug-Eluting Beads Transarterial Chemoembolization in Patients with Unresectable, Advanced Hepatocellular Carcinoma: A Real-World, Multicenter, Retrospective Study.

Introduction: Lenvatinib is the first-line treatment for advanced hepatocellular carcinoma (HCC). We aimed to compare the clinical outcomes of lenvatinib plus drug-eluting beads transarterial chemoembolization (DEB-TACE) versus lenvatinib alone in real-world practice. Methods: This retrospective analysis included 142 consecutive patients who received lenvatinib plus DEB-TACE and 69 patients who received lenvatinib alone as first-line treatment from 15 Chinese academic centers from November 2018 to November 2019. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria, and safety profiles were compared between the two groups. Results: The median OS and PFS were significantly longer in the combined therapy group than in the monotherapy group in whole cohort (median OS, 15.9 vs. 8.6 months, p = 0.0022; median PFS, 8.6 vs. 4.4 months, p < 0.001) and after propensity score matching analysis (median OS, 13.8 vs. 7.8 months, p = 0.03; median PFS, 7.8 vs. 4.5 months, p = 0.009). Moreover, the treatment option was an independent prognostic factor for OS and PFS with adjustment based upon baseline characteristics (adjusted hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.36-0.78, p = 0.001, and adjusted HR: 0.42, 95% CI: 0.30-0.60, p < 0.001, respectively) and propensity score (adjusted HR: 0.52, 95% CI: 0.36-0.76, p = 0.001, and adjusted HR: 0.46, 95% CI: 0.33-0.64, p < 0.001, respectively). Moreover, a greater ORR was observed in the combined group (ORR: 46.48% vs. 13.05%, p < 0.001). Furthermore, the most common adverse events (AEs) were elevated aspartate aminotransferase (54.9%) and fatigue (46.4%) in the lenvatinib plus DEB-TACE group and lenvatinib group, respectively. Most AEs were mild-to-moderate and manageable. Conclusions: With well-tolerated safety, lenvatinib plus DEB-TACE was more effective than lenvatinib monotherapy in improving OS, PFS, and ORR. Thus, it may be a promising treatment for advanced HCC. Future prospective studies confirming these findings are warranted.

Optimal time point of response assessment for predicting survival is associated with tumor burden in hepatocellular carcinoma receiving repeated transarterial chemoembolization.

OBJECTIVES: Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. METHODS: A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively. RESULTS: Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). CONCLUSIONS: ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden. KEY POINTS: • This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. • Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. • For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.

Identify optimal HAP series scores for unresectable HCC patients undergoing TACE plus sorafenib: A Chinese multicenter observational study.

Background: Hepatoma arterial-embolization prognostic (HAP) series scores have been proposed for prognostic prediction in patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE). However, their prognostic value in TACE plus sorafenib (TACE-S) remains unknown. Here, we aim to evaluate their prognostic performance in such conditions and identify the best model for this combination therapy. Methods: Between January 2012 and December 2018, consecutive patients with uHCC receiving TACE-S were recruited from 15 tertiary hospitals in China. Cox regression analyses were used to investigate the prognostic values of baseline factors and every scoring system. Their prognostic performance and discriminatory performance were evaluated and confirmed in subgroup analyses. Results: A total of 404 patients were enrolled. In the whole cohort, the median follow-up period was 44.2 (interquartile range (IQR), 33.2-60.7) months, the median overall survival (OS) time was 13.2 months, and 336 (83.2%) patients died at the end of the follow-up period. According to multivariate analyses, HAP series scores were independent prognostic indicators of OS. In addition, the C-index, Akaike information criterion (AIC) values, and time-dependent area under the receiver operating characteristic (ROC) curve (AUC) indicated that modified HAP (mHAP)-III had the best predictive performance. Furthermore, the results remained consistent in most subsets of patients. Conclusion: HAP series scores exhibited good predictive ability in uHCC patients accepting TACE-S, and the mHAP-III score was found to be superior to the other HAP series scores in predicting OS. Future prospective high-quality studies should be conducted to confirm our results and help with treatment decision-making.

