Tumor burden affects the progression pattern on the prognosis in patients treated with sorafenib.

The progression pattern of tumors has an impact on the survival of patients with advanced hepatocellular carcinoma (HCC) and has been applied in the design of clinical trials for multiple second-line drugs. Previous research results have been contradictory, and the clinical impact of different progression patterns and their role in survival are still in question. Purpose: The study aims to analyze the impact of different progression patterns and tumor burden size on survival of HCC patients, as well as their interactions, through a retrospective cohort study. Patients and methods: The study involved 538 patients who had undergone treatment with sorafenib and had shown radiographic progression. The progression pattern was analyzed using Cox regression by including an interaction term between progression pattern and tumor burden, which was then visualized through a graphical analysis. Tumor burden was categorized into low, medium, and high subgroups based on the six-and-twelve criteria, allowing for an exploration of the effect of progression pattern on survival in different tumor burden situations. Results: Compared to patients with only intrahepatic progression (NIH/IHG) with an overall survival (OS) of 14.1/19.9 months and post-progression survival (PPS) of 8.1/13.1 months respectively, patients with extrahepatic lesions (NEH/EHG) had worse overall and postprogressive survival (OS: 9.3/9.2 months, PPS: 4.9/5.1 months). The hazard ratio for extrahepatic progression (NEH/EHG) compared to intrahepatic progression (NIH/IHG) at low, medium, and high tumor burden were [HR 2.729, 95%CI 1.189-6.263], [HR 1.755, 95%CI 1.269-2.427], and [HR 1.117, 95%CI 0.832-1.499], respectively. Conclusion: The study concluded that the interaction between the tumor progression patterns and tumor burden significantly affects the prognosis of HCC patients. As the tumor burden increases, the sensitivity of the patient's risk of death to the progression pattern decreases. These findings are valuable in personalized treatment and trial design.

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.

Transjugular intrahepatic portosystemic shunt with or without gastro-oesophageal variceal embolisation for the prevention of variceal rebleeding: a randomised controlled trial.

BACKGROUND: The role of variceal embolisation at the time of transjugular intrahepatic portosystemic shunt (TIPS) creation for the prevention of gastro-oesophageal variceal rebleeding remains controversial. This study aimed to evaluate whether adding variceal embolisation to TIPS placement could reduce the incidence of rebleeding after TIPS in patients with cirrhosis. METHODS: We did an open-label, randomised controlled trial at one university hospital in China. Eligible patients were aged 18-75 years with cirrhosis and had variceal bleeding in the past 6 weeks, and they were randomly assigned (1:1) to receive TIPS (with a covered stent in both groups) plus variceal embolisation (TIPS plus embolisation group) or TIPS alone (TIPS group) to prevent variceal rebleeding. Randomisation was done using a web-based randomisation system using a Pocock and Simon's minimisation method, stratified by Child-Pugh class (A vs B vs C). Clinicians and patients were not masked to treatment allocation; individuals involved in data analysis were masked to treatment assignment. The primary endpoint was the 2-year cumulative incidence of variceal rebleeding after randomisation, and analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT02119988. FINDINGS: Between June 16, 2014, and Feb 3, 2016, 205 patients were screened, of whom 134 were randomly allocated to the TIPS plus embolisation group (n=69) and the TIPS group (n=65). TIPS placement and variceal embolisation was successful in all 134 patients, all were included in the analysis. There was no significant difference in the 2-year cumulative incidence of variceal rebleeding between the two groups (TIPS plus embolisation 11·6% [95% CI 4·0-19·1] vs TIPS 13·8% [5·4-22·2]; hazard ratio 0·82 [95% CI 0·42-1·61]; p=0·566). Adverse events were similar between the two groups; the most common adverse events were peptic ulcer or gastritis (12 [17%] of patients in the TIPS plus embolisation group vs 13 [20%] of patients in the TIPS group), new or worsening ascites (ten [14%] vs six [9%]), and hepatocellular carcinoma (four [6%] vs six [9%]). The numbers of deaths were also similar between groups (24 [35%] vs 25 [38%]) INTERPRETATION: Adding variceal embolisation to TIPS did not significantly reduce the incidence of variceal rebleeding in patients with cirrhosis. Our findings do not support concomitant variceal embolisation during TIPS for the prevention of variceal rebleeding. FUNDING: National Key Technology R&D Program, Boost Program of Xijing Hospital, and China Postdoctoral Science Foundation.

