Efficacy comparison of immune combination therapies in subgroups for advanced hepatocellular carcinoma patients: Systematic review and network meta-analysis.

BACKGROUND: There is a lack of precision in the immunotherapy strategy tailored for patients exhibiting diverse clinical characteristics. This study aims to employ a rigorous network meta-analysis (NMA) approach to systematically evaluate the effectiveness of immune-combination therapies among patients with advanced hepatocellular carcinoma, taking into account their varying clinico-characteristics. METHODS: Studies were retrieved from PubMed, Embase, Cochrane Library, and Web of Science databases. The included first-line phase III studies were categorized into three types: immunotherapy combined with anti-angiogenetic agents, immunotherapy combined with tyrosine kinase inhibitors, and dual immunotherapy, with sorafenib serving as the control group. The primary endpoint used to assess efficacy was overall survival (OS), facilitating a comparative analysis among the three treatment modalities. Furthermore, subgroup analyses were conducted to evaluate the varying effectiveness for patients with diverse clinico-characteristics. Secondary outcome measures included progression-free survival, objective response rate, and toxicity assessment. RESULTS: A total of 6 studies were included in the NMA, encompassing a cohort of 3840 patients. The results revealed that immunotherapy combined with anti-angiogenetic agents exhibited a significantly enhanced therapeutic effect in terms of improving OS compared to sorafenib (HR = 0.61, 95% CrI, 0.42-0.90). Furthermore, based on various clinicopathological features, this combination therapy demonstrated superior OS responses in specific patient subgroups: BCLC C (HR = 0.63, 95% CrI, 0.42-0.93), ECOG 1 (HR = 0.57, 95% CrI, 0.36-0.91), with extrahepatic spread (EHS) (HR = 0.59, 95% CrI, 0.37-0.92), alpha fetoprotein (AFP)<400ng/ml (HR = 0.56, 95% CrI, 0.33-0.94) and viral hepatitis positivity (HR = 0.56, 95% CrI, 0.39-0.77) (especially HBV (HR = 0.58, 95% CrI, 0.40-0.85)). Importantly, the advantage of this combination therapy was even more pronounced in patients with viral hepatitis positivity. Also, the adverse events associated with immunotherapy combined with antiangiogenic drugs were moderate. CONCLUSIONS: Immunotherapy combined with anti-angiogenetic agents could represent the most effective first-line intervention for achieving improved OS, particularly in patients with viral hepatitis positivity.

Impact of three-dimensional reconstruction visualization technology on short-term and long-term outcomes after hepatectomy in patients with hepatocellular carcinoma: a propensity-score-matched and inverse probability of treatment-weighted multicenter study.

BACKGROUND: Three-dimensional reconstruction visualization technology (3D-RVT) is an important tool in the preoperative assessment of patients undergoing liver resection. However, it is not clear whether this technique can improve short-term and long-term outcomes in patients with hepatocellular carcinoma (HCC) compared with two-dimensional (2D) imaging. METHOD: A total of 3402 patients from five centers were consecutively enrolled from January 2016 to December 2020, and grouped based on the use of 3D-RVT or 2D imaging for preoperative assessment. Baseline characteristics were balanced using propensity score matching (PSM, 1:1) and stabilized inverse probability of treatment-weighting (IPTW) to reduce potential selection bias. The perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) were compared between the two groups. Cox-regression analysis was used to identify the risk factors associated with RFS. RESULTS: A total of 1681 patients underwent 3D-RVT assessment before hepatectomy (3D group), while 1721 patients used 2D assessment (2D group). The PSM cohort included 892 patient pairs. In the IPTW cohort, there were 1608.3 patients in the 3D group and 1777.9 patients in the 2D group. In both cohorts, the 3D group had shorter operation times, lower morbidity and liver failure rates, as well as shorter postoperative hospital stays. The 3D group had more margins ≥10 mm and better RFS than the 2D group. The presence of tumors with a diameter ≥5 cm, intraoperative blood transfusion and multiple tumors were identified as independent risk factors for RFS, while 3D assessment and anatomical resection were independent protective factors. CONCLUSION: In this multicenter study, perioperative outcomes and RFS of HCC patients following 3D-RVT assessment were significantly different from those following 2D imaging assessment. Thus, 3D-RVT may be a feasible alternative assessment method before hepatectomy for these patients.