Epigenetic silencing of miR-144/451a cluster contributes to HCC progression via paracrine HGF/MIF-mediated TAM remodeling.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the malignancies with the highest mortality. The key regulators and their interactive network in HCC pathogenesis remain unclear. Along with genetic mutations, aberrant epigenetic paradigms, including deregulated microRNAs (miRNAs), exert profound impacts on hepatocyte transformation and tumor microenvironment remodeling; however, the underlying mechanisms are largely uncharacterized. METHODS: We performed RNA sequencing on HCC specimens and bioinformatic analyses to identify tumor-associated miRNAs. The miRNA functional targets and their effects on tumor-infiltrating immune cells were investigated. The upstream events, particularly the epigenetic mechanisms responsible for miRNA deregulation in HCC, were explored. RESULTS: The miR-144/miR-451a cluster was downregulated in HCC and predicted a better HCC patient prognosis. These miRNAs promoted macrophage M1 polarization and antitumor activity by targeting hepatocyte growth factor (HGF) and macrophage migration inhibitory factor (MIF). The miR-144/miR-451a cluster and EZH2, the catalytic subunit of polycomb repressive complex (PRC2), formed a feedback circuit in which miR-144 targeted EZH2 and PRC2 epigenetically repressed the miRNA genes via histone H3K27 methylation of the promoter. The miRNA cluster was coordinately silenced by distal enhancer hypermethylation, disrupting chromatin loop formation and enhancer-promoter interactions. Clinical examinations indicated that methylation of this chromatin region is a potential HCC biomarker. CONCLUSIONS: Our study revealed novel mechanisms underlying miR-144/miR-451a cluster deregulation and the crosstalk between malignant cells and tumor-associated macrophages (TAMs) in HCC, providing new insights into HCC pathogenesis and diagnostic strategies.

Exploratory Analysis to Identify Candidates Benefitting from Combination Therapy of Transarterial Chemoembolization and Sorafenib for First-Line Treatment of Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Observational Study.

INTRODUCTION: The benefits of combining transarterial chemoembolization (TACE) and sorafenib (TACE-S) over TACE alone for treatment of unresectable hepatocellular carcinoma (HCC) remain controversial. Yet, such populations are heterogeneous in terms of baseline characteristics. OBJECTIVE: To investigate the predictors of survival benefits from added sorafenib and identify the potential candidates for TACE-S. METHODS: This multicenter observational study was conducted in 17 Chinese tertiary hospitals for patients with unresectable, liver-confined HCC. Eligible patients with performance status score of ≤1 and Child-Pugh score of ≤7 were treated with TACE or TACE-S. Interactions between treatment and baseline variables were evaluated to find indicators for survival benefits, based on which the patients were stratified. Multivariate models adjusted for baseline characteristics or propensity score were used to compare overall survival (OS) and time to tumor progression (TTP). RESULTS: From January 2009 to December 2015, 1,719 consecutive patients received TACE (n = 1,406) or TACE-S (n = 313). Although TACE-S compared with TACE improved TTP (adjusted hazard ratio [HR] 0.75, p = 0.008), no difference in OS was observed (adjusted HR 0.87, p = 0.090). Nevertheless, the tumor burden (sum of maximum diameter of largest tumor [cm] and tumor number) and albumin-bilirubin (ALBI) score independently predicted the survival benefits from added sorafenib (interaction p< 0.001). For patients with either moderate tumor burden (7-13) or low ALBI score (no more than -2.8) defined as candidates, TACE-S prolonged OS (adjusted HR 0.73, p = 0.003) and TTP (adjusted HR 0.72, p = 0.014) compared to TACE alone, whereas its superiority disappeared in non-candidates. CONCLUSIONS: Not all unresectable HCC patients but those with moderate tumor burden or low ALBI score achieve survival benefits from TACE-S compared with TACE alone. Future randomized controlled trials focusing on the subset are warranted.

