Preparation, characterisation, pharmacokinetics and distribution of esculin microspheres administered via intravitreal injection into rabbit brain.

This study explored the distribution of esculin microspheres in rabbit brain tissue following intravitreal injection and investigated the possibility of direct entry of the drug into the brain through the eye, to develop a formulation with enhanced therapeutic efficacy against Parkinson's disease.Chitosan microspheres of esculin were prepared via an emulsification cross-linking method and their characteristics were evaluated, including angle of repose, bulk density, and swelling ratio. Furthermore, the pharmacokinetic parameters and brain tissue distribution in rabbits were compared among groups administered esculin eye drops, intravitreal esculin solution, and intravitreal esculin microspheres, to determine whether esculin could enter the brain through an ocular route.The results showed that the prepared esculin microspheres were spherical and had good fluidity. Notably, intravitreal administration enhanced the area under the curve (AUC) of esculin in the thalamus. Delivery through microspheres prolonged the drug retention time in both rabbit plasma and brain tissues, as well as the brain-targeting efficiency of esculin.The collective findings indicated that there may be a direct eye-brain pathway facilitating enter of esculin microspheres into brain tissue after intravitreal injection, supporting the utility of intravitreal esculin microspheres as an effective therapeutic formulation for Parkinson's disease, a long-term chronic condition.

Development and Assessment of Acyclovir Gel Plaster Containing Sponge Spicules.

Acyclovir is an acyclic purine nucleoside analog that is highly effective in inhibiting the herpes simplex virus. However, topical acyclovir has poor efficacy because of its low skin permeability. This study aimed to develop an acyclovir gel plaster containing sponge spicules (AGP-SS) to achieve synergistic improvements in skin absorption and deposition of acyclovir. The process of preparing the gel plaster was optimized by orthogonal experiments, while the composition of the formulation was optimized using the Plackett-Burman and Box-Behnken experimental designs. The selected formula was tested for physical properties, in vitro release, stability, ex vivo permeation, skin irritation, and pharmacokinetics. The optimized formulation exhibited good physical characteristics. In vitro release and ex vivo permeation studies showed that acyclovir release from AGP-SS was dominated by diffusion with significantly higher skin permeation (20.00 ± 1.07 µg/cm2) than that of the controls (p < 0.05). Dermatopharmacokinetic analyses revealed that the maximum concentration (78.74 ± 11.12 µg/g), area under the curve (1091.81 ± 29.05 µg/g/h) and relative bioavailability (197.12) of AGP-SS were higher than those of the controls. Therefore, gel plaster containing sponge spicules show potential for development as transdermal delivery systems to achieve higher skin absorption and deposition of acyclovir, especially in deep skin layers.

Transdermal administration of ibuprofen-loaded hexagonal liquid crystal gel for enhancement of drug concentration in the uterus: in vitro and in vivo evaluation.

Primary dysmenorrhea is a common disease in women, and oral administration of Ibuprofen (IBU) is associated with first-pass effects and gastrointestinal irritation. Here, we developed ibuprofen-loaded hexagonal liquid crystal (IBU HLC) gel for transdermal administration. In this study, the structure of prepared IBU HLC was characterized using polarizing microscopey (PLM) and small angle X ray diffraction (SAXS). In vitro drug release behavior and percutaneous penetration were investigated, and drug transdermal behavior was observed by confocal laser scanning microscope (CLSM). Finally, the pharmacokinetic profile and tissue distribution were investigated after transdermal administration. The PLM and SAXS results showed that the inner structure of IBU HLC was hexagonal phase. Moreover, in vitro release, skin permeation and CLSM demonstrated that IBU HLC had an excellent sustained-release effect, and a good transdermal penetration effect accompanied by the combination of multiple percutaneous routes. Pharmacokinetic studies indicated that IBU entered the blood circulation through abdominal transdermal administration in small amounts, mainly entering the uterus, and had a certain targeting ability. In conclusion, the IBU HLC gel would be a promising sustained-release preparation for transdermal administration to relieve dysmenorrhea with a significant drug concentration in the uterus.