A novel remnant liver-first strategy for liver autotransplantation in patients with end-stage hepatic alveolar echinococcosis: a retrospective case series.

BACKGROUND: Ex vivo liver resection combined with autotransplantation is an effective therapeutic strategy for unresectable end-stage hepatic alveolar echinococcosis (HAE). However, ex vivo liver resection combined with autotransplantation is a technically demanding and time-consuming procedure associated with significant morbidity and mortality. The authors aimed to present our novel remnant liver-first strategy of in vivo liver resection combined with autotransplantation (IRAT) technique for treating patients with end-stage HAE. METHODS: This retrospective study included patients who underwent IRAT between January 2014 and December 2020 at two institutions. Patients with end-stage HAE were carefully assessed for IRAT by a multidisciplinary team. The safety, feasibility, and outcomes of this novel technique were analyzed. RESULTS: IRAT was successfully performed in six patients, with no perioperative deaths. The median operative time was 537.5 min (range, 501.3-580.0), the median anhepatic time was 59.0 min (range, 54.0-65.5), and the median cold ischemia time was 165.0 min (range, 153.8-201.5). The median intraoperative blood loss was 700.0 ml (range, 475.0-950.0). In-hospital complications occurred in two patients. No Clavien-Dindo grade III or higher complications were observed. At a median follow-up of 18.6 months (range, 15.4-76.0) , all patients were alive. No recurrence of HAE was observed. CONCLUSION: The remnant liver-first strategy of IRAT is feasible and safe for selected patients with end-stage HAE. The widespread adoption of this novel technique requires further studies to standardize the operative procedure and identify patients who are most likely to benefit from it.

Clinico-characteristics of patients which correlated with preferable treatment outcomes in immunotherapy for advanced hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is the third-most lethal malignant tumor worldwide. The rapid development of immunotherapy utilizing immune checkpoint inhibitors for advanced HCC patients has been witnessed in recent years, along with numerous randomized clinical trials demonstrating the survival benefits for these individuals. This systematic review and meta-analysis aimed to identify specific clinico-pathological characteristics of advanced HCC patients that may lead to preferable responses to immunotherapy in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). METHODS: The included clinical trials were retrieved from PubMed, Embase, the Cochrane library, and the Web of Science databases published in English between 1 January 2002 and 20 October 2022. A systematic review and meta-analysis for first-line and second-line phase II/III studies were conducted on immunotherapy for patients with advanced HCC by using OS as the primary outcome measure, and PFS and ORR as the secondary outcome measures to obtain clinico-pathological characteristics of patients which might be preferable responses to programmed death-1 (PD-1) and programmed cell death-Ligand 1 (PD-L1) inhibitors. Toxicity and specific treatment-related adverse events (TRAEs) were also determined. RESULTS: After screening 1392 relevant studies, 12 studies were included in this systematic review and meta-analysis to include 5948 patients. Based on the analysis of interaction, the difference in OS after first-line immunotherapy between the subgroups of viral hepatitis [hazard ratio (HR)=0.73 vs 0.87, P for interaction=0.02] and macrovascular invasion and/or extrahepatic spread (HR=0.73 vs 0.89, P for interaction=0.02) were significant. The difference in PFS between the subgroups of viral hepatitis was highly significant (pooled HR=0.55 vs 0.81, P for interaction=0.007). After second-line immunotherapy, the difference in ORR between the subgroups of Barcelona Clinic Liver Cancer was significant (pooled ES=0.12 vs 0.23, P for interaction=0.04). Compared with PD-L1 inhibitors, PD-1 inhibitors may have a higher probability to cause TRAEs. Diarrhea, increased aspartate aminotransferase, and hypertension were the top three TRAEs. CONCLUSIONS: This systematic review and meta-analysis represents the first pilot study aimed at identifying crucial clinico-pathological characteristics of patients with advanced HCC that may predict favorable treatment outcomes in terms of OS, PFS, and ORR to immunotherapy. Findings suggest that patients with viral hepatitis positivity (especially hepatitis B virus) and macrovascular invasion and/or extrahepatic spread may benefit more in OS when treated with PD-1/PD-L1 immune checkpoint inhibitors.