Validation of the six-and-twelve criteria among patients with hepatocellular carcinoma and performance score 1 receiving transarterial chemoembolization.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended for patients with intermediate hepatocellular carcinoma (HCC) according to treatment guidelines. However, a large number of patients with advanced HCC also receive TACE in clinical practice, especially for those with liver-confined HCC and Eastern Cooperative Oncology Group score (ECOG) 1. In view of previous studies, such patients have different prognoses from advanced HCC patients with macrovascular invasion or extrahepatic spread; therefore, patients with ECOG 1 alone might be classified into the intermediate stage and benefit from TACE treatment, but a study particularly focusing on such patients and exploring the effectiveness of TACE therapy is lacking. AIM: To investigate treatment outcomes of TACE in HCC patients with ECOG 1 alone and propose a specific prognostic model. METHODS: Patients from 24 Chinese tertiary hospitals were selected in this nationwide multicenter observational study from January 2010 to May 2016. Overall survival (OS) was estimated using Kaplan-Meier curves and compared by the log-rank test. Multivariate Cox regression was used to develop the potential prognostic models. The discriminatory ability of the models was compared and validated in various patient subgroups. The individual survival prediction for six-and-twelve (6&12) criteria, defined as the algebraic sum of tumor size (cm) and tumor number, was illustrated by contour plot of 3-year survival probability and nomogram. RESULTS: A total of 792 eligible patients were included. During follow-up, median OS reached 18.9 mo [95% confidence interval (CI): 16.9-21.0]. Three independent multivariate analyses demonstrated that tumor size, tumor number, α-fetoprotein level, albumin-bilirubin grade and total bilirubin were prognostic factors of OS (P < 0.05). The previously proposed 6&12 criteria was comparable or even better than currently proposed with the highest predictive ability. In addition, the 6&12 criteria was correlated with OS in various subgroups of patients. The patients were stratified into three strata with score ≤ 6, > 6 but ≤ 12, and > 12 with different median OS of 39.8 mo (95%CI: 23.9-55.7), 21.1 mo (95%CI: 18.4-23.8) and 9.8 mo (95%CI: 8.3-11.3), respectively (P < 0.001). CONCLUSION: TACE is effective for advanced HCC patients with ECOG 1 alone, and the 6&12 criteria may help with clinical decision-making.

Comparison between Child-Pugh Score and albumin-bilirubin grade in patients treated with the combination therapy of transarterial chemoembolization and sorafenib for hepatocellular carcinoma.

BACKGROUND: Albumin-Bilirubin (ALBI) grade has been proposed for the evaluation of liver function in hepatocellular carcinoma (HCC). The combination therapy of transarterial chemoembolization (TACE) and sorafenib is widely used for HCC patients with preserved liver function; our study aimed to investigate and compare the discriminating values of ALBI grade and Child-Pugh score in overall survival (OS). METHODS: A total of 173 HCC patients with preserved liver function (Child-Pugh A) were enrolled. The prognostic values of OS for ALBI grade and Child-Pugh score were separately investigated. RESULTS: In multivariate analyses, both ALBI grade and Child-Pugh score could significantly stratify the patients with different OS [adjusted hazard ratio (HR) 2.15 and 1.48, P<0.001 and P=0.035 for ALBI grade and Child-Pugh score]. In addition, time-dependent ROC analysis demonstrated that the ALBI grade had a better discriminatory ability than Child-Pugh score in predicting survival, especially for long-term outcomes. According to the subgroup analyses, the ALBI grade remained significant in more patient subsets and was more consistent than Child-Pugh score for the prediction of OS. CONCLUSIONS: ALBI grade was better than Child-Pugh score in stratifying prognosis for HCC patients with preserved liver function (Child-Pugh A) and treated by the combination therapy of TACE and sorafenib.

