Xiu-Ping Zhang

Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis

Background The benefits of transarterial chemoembolization plus sorafenib (TACE-S) in hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remain controversial. We compared the effectiveness and safety of TACE-S and TACE for HCC with PVTT. Methods The Cochrane Library, PubMed, EMBASE, Chinese National Knowledge Infrastructure, VIP, Wan Fang, and Sino Med databases were systematically searched for studies of HCC with PVTT treated using TACE-S. Two authors independently extracted study outcomes, including overall survival (OS), time to progression (TTP), objective response (tumor response) and adverse events (AEs). Results Eight high-quality, retrospective studies with 1091 patients (TACE-S=356, TACE=735) were included in the review. Five retrospective studies with 973 patients (TACE-S=238, TACE=735) were included in the meta-analysis. The objective response rate (ORR, OR=3.59, 95% CI=1.74–7.39; I2=21%, P=0.0005) and disease control rate (DCR, OR=4.72, 95% CI=1.75–12.72; I2=56%, P=0.002) favored TACE-S. TACE-S significantly increased 6-month OS (OR=3.47; 95% CI=2.47–4.89; I2=0%, P < 0.00001) and 1-year OS (OR=3.10; 95% CI=2.22–4.33; I2=41%, P < 0.00001). The hazard ratio (HR) for OS (HR=0.62; 95% CI=0.51–0.75; I2=30%, P < 0.00001) also indicated that TACE-S was superior to TACE. TACE-S with PVTT had better outcomes in the first-order portal vein branch and lower-order portal vein branches than in the main portal vein and upper branches to superior mesenteric vein. The most common AEs were hand-foot skin reaction (HFSR, 178; 73%), diarrhea (142; 58%) and alopecia (76; 31%); AEs of grade 3/4 were rare. Conclusions TACE-S may improve OS, ORR, TTP and DCR for HCC patients with PVTT compared to TACE.

hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating β-Catenin Signaling

Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2), with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has, however, not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic β-catenin destruction complex, inhibited β-catenin degradation, and activated β-catenin/T-cell factor signaling. Downstream of the β-catenin cascade, IL6 mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the β-catenin/IL6 pathway.Significance: hPCL3s has an oncogenic role in hepatocellular carcinoma by activating the β-catenin/IL6 signaling axis to promote metastasis. Cancer Res; 78(10); 2536-49. ©2018 AACR.

A serological scoring system to predict lymph node metastasis in patients with hepatocellular carcinoma

BACKGROUND Lymph node metastasis (LNM)has widely been recognized as a poor prognostic indicator for hepatocellular carcinoma (HCC) patients. Preoperative prediction of LNM is important for clinicians to decide on treatment. This study was designed to develop a simple and convenient system to predict LNM. METHODS Consecutive HCC patients who were suspected to have LNM were divided into a training, an internal validation and an external validation cohort. The receiver operating characteristic (ROC) analysis was used to determine the threshold value of the preoperative serological variables. A nomogram visualization system model was then established. RESULT Of the 287 patients, there were 31 patients who had LNM (10.8%), and 21 of 203 patients (10.3%) were in the training cohort and 10 of 84 patients (11.9%) in the internal validation cohort. Sixteen of 176 patients (9.1%) in the external validation cohort had LNM. The serological indices including neutrophil/lymphocyte rate, age, platelet, prothrombin time, and total protein, were included in the nomogram. The areas of the ROC curve were 0.846, 0.679 and 0.738 in predicting LNM in the training cohort, the internal validation cohort and the external validation cohort, respectively. CONCLUSION The scoring system constructed using the preoperative serological variables predicted LNM in HCC patients.

Hepatocellular carcinoma with hepatic vein invasion should not be considered as a contraindication for liver resection

tion points of 25 at the time of listing and received additional points every 90 days. At transplant, her Model for End-Stage Liver Disease score was 35. OLT corrects the enzyme defects in the liver and prevents further acute attacks in AIP. Porphobilinogen declines within the first 48 hours posttransplant, as was the case in this report. As Jaramillo-Calle et al. noted, neurologic deficits do not reliably reverse after OLT. The long-term outcomes for OLT in AIP patients are similar to those for the general OLT patient population, with 3-month survival at 93% and 5-year survival at 77%. We agree that OLT should be considered for AIP patients with severe recurrent attacks, resistance to intravenous heme, and persistent or progressing neurological deficits. It remains to be seen if givosiran, a promising small interfering RNA therapy currently in trials, will be effective in patients with heme resistance.