Synthetic miR-26a mimics delivered by tumor exosomes repress hepatocellular carcinoma through downregulating lymphoid enhancer factor 1.

BACKGROUND: The dysregulation of exosomal microRNAs plays an important role in the progression of hepatocarcinogenesis. In this study, we investigated the therapeutic potential of synthetic exosomal miR-26a against HCC cells and explored the feasibility of tumor-derived exosomes as drug delivery vehicles. METHODS: Proliferation and migration assays were performed to examine the effects of miR-26a on HCC in vitro. The direct target gene of miR-26a was identified through miRecords analysis and target validation. The transferring efficiency and anti-HCC effect of exosomes with different origin were studied and the optimal miR-26a delivery method was established and verified in vitro and in vivo. In addition, the relationships between prognosis of HCC patients and miR-26a expression in HCC serum and exosomes were retrospectively analyzed. RESULTS: Here, we found that tumor cell-derived exosomes were taken in preferentially by HCC cells and promoted HCC progression through Wnt pathway by low-density lipoprotein receptor-related protein 6 (LRP6). HCC cells with vacuolar protein sorting-associated protein 35 knocked down were adopted to generate engineered LRP6-exosomes. The engineered HCC-derived exosomes loading miR-26a inhibited HCC progression in vitro and in vivo effectively. Overexpression of miR-26a impaired the growth and migration of HCC by targeting lymphoid enhancer factor 1 (LEF1). Moreover, low expression of exosomal miR-26a was an independent prognostic factor for recurrence and survival in HCC patients. CONCLUSIONS: Our findings suggested the exosomal miR-26a could serve as a non-invasive prognostic marker for HCC patients. Genetically modified tumor-derived exosomes showed preferable transfection efficiency but reduced Wnt activity, which provides a novel therapeutic strategy for HCC.

Novel liver vein deprivation technique that promotes increased residual liver volume (with video): A case report.

BACKGROUND: Inadequate volume of future liver remnant (FLR) is a major challenge for hepatobiliary surgeons treating large or multiple liver tumors. As an alternative to associating liver partition and portal vein ligation (ALPPS) for staged hepatectomy and liver venous deprivation (LVD) using stage 1 interventional radiology for vascular embolization combined with stage 2 open liver resection have been used. CASE SUMMARY: A novel modified LVD technique was performed in a patient with pancreatic neuroendocrine tumor with liver metastases by using stage 1 laparoscopic ligation of the right hepatic vein, right posterior portal vein, and short hepatic veins combined with local excision of three liver metastases in the left hemiliver. The operation was followed three days later by interventional radiology to embolize an anomalous right anterior portal vein to complete LVD. A stage 2 laparoscopic right hemihepatectomy and pancreaticosplenectomy were then carried out. CONCLUSION: The minimally invasive technique promoted a rapid increase, comparable to ALPPS, in volume of the FLR after the stage 1 operation to allow the laparoscopic stage 2 resection to be performed.

Histological Severity of Cirrhosis Influences Surgical Outcomes of Hepatocellular Carcinoma After Curative Hepatectomy.

