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.

Pre-emptive TIPS in high-risk acute variceal bleeding. An updated and revised individual patient data meta-analysis.

BACKGROUND AND AIMS: A previous individual patient data meta-analysis (IPD-MA) showed that compared with drugs+endoscopy, the placement of transjugular portosystemic shunt within 72 hours of admission (pre-emptive transjugular intrahepatic portosystemic shunt: p-TIPS) increases the survival of high-risk patients (Child-Pugh B+ active bleeding and Child-Pugh C<14 points) with cirrhosis and acute variceal bleeding. However, the previous IPD-MA was not a two-stage meta-analysis, did not consider the potential risk of selection bias of observational studies, and did not include the most recent randomized clinical trial. We performed an updated and revised IPD-MA to reassess the efficacy of p-TIPS, addressing all previous issues. APPROACH AND RESULTS: We included all studies from the previous IPD-MA and searched for other possible eligible publications until September 2022. We performed a two-stage IPD-MA of data from 8 studies (4 randomized clinical trials and 4 observational). In addition, we performed a sensitivity analysis excluding those patients dying up to the first 72 hours after admission in the Drugs+Endoscopy arms of the 4 observational studies. The primary end point was the effects of p-TIPS versus Drugs+Endoscopy on 1-year survival.We identified 1389 patients (342 p-TIPS and 1047 Drugs+Endoscopy). The two-stage IPD-MA showed that p-TIPS significantly reduced the mortality in the overall population (HR=0·43, 95% CI: 0.32-0.60, p <0.001. This effect was observed in both subgroups of patients with Child-Pugh. The sensitivity analysis confirmed the survival benefit of p-TIPS. CONCLUSIONS: The updated two-stage IPD-MA confirms the significant survival advantage of p-TIPS in high-risk patients with cirrhosis and acute variceal bleeding. As a result, we recommend p-TIPS as the preferred first-choice treatment for these patients.

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

'Potentially curative therapies' for hepatocellular carcinoma: how many patients can actually be cured?

BACKGROUND: Treatment of hepatocellular carcinoma (HCC) is predicated on early diagnosis such that 'curative therapies' can be successfully applied. The term 'curative' is, however, poorly quantitated. We aimed to complement our previous work by developing a statistical model to predict cure after ablation and to use this analysis to compare the true curative potential of the various 'curative' therapies. METHODS: We accessed data from 1571 HCC patients treated in 5 centres receiving radiofrequency (RFA) or microwave (MWA) ablation and used flexible parametric modelling to determine the curative fraction. The results of this analysis were then combined with our previous estimations to provide a simple calculator applicable to all patients undergoing potentially curative therapies. RESULTS: The cure fraction was 18.3% rising to about 40% in patients with good liver function and very small tumours. CONCLUSION: Cure for HCC treated with ablation occurs in the order of 20% to 30%, similar to that achievable by resection but much inferior to transplantation where the analogous figure is >70%. We provide a 'calculator' that permits clinicians to estimate the chance of cure for any individual patient, based on readily available clinical features.

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.

Budd-Chiari syndrome: consensus guidance of the Asian Pacific Association for the study of the liver (APASL).

Budd Chiari syndrome (BCS) is a diverse disease with regard to the site of obstruction, the predisposing thrombophilic disorders and clinical presentation across the Asia-Pacific region. The hepatic vein ostial stenosis and short segment thrombosis are common in some parts of Asia-Pacific region, while membranous obstruction of the vena cava is common in some and complete thrombosis of hepatic veins in others. Prevalence of myeloproliferative neoplasms and other thrombophilic disorders in BCS varies from region to region and with different sites of obstruction. This heterogeneity also raises several issues and dilemmas in evaluation and approach to management of a patient with BCS. The opportunity to recanalize hepatic vein in patients with hepatic vein ostial stenosis or inferior vena cava stenting or pasty among those membranous obstruction of the vena cava is a unique opportunity in the Asia-Pacific region to restore hepatic outflow closely mimicking physiology. In order to address these issues arising out of the diversity as well as the unique features in the region, the Asia Pacific Association for Study of Liver has formulated these guidelines for clinicians.