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.

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.

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.

Prevalence of prothrombotic factors in patients with Budd-Chiari syndrome or non-cirrhotic nonmalignant portal vein thrombosis: A hospital-based observational study.

BACKGROUND AND AIM: Comprehensive investigations on the prothrombotic factors of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and non-cirrhotic nonmalignant portal vein thrombosis (PVT), in Eastern patients are scarce. METHODS: Between March 2012 and July 2017, 812 consecutive patients, including 418 BCS and 394 non-cirrhotic nonmalignant PVT patients, were admitted to Xijing Hospital (a Chinese tertiary academic hospital) and screened for prothrombotic factors. Odds ratios (ORs), 95% confidence intervals (CIs), and P-trends were calculated by using conditional logistic regression. RESULTS: The prevalence of myeloproliferative neoplasms (MPNs) was only 6.3% among BCS patients but 28.3% among PVT patients. Notably, the presence of MPNs was associated with a higher risk of hepatic vein-type BCS (OR 9.9, 95% CI 3.6-26.7, P-trend < 0.001) and extensive thrombosis in PVT (OR 4.1, 95% CI 1.9-8.9, P-trend < 0.001). Calreticulin mutations existed in 2.7% of SVT patients. Furthermore, the prevalence of antiphospholipid antibody syndrome and protein C, protein S, or antithrombin deficiency in BCS patients was 7.3% and 22.5%, respectively, similar to that in patients with PVT (7.4% and 25.7%). In addition, factor V Leiden mutation, prothrombin G20210A mutation, and paroxysmal nocturnal hemoglobinuria were identified in < 1% of both BCS and PVT patients. CONCLUSION: There is a significant positive association between MPNs and hepatic vein-type BCS or non-cirrhotic nonmalignant PVT with extensive thrombosis. Additionally, calreticulin mutations should be tested in JAK2V617F -negative SVT patients in China. However, screening for factor V Leiden mutation, prothrombin G20210A mutation, and paroxysmal nocturnal hemoglobinuria may be unnecessary.

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.

TIPSS for variceal bleeding in patients with idiopathic non-cirrhotic portal hypertension: comparison with patients who have cirrhosis.

BACKGROUND: In patients with idiopathic non-cirrhotic portal hypertension (INCPH), the usual recommended strategy for management of variceal bleeding is the same as that in cirrhosis. However, this policy has been challenged by the different natural history between INCPH and cirrhosis. AIM: To compare outcomes after transjugular intrahepatic portosystemic shunt (TIPSS) between INCPH and cirrhotic patients admitted for variceal bleeding. METHODS: Between March 2001 and September 2015, 76 consecutive patients with biopsy-proven INCPH undergoing TIPSS for variceal bleeding in a tertiary-care centre were included. 76 patients with cirrhotic portal hypertension receiving TIPSS for variceal bleeding, and matched for age, sex, Child-Pugh class, stent type and index year of TIPSS creation served as controls. RESULTS: Patients with INCPH, compared to those with cirrhosis, had significantly lower mortality (11% vs 36% at 5 years, adjusted HR, 0.37; 95% CI 0.15-0.87, P = 0.022), overt hepatic encephalopathy (16% vs 33% at 5 years, adjusted HR, 0.35; 95% CI 0.16-0.75, P = 0.007) and hepatic impairment, despite similar rates of further bleeding (33% vs 32% at 5 years, adjusted HR, 0.72; 95% CI 0.36-1.44, P = 0.358), and shunt dysfunction (35% vs 36% at 5 years, adjusted HR, 0.84; 95% CI 0.41-1.72, P = 0.627). These findings were consistent across different relevant subgroups. CONCLUSIONS: Patients with INCPH treated with TIPSS for variceal bleeding had similar progression of portal hypertension (further bleeding and shunt dysfunction) but fewer complications of liver disease (overt hepatic encephalopathy and hepatic insufficiency) and lower mortality rate compared with cirrhotic patients with comparable liver function.

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.

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.