Background: Hepatocellular carcinoma (HCC) is frequently associated with cirrhosis. The present study investigated the impact of histological severity of cirrhosis on surgical outcomes for HCC and further developed novel nomograms to predict postoperative recurrence and survival. Methods: A total of 1524 consecutive patients undergoing curative hepatectomy for HCC between 1999 and 2015 were retrospectively studied. Cirrhotic severity was histologically staged according to the Laennec staging system. Short- and long-term outcomes were investigated. Recurrence-free survival (RFS) and overall survival (OS) predictive nomograms were constructed based on the results of multivariate analysis. The predictive accuracy of the nomograms was measured by the concordance index (C-index) and calibration. Results: Patients in the severe cirrhosis group had significantly higher morbidity and mortality rates than patients in the no, mild, and moderate cirrhosis groups. The 5-year RFS and OS rates were 36.8% and 64.5%, respectively, in the no cirrhosis group, compared to 34.8% and 60.4% in the mild cirrhosis group, 17.3% and 43.4% in the moderate cirrhosis group, and 6.1% and 20.1% in the severe cirrhosis group. Long-term survival outcomes were significantly worse as cirrhotic severity was increased. The C-index was 0.727 for the RFS nomogram and 0.746 for the OS nomogram. Calibration curves showed good agreement between actual observations and nomogram predictions. The 2 nomograms had a superior discriminatory ability to predict RFS and OS compared to other staging systems. Conclusion: Histological severity of cirrhosis significantly affected surgical outcomes in HCC patients undergoing curative hepatectomy. The novel nomograms, including histological severity of cirrhosis, showed an accurate prediction of postoperative recurrence and survival.

Adjuvant Sorafenib Following Radiofrequency Ablation for Early-Stage Recurrent Hepatocellular Carcinoma With Microvascular Invasion at the Initial Hepatectomy.

Background: The efficacy of radiofrequency ablation (RFA) for patients with early-stage recurrent hepatocellular carcinoma (HCC) with microvascular invasion (MVI) at the initial hepatectomy is limited. Our study aimed to explore whether adjuvant sorafenib following RFA could improve the situation. Methods: We retrospectively included 211 patients with early-stage (tumor number of ≤3 and tumor size of 2-5 cm) recurrent HCC with MVI at the initial hepatectomy who underwent adjuvant sorafenib following RFA or RFA alone in 13 centers from June 2013 to June 2020. In the combination group, sorafenib of 400 mg twice daily was administered within 7 days after RFA. Overall survival (OS) and recurrence-free survival (RFS) were compared. Subgroup analysis based on MVI grade was performed. MVI grade was based on the practice guidelines for the pathological diagnosis of HCC and included M1 (≤5 MVI sites, all located within adjacent peritumoral liver tissues 0-1 cm away from the tumor margin) and M2 (>5 MVI sites, or any MVI site located within adjacent peritumoral liver tissues > 1 cm away from the tumor margin). Results: A total of 103 patients received the combination therapy and 108 patients received RFA alone. The combination therapy provided better survival than RFA alone (median RFS: 17.7 vs. 13.1 months, P < 0.001; median OS: 32.0 vs. 25.0 months, P = 0.002). Multivariable analysis revealed that treatment allocation was an independent prognostic factor. On subgroup analysis, the combination therapy provided better survival than RFA alone in patients with M1 along with either a tumor size of 3-5 cm, tumor number of two to three, or alpha-fetoprotein (AFP) > 400 µg/L, and in those with M2 along with either a tumor size of 2-3 cm, one recurrent tumor, or AFP ≤ 400 µg/L. Conclusions: Adjuvant sorafenib following RFA was associated with better survival than RFA alone in patients with early-stage recurrent HCC with MVI at the initial hepatectomy. Moreover, MVI grade could guide the application of adjuvant sorafenib.

Biomarkers for hepatocellular carcinoma based on body fluids and feces.

Novel non-/minimally-invasive and effective approaches are urgently needed to supplement and improve current strategies for diagnosis and management of hepatocellular carcinoma (HCC). Overwhelming evidence from published studies on HCC has documented that multiple molecular biomarkers detected in body fluids and feces can be utilized in early-diagnosis, predicting responses to specific therapies, evaluating prognosis before or after therapy, as well as serving as novel therapeutic targets. Detection and analysis of proteins, metabolites, circulating nucleic acids, circulating tumor cells, and extracellular vesicles in body fluids (e.g., blood and urine) and gut microbiota (e.g., in feces) have excellent capabilities to improve different aspects of management of HCC. Numerous studies have been devoted in identifying more promising candidate biomarkers and therapeutic targets for diagnosis, treatment, and monitoring responses of HCC to conventional therapies, most of which may improve diagnosis and management of HCC in the future. This review aimed to summarize recent advances in utilizing these biomarkers in HCC and discuss their clinical significance.