A comparison of transcatheter arterial chemoembolization used with and without apatinib for intermediate- to advanced-stage hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer worldwide and prognosis for patients with the disease remains poor. Most patients are diagnosed at an advanced stage and are only eligible for palliative therapy. As a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (VEGFR2-TKI), apatinib has a certain antitumor effect for a variety of solid tumors. In clinical practice, clinicians have attempted to treat intermediate- to advanced-stage HCC patients with a combination of transcatheter arterial chemoembolization (TACE) and apatinib. However, a consensus on the therapeutic effects of this treatment is yet to be reached. This meta-analysis was conducted to compare the therapeutic efficacy and clinical safety of the combination therapy of TACE plus apatinib with that of TACE alone in patients with intermediate- to advanced-stage HCC. METHODS: Relevant studies were identified by searching PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), Chinese Science and Technology Periodical Database (VIP) and the reference lists of retrieved articles up to July 31, 2019. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to express the therapeutic effects of TACE plus apatinib versus TACE on survival, objective response rate, disease control rate, progressive disease rate and adverse events using a mixed-effect model. Subgroup analyses of study type, dosage of apatinib, TACE regimen, study sample size between treatment groups and control groups were performed. Publication bias was assessed using fail-safe N, Begg-Mazumdar test and Egger's test. RESULTS: From 23 eligible studies, a total of 1,342 patients were included in this review and meta-analysis. Among these studies, 18 were randomized clinical trials and 5 were case-control studies. Compared with those being treated with TACE alone, patients receiving TACE plus apatinib showed significantly better half-year survival (OR, 2.741, 95% CI, 1.745-4.306) and 1-year survival (OR, 2.284, 95% CI, 1.442-3.620). The superiority of TACE and apatinib over TACE monotherapy was evident in the disease control rate (OR, 2.919, 95% CI, 2.184-3.903), objective response rate (OR, 2.683, 95% CI, 2.099-3.429) and progressive disease rate (OR, 0.341, 95% CI, 0.255-0.456), respectively. CONCLUSIONS: The combination treatment of apatinib and TACE provides better survival benefits for intermediate- to advanced-stage HCC patients when compared to TACE monotherapy and should be recommended for suitable patients with unresectable HCC. However, further investigation into future prospective clinical studies is warranted.

Validation and evaluation of clinical prediction systems for first and repeated transarterial chemoembolization in unresectable hepatocellular carcinoma: A Chinese multicenter retrospective study.

BACKGROUND: The treatment outcome of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) varies greatly due to the clinical heterogeneity of the patients. Therefore, several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE (re-TACE). AIM: To investigate the correlations between prognostic systems and radiological response, compare the predictive abilities, and integrate them in sequence for outcome prediction. METHODS: This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016. The Hepatoma Arterial-embolization Prognostic (HAP) score system and its modified versions (mHAP, mHAP2 and mHAP3), as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival (OS) prediction for first TACE. The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART (assessment for re-treatment with TACE) and ABCR (alpha-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh and Response) systems for post re-TACE survival (PRTS). RESULTS: All the prognostic systems were correlated with radiological response achieved by first TACE, and the six-and-twelve criteria exhibited the highest correlation (Spearman R = 0.39, P = 0.026) and consistency (Kappa = 0.14, P = 0.019), with optimal performance by area under the receiver operating characteristic curve of 0.71 [95% confidence interval (CI): 0.68-0.74]. With regard to the prediction of OS, the mHAP3 system identified patients with a favorable outcome with the highest concordance (C)-index of 0.60 (95%CI: 0.57-0.62) and the best area under the receiver operating characteristic curve at any time point during follow-up; whereas, PRTS was well-predicted by the ABCR system with a C-index of 0.61 (95%CI: 0.59-0.63), rather than ART. Finally, combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo, compared with non-candidates with a median PRTS of 20.0 mo (log-rank test P < 0.001). CONCLUSION: Radiological response to TACE is closely associated with tumor burden, but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.

Sorafenib may enhance antitumour efficacy in hepatocellular carcinoma patients by modulating the proportions and functions of natural killer cells.