Percutaneous Transhepatic Biliary Stent Implantation for Obstructive Jaundice of Perihilar Cholangiocarcinoma: A Prospective Study on Predictors of Stent Patency and Survival in 92 Patients.

PURPOSE: To evaluate prognostic factors for stent patency and survival in patients with perihilar cholangiocarcinoma (pCCA) who underwent percutaneous biliary stent placement. MATERIALS AND METHODS: This prospective study followed 92 consecutive patients with pCCA who underwent metal stent placement between January 2013 and July 2014. Of the total number of patients, 11 had ascites, and 36 had biliary obstruction for > 1 month at the time of stent placement. Cumulative patency and survival rates were assessed with Kaplan-Meier curves, and independent predictors were calculated with Cox regression. A new formula was developed to predict patient survival. RESULTS: Tumor size was significantly associated with stent patency (hazard ratio = 2.425; 95% confidence interval, 1.134-5.168). Independent predictors of survival included lymph node metastasis, intrahepatic mass lesion, cancer antigen 19-9 (CA19-9), ascites, and duration of jaundice. A new equation was developed to assess risk: R = 7 × (duration of biliary obstruction-0 if < 30 d, 1 if > 30 d) + 7 × (CA19-9-0 if < 500, 1 if > 500) + 7 × (ascites-0 if none present, 1 if ascites present) + 10 × (lymph node metastasis-0 if no metastasis, 1 if metastasis present) + 9 (intrahepatic mass lesion-0 if absent, 1 if present). Among patients who developed stent occlusion, patients who underwent recanalization of the occluded stent had longer survival compared with patients who did not undergo recanalization (109 d vs 29 d, P = .001). CONCLUSIONS: Prognostic factors for survival after percutaneous stent placement in patients with pCCA were tumor stage, duration of jaundice, CA19-9, and ascites. Tumor size affected stent patency. Prognosis for patients with reintervention after occlusion of the stent improved.

Early sorafenib-related adverse events predict therapy response of TACE plus sorafenib: A multicenter clinical study of 606 HCC patients.

The purpose of our study was to test the hypothesis that sorafenib-related dermatologic adverse events (AEs) as an early biomarker can predict the long-term outcomes following the combination therapy of transarterial chemoembolization (TACE) plus sorafenib (TACE-S). The intermediate-stage hepatocellular carcinoma patients who received either TACE-S or TACE-alone treatment were consecutively included into analysis. In the TACE-S group, patients with ≥ grade 2 dermatologic AEs within the first month of sorafenib initiation were defined as responders; whereas those with < grade 2 were defined as nonresponders. In the TACE-S group, the median overall survival (OS) of the responders was significantly longer than that of nonresponders (28.9 months vs. 16.8 months, respectively; p = 0.004). Multivariate analysis demonstrated that nonresponders were significantly associated with an increased risk of death compared with responders (HR = 1.9; 95% confidence Interval-CI: 1.3-2.7; p = 0.001). The survival analysis showed that the median OS was 27.9 months (95% CI: 25.0-30.8) among responders treated with TACE-S vs.18.3 months (95% CI: 14.5-22.1) among those who received TACE-alone (p = 0.046). The median time to progression was 13.1 months (95% CI: 4.4-21.8) in the TACE-S group, a duration that was significantly longer than that in the TACE-alone group [5 months (95% CI: 6.4-13.3), p = 0.014]. This study demonstrated that sorafenib-related dermatologic AEs are clinical biomarkers to identify responders from all of the patients for TACE-S therapy. Sorafenib-related dermatologic AEs, clinical biomarkers, can predict the efficacy of TACE-S in future randomized controlled trials.

The Prognostic Value of Alpha-Fetoprotein Response for Advanced-Stage Hepatocellular Carcinoma Treated with Sorafenib Combined with Transarterial Chemoembolization.