Prognostic significance of regional lymphadenectomy in T1b gallbladder cancer: Results from 24 hospitals in China.

BACKGROUND: Whether regional lymphadenectomy (RL) should be routinely performed in patients with T1b gallbladder cancer (GBC) remains a subject of debate. AIM: To investigate whether RL can improve the prognosis of patients with T1b GBC. METHODS: We studied a multicenter cohort of patients with T1b GBC who underwent surgery between 2008 and 2016 at 24 hospitals in 13 provinces in China. The log-rank test and Cox proportional hazards model were used to compare the overall survival (OS) of patients who underwent cholecystectomy (Ch) + RL and those who underwent Ch only. To investigate whether combined hepatectomy (Hep) improved OS in T1b patients, we studied patients who underwent Ch + RL to compare the OS of patients who underwent combined Hep and patients who did not. RESULTS: Of the 121 patients (aged 61.9 ± 10.1 years), 77 (63.6%) underwent Ch + RL, and 44 (36.4%) underwent Ch only. Seven (9.1%) patients in the Ch + RL group had lymph node metastasis. The 5-year OS rate was significantly higher in the Ch + RL group than in the Ch group (76.3% vs 56.8%, P = 0.036). Multivariate analysis showed that Ch + RL was significantly associated with improved OS (hazard ratio: 0.51; 95% confidence interval: 0.26-0.99). Among the 77 patients who underwent Ch + RL, no survival improvement was found in patients who underwent combined Hep (5-year OS rate: 79.5% for combined Hep and 76.1% for no Hep; P = 0.50). CONCLUSION: T1b GBC patients who underwent Ch + RL had a better prognosis than those who underwent Ch. Hep + Ch showed no improvement in prognosis in T1b GBC patients. Although recommended by both the National Comprehensive Cancer Network and Chinese Medical Association guidelines, RL was only performed in 63.6% of T1b GBC patients. Routine Ch + RL should be advised in T1b GBC.

Consensus recommendations of three-dimensional visualization for diagnosis and management of liver diseases.

Three-dimensional (3D) visualization involves feature extraction and 3D reconstruction of CT images using a computer processing technology. It is a tool for displaying, describing, and interpreting 3D anatomy and morphological features of organs, thus providing intuitive, stereoscopic, and accurate methods for clinical decision-making. It has played an increasingly significant role in the diagnosis and management of liver diseases. Over the last decade, it has been proven safe and effective to use 3D simulation software for pre-hepatectomy assessment, virtual hepatectomy, and measurement of liver volumes in blood flow areas of the portal vein; meanwhile, the use of 3D models in combination with hydrodynamic analysis has become a novel non-invasive method for diagnosis and detection of portal hypertension. We herein describe the progress of research on 3D visualization, its workflow, current situation, challenges, opportunities, and its capacity to improve clinical decision-making, emphasizing its utility for patients with liver diseases. Current advances in modern imaging technologies have promised a further increase in diagnostic efficacy of liver diseases. For example, complex internal anatomy of the liver and detailed morphological features of liver lesions can be reflected from CT-based 3D models. A meta-analysis reported that the application of 3D visualization technology in the diagnosis and management of primary hepatocellular carcinoma has significant or extremely significant differences over the control group in terms of intraoperative blood loss, postoperative complications, recovery of postoperative liver function, operation time, hospitalization time, and tumor recurrence on short-term follow-up. However, the acquisition of high-quality CT images and the use of these images for 3D visualization processing lack a unified standard, quality control system, and homogeneity, which might hinder the evaluation of application efficacy in different clinical centers, causing enormous inconvenience to clinical practice and scientific research. Therefore, rigorous operating guidelines and quality control systems need to be established for 3D visualization of liver to develop it to become a mature technology. Herein, we provide recommendations for the research on diagnosis and management of 3D visualization in liver diseases to meet this urgent need in this research field.