Dysfunction of natural killer (NK) cells is associated with poor prognosis in hepatocellular carcinoma (HCC). We explored the phenotypic and functional characteristics of peripheral blood NK cells in HCC patients following sorafenib treatment.Peripheral blood samples were collected from 60 HCC patients in a single centre (2015~2017) and 45 healthy donors. The percentage and cytoplasmic granule production of NK cells were analysed. Subset proportions were evaluated for their associations with the modified Response Evaluation Criteria in Solid Tumors (mRECIST), time to progression, and median overall survival (OS).Compared with baseline, the percentages of total and CD56dimCD16+ NK cells increased after two months of treatment, while the percentage of CD56brightCD16- NK cells decreased, leading to a dramatically reduced ratio of CD56bright and CD56dim NK cells (ratiobri/dim). Patients with low ratiobri/dim exhibited better mRECIST responses and longer median OS than those with high ratiobri/dim. The expression levels of granzyme B and perforin in total NK cells and in both subsets of cells were increased after treatment.This study showed that sorafenib could affect the proportions and functions of peripheral CD56brightCD16- and CD56dimCD16+ NK cells, which was associated with the outcomes including OS of HCC patients.

As Clinical Markers, Hand-Foot-Skin Reaction and Diarrhea Can Predict Better Outcomes for Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization plus Sorafenib.

Background: Combination therapy of transarterial chemoembolization plus sorafenib (TACE-S) has been proven to be safe and effective for hepatocellular carcinoma (HCC); however, this combination therapy is associated with a high incidence of adverse events (AEs). Our study focused on the relationships between AEs and treatment outcomes and aimed to discover AE-based clinical markers that can predict the survival benefits of combination treatment. Methods: From January 2010 to June 2014, a total of 235 HCC patients treated with TACE-S were retrospectively enrolled. Major sorafenib-related AEs were prospectively recorded, and their correlations with overall survival (OS) were analysed using time-dependent covariate Cox regression analyses. Results: The majority of the patients (200, 85.1%) were male, and the median age was 51 years old. After two years of follow-up, the median OS of the study population reached 12.4 months. In all, 218 patients (92.8%) presented at least one AE, and 174 (74.0%) suffered AEs ≥2 grade. Based on time-dependent multivariate analyses, the development of hand-foot skin reaction (HFSR) ≥2 grade (HR = 0.43, 95% CI: 0.32-0.58, P < 0.001) and diarrhoea ≥1 grade (HR = 0.72, 95% CI: 0.53-0.97, P=0.029) were identified as independent predictors of prolonged OS. Moreover, patients who developed both HFSR ≥2 grade and diarrhoea ≥1 grade achieved better outcomes than those patients who developed either or neither of these AEs (HR = 1.51, 95% CI: 1.11-2.06, P=0.009). Conclusions: The development of HFSR ≥2 grade or diarrhoea ≥1 grade during TACE-S treatment indicated prolonged OS, and these AEs should be considered important clinical markers for predicting patient prognoses.

Early TIPS with covered stents versus standard treatment for acute variceal bleeding in patients with advanced cirrhosis: a randomised controlled trial.