A Novel Molecular Reservoir Based on Reverse Self-Assembled Liquid Crystals - A New Strategy for Prolonging the Duration in Action of Analgesics.

PURPOSE: The aim of this study was to develop liquid crystal (LC) precursors to obtain novel long-acting analgesics for injection based on depot systems and compare the difference between the cubic and hexagonal precursors in delivering Diclofenac sodium (DS). METHODS: Diclofenac sodium liquid crystal precursor injections were prepared and characterized, followed by in vitro release, pharmacodynamic, and pharmacokinetic studies. RESULTS: The optimal formulations were prepared with a ratio of Phytantriol/ethanol/water as 76:19:5 for cubic LC precursors, and a ratio of Phytantriol/ethanol/water/Vitamine-E acetate as 72:18:5:5 for hexagonal, both loading various drug dosages (2.5%, 3.75% and 5%), respectively. Polarized light microscopy and small angle diffraction confirmed that the precursors were isotropic fluids and transformed into gels with Pn3m or HII framework in water. Rheological studies have shown that precursors belong to Newtonian fluids and gels to pseudoplastic fluids. The release showed that the DS in the commercial injection (DS-inj) was completely liberated within 6 h, whereas only 46.55% and 49.73% of the DS in 2.5% cubic precursors and 2.5% hexagonal precursors were freed, respectively. Pharmacodynamic studies have shown that cubic, hexagonal and DS-inj raised the pain threshold in mice by 169.4%, 157.3% and 113.79%, respectively. The mean retention times of DS in cubic and hexagonal were 3.16 and 2.67 times longer than DS-inj, respectively, according to pharmacokinetic results. CONCLUSION: In conclusion, cubic and hexagonal are both promising analgesic sustained release formulations. In addition, based only on the current comparison, cubic seems to have a better long-acting effect.

In situ formation of injectable organogels for punctal occlusion and sustained release of therapeutics: design, preparation, in vitro and in vivo evaluation.

The treatment of dry eye mainly includes instillation of cyclosporine A (CsA) nanoemulsion or the use of punctal plugs. Therefore, in this study, a novel injectable in situ organogel plug was developed using CsA as a model drug, stearic acid, injectable soybean oil, and N-methyl-2-pyrrolidinone (NMP) (1.25:10:0.6, w/v/v) as gel materials, to provide a dual mechanism for dry eye treatment. The formulated CsA injectable in situ organogel (CsA-OG) was evaluated in terms of stability, in vitro release, rheology, ocular irritation, punctal occlusion tests, and ocular distribution assessment. In vivo ocular distribution investigations showed that CsA-OG achieved considerably higher Cmax (1.94, 1.92 and 1.97-fold respectively) and AUC0-72h in the cornea, conjunctiva, and sclera (2.49, 2.27 and 2.15-fold respectively) than ciclosporin eye drops (p < 0.05). In vitro model evaluation demonstrated significant decrease in flow flux to 52.78 % at 2 min after CsA-OG injection. According to evaluation of the in vivo model, the organogel plug can completely block the lacrimal passages and greatly decrease the lacrimal drainage rate (p < 0.05). The above results suggest that these intracanalicular CsA-OG plugs can offer more extensive clinical applications than existing lacrimal drainage plugs and may act as a drug delivery system.

Development of a Thermosensitive In-Situ Gel Formulations of Vancomycin Hydrochloride: Design, Preparation, In Vitro and In Vivo Evaluation.