This retrospective cohort study aimed to evaluate the prognostic value of the alpha-fetoprotein (AFP) response in advanced-stage hepatocellular carcinoma (HCC) patients treated with sorafenib combined with transarterial chemoembolization. From May 2008 to July 2012, 118 HCC patients with baseline AFP levels >20 ng/ml treated with combination therapy were enrolled. A receiver operating characteristic curve was used to generate a cutoff point for AFP changes for predicting survival. The AFP response was defined as an AFP decrease rate [ΔAFP(%)] greater than the cutoff point. The ΔAFP(%) was defined as the percentage of changes between the baseline and the nadir values within 2 months after therapy. The median follow-up time was 8.8 months (range 1.2-66.9). A level of 46% was chosen as the threshold value for ΔAFP (sensitivity = 53.7%, specificity = 83.3%). The median overall survival was significantly longer in the AFP response group than in the AFP non-response group (12.8 vs. 6.4 months, P = 0.001). Multivariate analysis showed that ECOG ≥ 1 (HR = 1.95; 95% CI 1.24-3.1, P = 0.004) and AFP nonresponse (HR = 1.71; 95% CI 1.15-2.55, P = 0.009) were associated with increased risk of death. In conclusion, AFP response could predict the survival of patients with advanced-stage HCC at an early time point after combination therapy.

Transjugular Intrahepatic Portosystemic Shunt for Extrahepatic Portal Venous Obstruction in Children.

OBJECTIVES: To evaluate the feasibility and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) for extrahepatic portal venous obstruction with recurrent variceal bleeding in children. METHODS: From November 2005 to December 2013, 28 consecutive paediatric patients with extrahepatic portal venous obstruction treated with TIPS for recurrent variceal bleeding refractory to medical/endoscopic therapy and/or surgical treatment in a tertiary-care centre were followed until last clinical evaluation or death. The median follow-up time was 36.0 months (range 4.0-106.0 months). RESULTS: Seventeen boys and 11 girls of ages 7.1 to 17.9 years (median 12.3 years) weighing 19.0 to 62.0 kg (median 33.5 kg) were treated. TIPS was successfully placed in 17 of 28 (60.7%) patients via a transjugular approach alone (n = 4), a combined transjugular/transhepatic approach (n = 9), or a combined transjugular/transsplenic approach (n = 4). Shunt dysfunction occurred in 6 of 17 (35.3%) patients. The cumulative 1- and 3-year free-from-variceal-rebleeding rates in TIPS success group were higher than those in TIPS failure group (75.0% and 67.5% vs 45.5% and 18.2%, respectively, P = 0.0075). Compared with the TIPS failure group, the improvements in the height-for-age z scores were greater in the TIPS success group (P = 0.017). Procedure-related complication occurred in 1 patient (3.6%), and no episode of post-TIPS hepatic encephalopathy occurred in any patient. Except 1 patient in the TIPS success group died at 115 postoperative days, all patients were alive. CONCLUSIONS: TIPS is feasible and effective in children with extrahepatic portal venous obstruction and recurrent variceal bleeding. TIPS could represent a less-invasive alternative to traditional surgical portosystemic shunting or a valuable treatment option if surgery and endoscopic treatment failed.

[Unilateral versus bilateral biliary drainage for malignant hilar obstruction: a systematic review and meta-analysis].

OBJECTIVE: To assess the efficacy and safety of bilateral versus unilateral biliary drainage in malignant hilar obstruction. METHODS: Topically relevant studies,regardless of randomized or observational design, were searched for in PubMed, EmBase and the Cochrane Library database. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated to compare the effect of the two treatments. RESULTS: Three randomized trials and 7 observational studies were included, involving 894 patients with malignant hilar obstruction. The meta-analysis assessment of primary outcomes showed that the stent patency rate was better in bilateral drainage than in unilateral drainage (Rr=2.03,95% CI [1.16-3.56], P=0.01), but there were no significant differences in successful drainage rate (Rr=1.07,95% CI [0.97-1.18], P=0.20) and patient survival rate (Rr=-0.16,95% CI [-0.40-0.08], P=0.20). In the analysis of secondary outcomes,there were also no significant differences in the technical success rate (Rr=1.05,95% CI [0.98-1.17], P=0.34),the early complication rate (Rr=1.15, 95% CI [0.75-1.76], P=0.52), late complication rate (Rr=1.09,95% CI [0.75-1.60], P=0.60) and 30-day mortality rate (Rr=0.68,95% CI [0.38-1.23], P=0.20). CONCLUSION: Although the cumulative stent patency was better for the bilateral than the unilateral drainage approach, based on the available data, there is not enough data to support bilateral drainage for malignant hilar obstruction. Well-designed randomized controlled trials are necessary to confirm it.