BACKGROUND: The survival benefit of early placement of transjugular intrahepatic portosystemic shunts (TIPS) in patients with cirrhosis and acute variceal bleeding is controversial. We aimed to assess whether early TIPS improves survival in patients with advanced cirrhosis and acute variceal bleeding. METHODS: We did an investigator-initiated, open-label, randomised controlled trial at an academic hospital in China. Consecutive patients with advanced cirrhosis (Child-Pugh class B or C) and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy were randomly assigned (2:1) to receive either early TIPS (done within 72 h after initial endoscopy [early TIPS group]) or standard treatment (vasoactive drugs continued to day 5, followed by propranolol plus endoscopic band ligation for the prevention of rebleeding, with TIPS as rescue therapy when needed [control group]). Randomisation was done by web-based randomisation system using a Pocock and Simon's minimisation method with Child-Pugh class (B vs C) and presence or absence of active bleeding as adjustment factors. The primary outcome was transplantation-free survival, analysed in the intention-to-treat population, excluding individuals subsequently found to be ineligible for enrolment. This study is registered with ClinicalTrials.gov, number NCT01370161, and is completed. FINDINGS: From June 26, 2011, to Sept 30, 2017, 373 patients were screened and 132 patients were randomly assigned to the early TIPS group (n=86) or to the control group (n=46). After exclusion of three individuals subsequently found to be ineligible for enrolment (two patients in the early TIPS group with non-cirrhotic portal hypertension or hepatocellular carcinoma, and one patient in the control group due to non-cirrhotic portal hypertension), 84 patients in the early TIPS group and 45 patients in the control group were included in the intention-to-treat population. 15 (18%) patients in the early TIPS group and 15 (33%) in the control group died; two (2%) patients in the early TIPS group and one (2%) in the control group underwent liver transplantation. Transplantation-free survival was higher in the early TIPS group than in the control group (hazard ratio 0·50, 95% CI 0·25-0·98; p=0·04). Transplantation-free survival at 6 weeks was 99% (95% CI 97-100) in the early TIPS group compared with 84% (75-96; absolute risk difference 15% [95% CI 5-48]; p=0·02) and at 1 year was 86% (79-94) in the early TIPS group versus 73% (62-88) in the control group (absolute risk difference 13% [95% CI 2-28]; p=0·046). There were no significant differences between the two groups in the incidence of hepatic hydrothorax (two [2%] of 84 patients in the early TIPS group vs one [2%] of 45 in the control group; p=0·96), spontaneous bacterial peritonitis (one [1%] vs three [7%]; p=0·12), hepatic encephalopathy (29 [35%] vs 16 [36%]; p=1·00), hepatorenal syndrome (four [5%] vs six [13%]; p=0·10), and hepatocellular carcinoma (four [5%] vs one [2%]; p=0·68). There was no significant difference in the number of patients who experienced other serious adverse events (ten [12%] vs 11 [24%]; p=0·07) or non-serious adverse events (21 [25%] vs 19 [42%]; p=0·05) between groups. INTERPRETATION: Early TIPS with covered stents improved transplantation-free survival in selected patients with advanced cirrhosis and acute variceal bleeding and should therefore be preferred to the current standard of care. FUNDING: National Natural Science Foundation of China, National Key Technology R&D Program, Optimized Overall Project of Shaanxi Province, Boost Program of Xijing Hospital.

Tumor Hypervascularity and hand-foot-skin reaction predict better outcomes in combination treatment of TACE and Sorafenib for intermediate hepatocellular carcinoma.

BACKGROUND: To validate the robust predictive values of tumor vascularity and hand-foot-skin reaction (HFSR) in combination treatment of transarterial chemoembolization (TACE) and sorafenib for patients with intermediate hepatocellular carcinoma (HCC), and then select the potential candidates who would survive best from such treatment. METHODS: A total of 132 treatment-naive patients with intermediate HCC undergoing combination therapy of TACE and sorafenib were recruited between January 2010 and December 2014. The tumor vascularity was defined according to digital subtraction angiography (DSA) and HFSR was assessed by the national cancer institute common terminology criteria for adverse events (NCI-CTCAE). The Mann-Whitney U test was used to assess the correlation between vascularity and radiologic response; time to radiologic progression (TTP) and overall survival (OS) were evaluated using Kaplan-Meier techniques and compared by log-rank test; factors associated with them were evaluated using multivariate Cox regression analysis. RESULTS: During a median follow up of 17.3 months, it was revealed that hypervascularity and development of ≥2 grade of HFSR within 60 days after sorafenib initiation were favorable predictors for TTP (HR 0.378, p < 0.001; HR 0.627, p = 0.018) and OS (HR 0.499, p = 0.002; HR 0.555, p = 0.004). The median TTP and OS for patients with both were 12.2 and 29.1 months, which were better than patients with either of them (6.0 months, HR 1.74, p = 0.012; 16.5 months, HR 1.73, p = 0.021), as well as those with neither (2.9 months, HR 3.74, p < 0.001; 11.9 months, HR 3.17, p < 0.001). CONCLUSIONS: Tumor hypervascularity and development of ≥2 grade of HFSR within 60 days were favorable predictive factors for the combination treatment of TACE and sorafenib, with both of which the patients survived longest and might be the potential candidates.

Development of a prognostic score for recommended TACE candidates with hepatocellular carcinoma: A multicentre observational study.