The purpose of this study was to develop a thermosensitive in situ gel delivery system based on Poloxamer 407 and Poloxamer 188 for ocular administration of vancomycin to treat systemic diseases. The vancomycin thermosensitive in situ gel was characterized using differential scanning calorimetry, rheological and drug release analyses. Additionally, pharmacokinetic studies and irritation tests of the gel were conducted after ocular administration in rabbits. The gel maintained a flowing liquid state under non-physiological conditions (25°C) to facilitate administration, and it transformed into a semi-solid state under physiological conditions (dilution with tears, 34°C), which prolonged its retention time in the eye. The gel erosion and drug release tests showed an excellent linear relationship between the cumulative drug release rate and the cumulative gel erosion rate, indicating a zero-order kinetic process. The pharmacokinetic analyses showed that the peak concentration, area under the curve, and bioavailability of the vancomycin thermosensitive in situ gel were 1.44, 1.98 and 1.93 times greater, respectively, that the values of vancomycin eye drops. Therefore, thermosensitive in situ gel may serve as a drug delivery system that can overcome the limitations of existing formulations of small-molecule peptides.

The predictive value of blood neutrophil-lymphocyte ratio in patients with end-stage liver cirrhosis following ABO-incompatible liver transplantation.

BACKGROUND: The study was designed to assess the role of preoperative neutrophil, lymphocyte, and neutrophil-lymphocyte ratio (NLR) in predicting survival outcomes of ABO-incompatible liver transplantation (LT). MATERIALS AND METHODS: We retrospectively collected the demographic and clinical characteristics of 71 patients with end-stage liver cirrhosis following ABO-incompatible LT in this study. Kaplan-Meier survival analysis and Cox multiple factors regression analysis were performed to determine the independent risk factors from preoperative blood parameters for poor prognosis. RESULTS: The 1-, 3-, and 5-year overall survival were 94.9%, 80.0%, and 80.0% in the normal NLR group, respectively, and 59.4%, 55,4%, and 55.4% in patients with up-regulated NLR, respectively (P = 0.001). Furthermore, no significant difference was observed on post-LT complications between normal NLR and high-NLR groups. The high NLR was identified as the only independent prognostic risk factor for recipient survival (P = 0.015, 95% confidence interval = 3.573 [1.284-9.943]). CONCLUSION: The preoperative high NLR could be considered as a convenient and available indicator for selecting ABO-incompatible LT candidates.

FAM83D associates with high tumor recurrence after liver transplantation involving expansion of CD44+ carcinoma stem cells.

To investigate the potential oncogene promoting recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT), throughput RNA sequencing was performed in a subgroup of HCC patients. The up-regulated FAM83D in HCC tissues was found and further verified in 150 patients by real-time PCR and immunohistochemistry. FAM83D overexpression significantly correlated with high HCC recurrence rate following LT and poor HCC characteristics such as high AFP, poor differentiation. Of cancer stem cells (CSCs) markers, CD44 expression was effectively suppressed when FAM83D was knocked down by siRNA. Meanwhile, the siRNA transfected cells suppressed formation of sphere and ability of self-renew. In a xenograft tumorigenesis model, FAM83D knockdown apparently inhibited tumor growth and metastasis. Microarray assays revealed that FAM83D promotes CD44 expression via activating the MAPK, TGF-ß and Hippo signaling pathways. Furthermore, CD44 knockdown presented reverse effect on above signaling pathways, which suggested that FAM83D was a key activator of loop between CD44 and above signaling pathways. In conclusion, FAM83D promotes HCC recurrence by promoting CD44 expression and CD44+ CSCs malignancy. FAM83D provides a novel therapeutic approach against HCC recurrence after LT.

MicroRNA-452 promotes stem-like cells of hepatocellular carcinoma by inhibiting Sox7 involving Wnt/ß-catenin signaling pathway.