Comparison of hydrochloric acid infusion radiofrequency ablation with microwave ablation in an ex vivo liver model.

Objectives: To compare sizes and shapes of ablation zones resulting from hydrochloric acid infusion radiofrequency ablation (HRFA) and microwave ablation (MWA), using normal saline infusion radiofrequency ablation (NSRFA) as a control, at a variety of matched power settings and ablation durations, in an ex vivo bovine liver model.Methods: A total of 90 ablation procedures were performed, using each of three modalities: NSRFA, HRFA, and MWA. For each modality, five ablation procedures were performed for each combination of power (80 W, 100 W, or 120 W) and duration (5, 10, 20, 30, 45, or 60 min). The size of ablation zones were compared using ANOVA, the Kruskal-Wallis test, or generalized linear regression.Results: For ablation durations up to 30 min, mean transverse diameter (TD) after HRFA and MWA did not differ significantly (ß = 0.13, p = .20). For ablation durations greater than 30 min, mean TD was significantly larger after HRFA than after MWA (ß = 1.657, p < .001). The largest TD (9.46 cm) resulted from HRFA performed with 100 W power for 60 min.Conclusions: Compared to MWA, monopolar HRFA with power settings of 80 W-120 W and durations of less than 30 min showed no significant difference. When duration of more than 30 min, HRFA created larger ablation zones than MWA.

Transarterial chemoembolization versus best supportive care for patients with hepatocellular carcinoma with portal vein tumor thrombus：a multicenter study.

BACKGROUND: This study aims to compare the efficacy and safety of treatment after transarterial chemoembolization(TACE) with best supportive care (BSC) in patients with hepatocellular carcinoma (HCC) with PVTT. METHODS: This retrospective study was conducted on 1,040 patients with HCC with PVTT who were treated either with TACE (n = 675) or BSC (n = 365). BSC did not include sorafenib. The two groups of patients were compared with or without propensity score matching. A subgroup analysis was subsequently performed by stratifying patients according to the stages of PVTT in the Cheng's PVTT classification. RESULTS: In PVTTtypes I-III, TACE was associated with significantly better overall survival (OS) thanBSC (P < 0.05). Within each type of PVTT for patients who received TACE or BSC, OS was significantly worse in patients with type IVPVTT than in any of the other three types of PVTT (all P < 0.05). TACE was associated with better long-termOS than BSC after propensity score matching or on stratification by the PVTT types. CONCLUSION: TACE was associated with better OS than BSC in HCC patients with PVTT types I-III but not type IV. Patients with type IV PVTT showed the worst prognosis, regardless of whether TACE or BSC was used.

Risk Factors, Patterns, and Outcomes of Late Recurrence After Liver Resection for Hepatocellular Carcinoma: A Multicenter Study From China.

Importance: Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer. Objective: To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC. Design, Setting, and Participants: This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018. Interventions: Liver resection for HCC. Main Outcomes and Measures: Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence. Results: Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence. Conclusions and Relevance: Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence.

Protein induced by vitamin K absence or antagonist-II versus alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: A systematic review with meta-analysis.