BACKGROUND & AIMS: Previous prognostic scores for transarterial chemoembolization (TACE) were mainly derived from real-world settings, which are beyond guideline recommendations. A robust model for outcome prediction and risk stratification of recommended TACE candidates is lacking. We aimed to develop an easy-to-use tool specifically for these patients. METHODS: Between January 2010 and May 2016, 1,604 treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh A5-B7 and performance status 0 undergoing TACE were included from 24 tertiary centres. Patients were randomly divided into training (n = 807) and validation (n = 797) cohorts. A prognostic model was developed and subsequently validated. Predictive performance and discrimination were further evaluated and compared with other prognostic models. RESULTS: The final presentation of the model was "linear predictor = largest tumour diameter (cm) + tumour number", which consistently outperformed other currently available models in both training and validation datasets as well as in different subgroups. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were further selected as cut-off values, leading to the "six-and-twelve" score which could divide patients into 3 strata with the sum of tumour size and number ≤6, >6 but ≤12, and >12 presenting significantly different median survival of 49.1 (95% CI 43.7-59.4) months, 32.0 (95% CI 29.9-37.5) months, and 15.8 (95% CI 14.1-17.7) months, respectively. CONCLUSIONS: The six-and-twelve score may prove an easy-to-use tool to stratify recommended TACE candidates (Barcelona Clinic Liver Cancer stage-A/B) and predict individual survival with favourable performance and discrimination. Moreover, the score could stratify these patients in clinical practice as well as help design clinical trials with comparable criteria involving these patients. Further external validation of the score is required. LAY SUMMARY: There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials. The six-and-twelve score provides patient survival prediction, especially in ideal candidates of TACE, outperforming other currently available models in both training and validation sets, as well as different subgroups. With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 strata with significantly different outcomes and may shed light on risk stratification of these patients in clinical practice as well as in clinical trials.

Hand-foot-skin reaction of grade ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC.

Background & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time-dependent receiver operating characteristic curves, the development of a hand-foot-skin reaction ≥ grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43-0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58-0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib-related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half.

Transarterial chemoembolization plus sorafenib for the management of unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Transarterial chemoembolization (TACE) is the recommended treatment for hepatocellular carcinoma (HCC) patients at Barcelona Clinic Liver Cancer (BCLC) B-stage, whereas sorafenib is an orally administered small molecule target drug for BCLC C-stage. This updated systemic review and meta-analysis focuses on identifying the efficacy of the combination of TACE with sorafenib, which remains controversial despite years of exploration. METHODS: PubMed, EMBASE, Scopus and the Cochrane Library were systematically reviewed to search for studies published from January 1990 to May 2017. Studies focusing on the efficacy of combination therapy for unresectable HCC were eligible. The hazard ratio (HR) with 95% confidence intervals (95% CIs) for time to progression (TTP), overall survival (OS), disease control rate (DCR) and aetiology were collected. The data were then analysed through fixed/random effects meta-analysis models with STATA 13.0. The incidence and severity of treatment-related adverse events (AEs) were also evaluated. RESULTS: Twenty-seven studies were included. Thirteen non-comparative studies reported median OS (ranging from 18.5 to 20.4 months), median TTP (ranging from 7 to 13.9 months) and DCR (ranging from 18.4 to 95%). Fourteen comparative studies provided median OS (ranging from 7.0 to 29.7 months) and median TTP (ranging from 2.6 to 10.2 months). Five comparative studies provided DCR (ranging from 32 to 97.2%). Forest plots showed that combination therapy significantly improved TTP (HR = 0.66, 95% CI 0.50-0.81, P = 0.002) rather than OS (HR = 0.63, 95% CI 0.55-0.71, P = 0.058), compared to TACE alone. DCR increased significantly in the combination therapy group (OR = 2.93, 95% CI 1.59-5.41, P = 0.005). Additional forest plots were drawn and no significant differences were observed with regard to survival outcome among various aetiologies. Forest plots for separate analysis of regions showed the HR for TTP was 0.62 (95% CI 0.45-0.79, P = 0.002) in the Asian countries group, and 0.82 (95% CI 0.59-1.05, P = 0.504)) in western countries. The HR for OS was 0.61 (95% CI 0.48-0.75, P = 0.050) in the Asian countries group and was 0.88 (95% CI 0.56-1.20, P = 0.845) in western countries. These data may indicate positive TTP outcome in Asian patients but not in European patients while no positive findings regarding OS were observed in either region. The most common AEs included fatigue, hand-foot skin reaction, diarrhoea and hypertension. CONCLUSIONS: Combination therapy may benefit unresectable HCC patients in terms of prolonged TTP and DCR. More well-designed studies are needed to investigate its superiority for OS.