The decrease of microRNA-452 (miR-452) in gliomas promoted stem-like features and tumorigenesis. However, the role of miR-452, especially in regulating cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) remains ambiguous. We enriched stem-like HCC cells by serial passages of hepatospheres with chemotherapeutic agents. Stem-like characteristics including the capabilities of chemo-resistance, stemness-related gene expression profiling, self-renewal, tumorigenicity and metastasis formation were detected. MiR-452 was markedly increased in the chemo-resistant hepatospheres and human HCC tissues. and the overexpression of miR-452 in HCC patients predicted poor overall survival. MiR-452 significantly promoted stem-like characteristics in vitro and in vivo. Further, Sox7 was identified as the direct target of miR-452, which could physically bind with ß-catenin and TCF4 in the nucleus and then inhibit the activity of Wnt/ß-catenin signaling pathway. Finally, the combined chemotherapy of doxorubicin and all-trans retinoic acid (ATRA) showed dramatically efficiency in suppressing HCC metastasis. These data suggested that miR-452 promoted stem-like traits of HCC, which might be a potential therapeutic target for HCC. The combination of doxorubicin and ATRA might be a promising therapy in HCC management.

High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation.

AIM: To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF). METHODS: Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes. RESULTS: The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR ≥ 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT. CONCLUSION: A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF.

Absolute lymphocyte count recovery at 1 month after transplantation predicts favorable outcomes of patients with hepatocellular carcinoma.

BACKGROUND AND AIMS: Absolute lymphocyte count (ALC) and the recovery of ALC after treatment have been identified as a prognostic biomarker for several malignancies. In this study, we aimed to investigate the prognostic role of peritransplant ALC and ALC recovery after liver transplantation (LT) in hepatocellular carcinoma (HCC) patients. METHODS: A total of 269 HCC patients undergoing LT were enrolled in our study. Clinicopathological data were retrospectively collected and reviewed. Peritransplant ALC and the change of ALC (2 weeks, 1 month, 3 months post-LT) were carefully monitored. All potential risk factors were analyzed by univariate and multivariate cox regression analysis. RESULTS: Over a mean follow-up of 35.9 months, 120 recurrences and 89 deaths were recorded. In the multivariate analysis, HCC with ALC no recovery at 1 month after LT (P < 0.001), high pretransplant alpha fetoprotein (P = 0.010), total tumor size > 8 cm (P = 0.003), and beyond Milan criteria (P < 0.001) were four independent risk factors for HCC recurrence. For overall survival (OS) after LT, ALC no recovery at 1 month after LT (P = 0.003), total tumor size > 8 cm (P = 0.011), pretransplant albumin < 2.8 g/dL (P = 0.049), model of end-stage liver disease score > 15 (P = 0.017), and beyond Milan criteria (P = 0.001) were significantly related to poor OS. When subgroup analyses were performed according to the Milan criteria, the results showed that the recovery of ALC at 1 month after LT still indicated longer recurrence-free survival (RFS) (P < 0.001) and OS (P = 0.005) beyond Milan criteria as well as RFS (P < 0.001) within Milan criteria, but not OS (P = 0.157) within Milan criteria. CONCLUSIONS: ALC recovery at 1 month after LT indicated favorable outcomes of HCC patients.

Role of overexpression of MACC1 and/or FAK in predicting prognosis of hepatocellular carcinoma after liver transplantation.

BACKGROUND: Metastasis-associated in colon cancer-1 (MACC1) acts as a promoter of tumor metastasis; however, the predictive value of MACC1 for hepatocellular carcinoma (HCC) after liver transplantation (LT) remains unclear. METHODS: We examined the expression of MACC1 and its target genes MET and FAK by quantitative PCR in 160 patients with HCC that was undergone LT. RESULTS: The patients with MACC1(high) or FAK(high) in HCCs showed a significantly shorter overall survival and higher cumulative recurrence rates after liver transplantation (LT), compared with MACC1(low) or FAK(low) group. Multivariate analysis indicated that MACC1 alone or combination of MACC1/FAK was an independent prognostic factor for overall survival and cumulative recurrence. CONCLUSIONS: MACC1 or combination of MACC1/FAK could serve as a novel biomarker in predicting the prognosis of HCC after LT.

Single nucleotide polymorphisms in the metastasis-associated in colon cancer-1 gene predict the recurrence of hepatocellular carcinoma after transplantation.