BACKGROUND: As a promising biomarker of hepatocellular carcinoma (HCC), protein induced by vitamin K absence or antagonist-II (PIVKA-II) has been studied extensively. However, its diagnostic capability varies across HCC studies. This study aimed to compare the performance of PIVKA-II with alpha-fetoprotein (AFP) in the diagnosis of HCC. DATA SOURCES: A systematic literature search was conducted to identify the studies from MEDLINE, Embase and Cochrane Library Databases, which were published up to December 20, 2017 to compare the diagnostic capability of PIVKA-II and AFP for HCC. The data were pooled using random effects model. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic curve (ROC) was employed to evaluate the diagnostic accuracy of each marker. RESULTS: Thirty-one studies were included. The pooled sensitivity (95% CI) of PIVKA-II and AFP was 0.66 (0.65-0.68) and 0.66 (0.65-0.67), respectively in diagnosis of HCC; and the corresponding pooled specificity (95% CI) was 0.89 (0.88-0.90) and 0.84 (0.83-0.85), respectively. The area under the ROC curve (AUC) of PIVKA-II and AFP was 0.856 (0.817-0.895) and 0.770 (0.728-0.811), respectively. Subgroup analysis showed that PIVKA-II was superior to AFP in terms of the AUC for both small HCC (< 3 cm) [0.863 (0.825-0.901) vs 0.717 (0.658-0.776)] and large HCC (≥ 3 cm) [0.854 (0.811-0.897) vs 0.729 (0.682-0.776)]; for American [0.926 (0.897-0.955) vs 0.698 (0.594-0.662)], European [0.772 (0.743-0.801) vs 0.628 (0.594-0.662)], Asian [0.838 (0.812-0.864) vs 0.785 (0.764-0.806)] and African [0.812 (0.794-0.840) vs 0.721 (0.675-0.767)] HCC patients; and for HBV-related [0.909 (0.866-0.951) vs 0.714 (0.673-0.755)] and mixed-etiology [0.847 (0.821-0.873) vs 0.794 (0.772-0.816)] HCC. CONCLUSION: This meta-analysis indicates that PIVKA-II is better than AFP in terms of the accuracy for diagnosing HCC, regardless of tumor size, patient ethnic group, or HCC etiology.

Adjuvant Transarterial Chemoembolization for HBV-Related Hepatocellular Carcinoma After Resection: A Randomized Controlled Study.

Purpose: The survival of patients with hepatocellular carcinoma (HCC) recurrence after curative resection is usually poor. We sought to evaluate the safety and efficacy of adjuvant transarterial chemoembolization (TACE) in HBV-related HCC patients with an intermediate (a single tumor larger than 5 cm without microvascular invasion) or high risk (a single tumor with microvascular invasion, or two or three tumors) of recurrence.Experimental Design: In this randomized phase 3 trial, 280 eligible patients were assigned to adjuvant TACE (n = 140) or no adjuvant treatment (control; n = 140) groups. The primary endpoint was recurrence-free survival (RFS); secondary endpoints included overall survival (OS) and safety. Multivariable Cox-proportional hazards model was used to determine the independent impact of TACE on patients' outcomes.Results: Patients who received adjuvant TACE had a significantly longer RFS than those in the control group [56.0% vs. 42.1%, P = 0.01; HR, 0.68; 95% confidence interval (CI), 0.49-0.93]. Patients in the adjuvant TACE group had 7.8% higher 3-year OS rate than the control group (85.2% vs. 77.4%; P = 0.04; HR, 0.59; 95% CI, 0.36-0.97). The impact of adjuvant TACE on RFS and OS remained significant after controlling for other known prognostic factors (HR, 0.67; P = 0.01 for RFS; and HR, 0.59; P = 0.04 for OS). There was no grade 3 or 4 toxicity after adjuvant TACE.Conclusions: For patients with HBV-related HCC who had an intermediate or high risk of recurrence after curative hepatectomy, our study showed adjuvant TACE significantly reduced tumor recurrence, improved RFS and OS, and the procedure was well tolerated. Clin Cancer Res; 24(9); 2074-81. ©2018 AACR.

Surrogate endpoint for overall survival in assessment of adjuvant therapies after curative treatment for hepatocellular carcinoma: a re-analysis of meta-analyses of individual patients' data.