Is Sorafenib an Optimal Treatment for Hepatocellular Carcinoma With Macrovascular Invasion or Metastatic Disease

We read with great interest the article by Finn et al. in Hepatology,(1) which explored therapies for advanced hepatocellular carcinoma (HCC) with macrovascular invasion or metastatic disease, applying a systematic review and meta-analysis. They reported that in advanced HCC patients with Child-Pugh A liver function, sorafenib is the only recommended treatment. Several observational studies evaluated locoregional therapies alone or in combination with other treatments, but were limited by a very low quality of evidence. The investigators’ conclusion echoes official guidelines in the United States and Europe, where oral sorafenib was the only recommended treatment for advanced HCC patients.(2) Based on the above, we would like to make the following comments. First, some investigators have recommended surgical treatment for selected patients with macrovascular invasion.(3,4) Liver resection (LR) is associated with a longer survival outcome than nonsurgical treatment in patients with portal vein tumor thrombus (PVTT). Similarly, patients with hepatic vein tumor thrombus (HVTT) have a better prognosis in patients with HVTT under LR. Given recent advances in perioperative nursing and surgical operation, surgery may be the first choice for some selected advanced HCC patients with macrovascular invasion. Second, this systematic review may not include all observational studies for therapies for advanced stage HCC patients because of different inclusion criteria and included time periods. Another meta-analysis concluded that LR may lead to longer overall survival for HCC patients with PVTT than transarterial chemoembolization.(5) In addition, some multidisciplinary combined therapies other than only oral sorafenib had a better prognosis in HCC patients with extrahepatic metastasis. In summary, this meta-analysis by Finn et al. a strong contribution that focuses on therapies for advanced HCC with macrovascular invasion or metastatic disease. Because of a low quality of evidence from several observational studies, it is vital to design high-quality multicenter, randomized, controlled trials to assess multidisciplinary combined diagnosis and treatment, instead of only sorafenib, in some selected patients with advanced HCC that includes macrovascular invasion or metastatic disease.

Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis

Polarity defects are frequently involved in liver diseases, such as chronic hepatitis and hepatocellular carcinoma (HCC). It was reported that vacuolar protein sorting 33B (Vps33b) plays critical roles in the maintenance of hepatocyte polarity; however, the functional roles and mechanisms of Vps33b in HCC occurrence and progression remain unknown. First of all, we showed that Vps33b is down‐regulated in human and mouse liver cancer samples, and the low expression levels of Vps33b correlate with the poor prognosis of many HCC patients. Liver‐specific Vps33b deficiency induces liver damage, progressive hepatitis, fibrosis, and HCC in male mice, indicating that Vps33b is a crucial contributory factor to hepatocarcinogenesis. Vps33b deficiency–caused liver damage was primarily due to the disorders of structural and functional hepatocyte polarity, which were reflected by the decreased protein levels of E‐cadherin because of inaccurate location to lysosomes and polarity defects at both apical and lateral plasma membrane proteins. The results of a mechanism study revealed that Vps33b interacts with VPS33B‐interacting protein, which is involved in polarity and apical protein restriction; vesicle‐trafficking protein Sec22b; and Flotillin‐1 in hepatocytes and is in charge of the normal distribution of polarity‐determined proteins. Expression levels of Vps33b negatively correlated with the degree of inflammatory cell infiltration in livers from diethylnitrosamine‐induced or transgenic HCC mouse models, and the inflammatory stimuli suppressed the expression of Vps33b in vitro. Conclusion: Down‐regulation of Vps33b expression is a critical step for inflammation‐driven HCC, and Vps33b serves as an important tumor suppressor in hepatocarcinogenesis.

Surveillance for Early-Stage Hepatocellular Carcinoma by Ultrasound Plus Alpha-Fetoprotein Measurement: More Details, More Significance

2 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 Dear Editors: We read with great interest the article by Tzartzeva et al recently published in Gastroenterology that explored, using a systematic review and meta-analysis, surveillance imaging and alpha-fetoprotein (AFP) for the early detection of hepatocellular carcinoma (HCC) in patients with cirrhosis. In this study, the authors reported that ultrasound examination alone to detect early-stage HCC has a low sensitivity in patients with cirrhosis. However, addition of AFP to ultrasound analysis significantly increases the sensitivity of HCC detection in clinical practice. The authors’ conclusion echoes the guidelines of the American Association for the Study of Liver Diseases/Barcelona Clinic for Liver Cancer staging system; however, they disagree about the value of adding the serum biomarker AFP as an adjunct surveillance test. We would like to raise the following comments. First, this meta-analysis contained numerous nonrandomized controlled trials, both retrospective and some prospective studies, which have a relatively low methodologic quality. Therefore, selection bias is highly apparent in the flow and timing of patient selection. Another key limitation is the significant heterogeneity between studies for subset analyses within the small number of included studies; 6 studies compared the accuracy of ultrasound examination with and without AFP for HCC detection, of which only 4 studies reported accuracy for early HCC detection and the dates of these studies ranged from 1994 to 2017. Second, the inclusion and exclusion criteria for this meta-analysis indicated that both patients with cirrhosis and chronic hepatitis were included, instead of only those with chronic hepatitis. As we known, liver cirrhosis has different causes, including viral hepatitis cirrhosis, alcoholic cirrhosis, and nonalcoholic fatty liver cirrhosis. The specificity and sensitivity of ultrasound examination with AFP for surveillance for early-stage HCC may differ by the type of hepatic cirrhosis. In addition, the baseline serologic level of AFP also varies by the etiology of liver cirrhosis, which could decrease the specificity of detection for early-stage HCC using ultrasound plus AFP measurement. According to another meta-analysis, there was a significantly higher sensitivity for early HCC with ultrasound examination every 6 months than with annual surveillance, but AFP provided no additional benefit to ultrasound examination.