Chemoembolization for Hepatocellular Carcinoma in Patients with Extrahepatic Spread: Prognostic Determinants and Appropriate Candidates.

PURPOSE: To investigate treatment outcome, prognostic factors for overall survival, and appropriate candidates for transarterial chemoembolization among patients with hepatocellular carcinoma (HCC) and extrahepatic spread (EHS). MATERIALS AND METHODS: From January 2010 to June 2014, 111 consecutive patients with HCC and EHS treated by transarterial chemoembolization alone were evaluated. Factors associated with overall survival were evaluated using Cox regression analysis, and a scoring equation was established to subgroup patients with EHS. RESULTS: Median follow-up was 3.8 months, and median overall survival was 3.8 months (95% confidence interval [CI], 2.9-4.7 months). Multivariate analysis demonstrated maximum tumor size ≥ 10 cm (hazard ratio [HR] 1.58; 95% CI, 1.02-2.46; P = .041), multifocal intrahepatic tumors (HR 1.55; 95% CI, 1.03-2.33; P = .037), and portal vein tumor thrombosis (PVTT) (HR 1.81; 95% CI, 1.12-2.91; P = .015) as significant predictors of overall survival. Based on these factors, a scoring equation was developed to predict treatment outcome of transarterial chemoembolization, with an area under the receiver operating characteristic curve of 0.76 in predicting 6-month survival. Using a cutoff score of 5.5, patients with HCC and EHS were divided into 2 groups with significantly different overall survival (8.1 months for EHS1 and 2.4 months for EHS2; P < .001). The described method of subgrouping remained discriminatory regardless of baseline characteristics. CONCLUSIONS: Maximum tumor size, intrahepatic tumor distribution, and presence of PVTT were significant determinants of overall survival for patients with HCC and EHS. Transarterial chemoembolization may be appropriate for patients with EHS but lower intrahepatic tumor burden.

mRECIST response combined with sorafenib-related adverse events is superior to either criterion alone in predicting survival in HCC patients treated with TACE plus sorafenib.

The mRECIST and dermatologic adverse events (AEs) can be used to assess the patient response to transarterial chemoembolization (TACE) and/or sorafenib for hepatocellular carcinoma (HCC). Here, we aimed to combine the two criteria to stratify the prognosis in patients with unresectable HCC receiving TACE plus sorafenib (TACE-S). In total, 176 consecutive HCC patients treated with TACE-S were enrolled. CT scans and laboratory tests were conducted pretreatment (at baseline, 5-7 days before the TACE-S) and post-treatment (at 1, 2 and 3 months). The radiological response was assessed according to mRECIST. Sorafenib-related AEs were recorded every 2 weeks after oral administration, and patients with dermatologic AEs of Grade 2 or more were defined as dermatologic responders. The earliest time at which mRECIST and dermatologic responses correlated with survival was 2 months after therapy. The mRECIST-dermatologic AE combination assessment stratified patients into three different prognoses; responders on both assessments exhibited the longest median overall survival (OS), followed by responders on one assessment and non-responders on both assessments (30.5, 17.4 and 8.3 months, respectively; p < 0.001). Achieving the highest C-index, the mRECIST-dermatologic AE combination showed better performance in predicting survival than either mRECIST or dermatologic AEs alone. Furthermore, the mRECIST-dermatologic AE combination remained a significant predictor of OS, even when the patients were stratified according to the BCLC stage, ECOG score or alpha-fetoprotein (AFP) value. This study showed that the combination of mRECIST response and dermatologic AEs is superior to either criterion used alone for predicting the survival of HCC patients treated with TACE-S.