The gold standard endpoint to evaluate the effect of treatment for hepatocellular carcinoma (HCC) is overall survival (OS), but it requires a longer follow-up period to observe. This study aimed to identify whether disease-free survival (DFS) could be used as a surrogate endpoint for OS to assess the efficacy of adjuvant therapies after curative treatment (surgical resection and ablation) for HCC patients. A systematic review was conducted to identify trials about curative treatment combined with or without adjuvant therapies (interferon, IFN; or transarterial chemoembolization, TACE) for HCC. Total of 2211 patients' data from 17 trials were analyzed. At the individual study level, DFS was strongly correlated to OS (ρ = 0.988 and 0.930, 95% CI: 0.965-0.996 and 0.806-0.976 for the studies comparing Radiofrequency ablation (RFA) + TACE to RFA alone; and for the studies comparing curative treatment + IFN to curative treatment alone, respectively). At the trial level, the effects of treatment on DFS and OS were also strongly correlated to each other (R = 0.815 and 0.854, 95% CI: 0.536-0.934 and 0.621-0.948, respectively). In conclusion, DFS could be used as a potential surrogate endpoint for OS to assess the effect of adjuvant therapies after curative treatment for HCC.

Novel microvascular invasion-based prognostic nomograms to predict survival outcomes in patients after R0 resection for hepatocellular carcinoma.

PURPOSE: To propose a novel histopathological classification system for microvascular invasion (MVI) and to establish nomograms to predict postoperative survival and early tumor recurrence in patients with hepatocellular carcinoma (HCC) after R0 liver resection. METHODS: The clinicopathological and follow-up data of 686 consecutive patients with HCC who underwent R0 liver resection in our hospital between December 2009 and April 2010 were retrospectively reviewed. A classification system was established based on histological characteristics of MVI. Nomograms were then formulated using a multivariate Cox proportional hazards model to analyze. The results were validated using bootstrap resampling and a new 225-patient validation cohort operated in May and June 2010 at the same institution. RESULTS: A 4-stratification classification system of MVI was established, which satisfactorily determined the risk of survival and early tumor recurrence. Then, an eight-factor nomogram for survival prediction and a seven-factor nomogram for prediction of early tumor recurrence were established. The concordance indices were 0.78 for the survival-prediction nomogram and 0.72 for the recurrence-prediction nomogram. These indices were both significantly higher than the following three commonly used staging systems: tumor-node-metastasis staging system (seventh edition, 0.67/0.65), Japan Integrated Staging System (0.58/0.58) and Chinese University Prognostic Index (0.52/0.51). The calibration curves showed good agreement between predictions by the nomograms and actual survival outcomes. These results were confirmed in the validation cohort. CONCLUSIONS: The novel classification system of MVI and the nomograms enabled more accurate predictions of risk of tumor recurrence and overall survival in patients with HCC after R0 liver resection.

Prognostic Value of a BCSC-associated MicroRNA Signature in Hormone Receptor-Positive HER2-Negative Breast Cancer.

PURPOSE: Breast cancer patients with high proportion of cancer stem cells (BCSCs) have unfavorable clinical outcomes. MicroRNAs (miRNAs) regulate key features of BCSCs. We hypothesized that a biology-driven model based on BCSC-associated miRNAs could predict prognosis for the most common subtype, hormone receptor (HR)-positive, HER2-negative breast cancer patients. PATIENTS AND METHODS: After screening candidate miRNAs based on literature review and a pilot study, we built a miRNA-based classifier using LASSO Cox regression method in the training group (n=202) and validated its prognostic accuracy in an internal (n=101) and two external validation groups (n=308). RESULTS: In this multicenter study, a 10-miRNA classifier incorporating miR-21, miR-30c, miR-181a, miR-181c, miR-125b, miR-7, miR-200a, miR-135b, miR-22 and miR-200c was developed to predict distant relapse free survival (DRFS). With this classifier, HR+HER2- patients were scored and classified into high-risk and low-risk disease recurrence, which was significantly associated with 5-year DRFS of the patients. Moreover, this classifier outperformed traditional clinicopathological risk factors, IHC4 scoring and 21-gene Recurrence Score (RS). The patients with high-risk recurrence determined by this classifier benefit more from chemotherapy. CONCLUSIONS: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This model may facilitate personalized therapy-decision making for HR+HER2- individuals.