PRMT1 Promoted HCC Growth and Metastasis In Vitro and In Vivo via Activating the STAT3 Signalling Pathway

Background/Aims: Although it has been widely accepted that protein arginine methyltransferase 1 (PRMT1) is a cancer-promoting gene in various cancers, the mechanism of PRMT1 in hepatocellular carcinoma (HCC) requires more exploration. This study aimed to investigate the role of PRMT1 in HCC growth and metastasis. Methods: We compared PRMT1 expression and clinicopathological characteristics using paired HCC and adjacent noncancerous liver tissues from 210 patients and immunohistochemistry analyses. Cell proliferation, colony formation and migration were determined in HCC cell lines with PRMT1 overexpression or downregulation through MTT, crystal violet and Boyden chamber assays. Tumour growth was monitored in a xenograft model, and intrahepatic metastasis models were established. Results: PRMT1 expression was greatly increased in clinical HCC samples and strongly associated with poor prognosis and recurrence; PRMT1 expression was also positively correlated with microvascular invasion (P = 0.024), tumour differentiation (P = 0.014), tumour size (P = 0.002), and portal vein tumour thrombus (PVTT) (P = 0.028). Cell proliferation, colony formation and migration in vitro were enhanced by PRMT1 upregulation and decreased by PRMT1 downregulation in HCC cell lines. Moreover, low PRMT1 expression resulted in slow tumour growth and decreased tumour weight in vivo, as well as tumour metastasis. These phenotypes were associated with STAT3 signalling pathway activation. Cryptotanshinone, a STAT3 inhibitor, inhibited STAT3 phosphorylation and reversed the HCC phenotype of PRMT1 expression. Conclusions: We revealed a significant role for PRMT1 in HCC progression and metastasis in vitro and in vivo via STAT3 signalling pathway activation. PRMT1 may be a potential novel prognostic biomarker and new therapeutic target for HCC.

FABP4 suppresses proliferation and invasion of hepatocellular carcinoma cells and predicts a poor prognosis for hepatocellular carcinoma

Adipocyte fatty acid‐binding protein (FABP4) is abundant in macrophage and adipocyte. It is known to be involved in lipid metabolism. The role of FABP4 has been reported in various cancers, such as non‐small cell lung cancer, breast cancer, ovarian cancer, and prostatic cancer. However, its role remains unclear in hepatocellular carcinoma (HCC). In our study, we investigated the expression of FABP4 at both mRNA and protein levels, and by examining 175 cases of patients with cancer of the liver tissue microarray, the significance between the expression of FABP4 and clinical characteristics had been discussed. We found that FABP4 was lowly expressed in HCC tissues compared to the corresponding tissue adjacent, and the expression of FABP4 was significantly associated with the tumor size, PVTT, recurrence‐free survival and overall survival. Moreover, multivariate Cox regression analysis indicated that the expression of FABP4, Alb, AFP, HBsAg, and PVTT were independent risk factors for overall survival, and the expression of FABP4, AFP, GGT, tumor size, and encapsulation were independent risk factors for HCC recurrence. In addition, we revealed that FABP4 suppressed HCC cell proliferation and invasion in vitro. Moreover, overexpression of FABP4 led to inhibit tumor growth and decreased tumor volume in vivo. These phenotypes were associated with altered expression of Snail and p‐STAT3. Our studies thus suggest that FABP4 could be a potential target for HCC chemotherapy.

Survival benefit of TACE combined with sorafenib for hepatocellular carcinoma patients with portal vein tumor thrombus

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor and the world’s fifth most common tumor. Portal vein tumor thrombosis (PVTT) have been appeared about 10–40% for HCC patients (1,2). PVTT predicted a dismal prognosis, because they promoted HCC recurrence and metastasis, impaired hepatic reserves, raised portal vein pressure, and reduced portal vein flow. The median survival time (MST) of HCC and PVTT patients is obviously decreased compared to those without PVTT. According to the invading location in portal vein of the PVTT, the studies from our group proposed “Cheng’s classification” to divided the PVTT into four types (type I, being segmental/sectoral branches of portal vein; type II, being left and/or right portal vein; type III, being main portal vein trunk, and type IV, being superior mesenteric vein) (3,4). According to the guidelines from Barcelona Clinic Liver Cancer (BCLC), HCC with PVTT was classified as advanced HCC (BCLC stage C). They recommended sorafenib as the standard treatments for patients with advanced HCC. However, some studies have shown that some treatment modalities like transarterial chemoembolization (TACE), radiotherapy (RT), transarterial radioembolization (TARE), and resection-based multimodal treatments in some selected HCC and PVTT patients may prefer better outcomes than sorafenib (5-7). Our comments were responded to “editorial on combination treatment beyond sorafenib alone for HCC with portal vein tumor thrombosis”, and indicated that the new advances treatments were applied for HCC patients with PVTT.