Folate-conjugated hydrophobicity modified glycol chitosan nanoparticles for targeted delivery of methotrexate in rheumatoid arthritis.

BACKGROUND: Targeted delivery to the Rheumatoid arthritis (RA) which is characterized by destruction and degeneration of bones due to chronic inflammation is of great need. RA being a chronic autoimmune disorder might result in severe disability and morbidity. A targeted delivery system is designed to deliver methotrexate (MTX) for RA. METHODS: Here, we synthesized folic acid (FA) conjugated hydrophobically modified glycol chitosan (GC) self-assembled nanoparticles (FA-GC-SA) for the targeted delivery of MTX to RA. The FA conjugation and hydrophobic modification of GC by stearic acid (SA) was confirmed by Fourier-transform infrared spectroscopy (FTIR). The FA-GC-SA was exploited for developing targeted nanoparticles encapsulating MTX by the ionic gelation method. The particles were characterized and evaluated for their targeting potential in in vitro cell culture studies. Further their in vivo efficacy in arthritis induced rats using collagen was also evaluated. RESULTS: FTIR confirms the successful modification of GC-SA and FA-GC-SA. The FA-GC-SA-MTX of size 153 ± 9 nm were prepared with high encapsulation efficiency of MTX. The FA-GC-SA-MTX size was further confirmed by transmission electron microscopy (TEM). In vitro cell studies revealed the superior efficacy of FA-GC-SA-MTX in cell cytotoxicity. Also, significantly higher cellular uptake of FA functionalized FA-GC-SA-MTX was observed in comparison to non-functionalized GC-SA-MTX attributed to folate receptors (FRs) mediated endocytosis. In vivo results confirms the potential of FA-GC-SA-MTX which reduces reduces the pro-inflammatory cytokines, paw thickness, and arthritis score in collagen induced rats. CONCLUSION: The results shows that FRs targeted FA-GC-SA-MTX has superior efficacy in the treatment of RA.

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.

The neutrophil-to-lymphocyte ratio is a predictive factor for the survival of patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is considered as a prognostic predictor of hepatocellular carcinoma (HCC). However, its prognostic ability is still controversial. This study aimed to evaluate the prognostic value of NLR changes in HCC patients undergoing transarterial chemoembolization (TACE). METHODS: The patients who were newly diagnosed with HCC and treated with TACE in our center from July 2010 to December 2014 were enrolled in the study. The factors, including NLR, were recorded at baseline and three days and one month after TACE. RESULTS: A total of 380 consecutive patients were studied retrospectively. The median NLR values at baseline, 3 days and 1 month after TACE (2.4, 6.3 and 2.4 respectively), were used as the cut-off value for patient stratification. Compared with the patients in low NLR group, those with high NLR had a larger tumor size. For baseline measurement, the low NLR group showed improved overall survival (OS) compared with the high group (median OS, 27.1 vs. 15.6 months, P=0.004). There was no survival difference between the low and high NLR groups when measured at 3 days and at 1 month after TACE (P>0.05). Multivariate analysis showed that baseline NLR >2.4 was an independent prognostic predictor of poor OS. There was significant survival difference between the normal NLR group and the high or increased NLR group, with a median OS of 29.1 and 19.1 months, respectively (P=0.023). CONCLUSIONS: The dynamic changes of baseline NLR are significantly associated with OS in HCC patients treated with TACE, and as a result patient selection and prognostic prediction may be refined.

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.

Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition).

BACKGROUND: Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. SUMMARY: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2017 Edition) in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition (2019 Edition) was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years. KEY MESSAGES: Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People's Republic of China in December 2019.

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.

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.

Prediction of Survival Among Patients Receiving Transarterial Chemoembolization for Hepatocellular Carcinoma: A Response-Based Approach.

BACKGROUND AND AIMS: The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. APPROACH AND RESULTS: Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. CONCLUSIONS: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.

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.

A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma.

BACKGROUND: The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response. METHODS: This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC. RESULTS: A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules (n = 8), and in the expansion, patients received 600 mg BID capsules (n = 28) or 400 mg BID tablets (n = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)]. CONCLUSIONS: Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827.