BACKGROUND: The newly identified metastasis-associated in colon cancer-1 (MACC1) gene is involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis in a variety of malignancies. Overexpression of MACC1 gene is a prognostic marker for poor outcome of hepatocellular carcinoma (HCC) patients. However, the association between genetic polymorphisms of MACC1 gene and poor outcome in HCC has been not been performed. We therefore investigated the correlation of MACC1 single nucleotide polymorphisms (SNPs) with tumor recurrence and overall survival in HCC patients undergoing liver transplantation (LT). METHODS: The study included 187 HCC patients treated with LT. Five polymorphisms in the MACC1 gene (rs1990172, rs3735615, rs4721888, rs2241056, rs975263) were genotyped in 183 cases of tumorous tissue sample and 117 cases of adjacent normal tissue sample using SNaP-Shot assays. The association of SNPs with tumor recurrence and overall survival was then analyzed by additive, dominant, recessive, and overdominant models in a cohort of 156 HCC patients. RESULTS: In terms of tumor recurrence, heterozygous of SNP rs1990172 and SNP rs975263 showed a significant high risk of relapse using univariate and multivariate analysis (overdominant, HR(95%CI)=2.27 [1.41-3.66], P=0.001; HR(95%CI)=2.16 [1.37-3.39], P=0.001). But the difference between heterozygous of these two SNPs and overall survival did not reach a significance in all models. The other three investigated SNPs were not significantly associated with tumor recurrence and overall survival (P>0.05). In addition, we found no significant difference in genotype frequencies between HCC and controls. CONCLUSIONS: Our data suggest that SNP rs1990172 and SNP rs975263 in the MACC1 gene may be potential genetic markers for HCC recurrence in LT patients.

Bisphosphonates for the prevention and treatment of osteoporosis in patients with rheumatic diseases: a systematic review and meta-analysis.

BACKGROUND: While bisphosphonates (BPs) are commonly used in clinical treatment for osteoporosis, their roles on osteoporosis treatment for rheumatic patients remain unclear. We performed a meta-analysis to evaluate the efficacy of BPs on fractures prevention and bone mass preserving in rheumatic patients. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials for relevant literatures with a time limit of Jan. 6, 2012. All randomized clinical trials of BPs for adult rheumatic patients with a follow-up of 6 months or more were included. We calculated relative risks (RRs) for fractures and weighted mean difference (WMD) for percent change of bone mineral density (BMD). Twenty trials were included for analysis. The RR in rheumatic patients treated with BPs was 0.61 (95%CI [0.44, 0.83], P = 0.002) for vertebral fractures, and 0.49 (95%CI [0.23, 1.02], P = 0.06) for non-vertebral fractures. The WMD of BMD change in the lumbar spine was 3.72% (95%CI [2.72, 4.72], P<0.001) at 6 months, 3.67% (95%CI [2.84, 4.50], P<0.001) at 12 months, 3.64% (95%CI [2.59, 4.69], P<0.001) at 24 months, and 5.87% (95%CI [4.59, 7.15], P<0.001) at 36 months in patients using BPs, as compared with those treated with calcium, vitamin D or calcitonin. In subgroup analyses, rheumatic patients using BPs for osteoporosis prevention had greater WMD than those using BPs for treating osteoporosis at 6 months (4.53% vs. 2.73%, P = 0.05) and 12 months (4.93% vs. 2.91%, P = 0.01). CONCLUSIONS/SIGNIFICANCE: In both short-term and middle-term, BPs can preserve bone mass and reduce the incidence of vertebral fractures in rheumatic patients, mainly for those who have GC consumption. The efficacy of BPs is better when using BPs to prevent rather than to treat osteoporosis in rheumatic patients.

Prognostic role of C-reactive protein in hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: C-reactive protein (CRP) which used to be a prototypical inflammatory cytokine has been identified involving in the progression of tumor-promoting inflammation. Several studies have indicated that CRP is a predictor for hepatocellular carcinoma (HCC), but the results are controversial. METHODS: We conducted a systematic review of ten studies (1885 patients) to examine the association of high serum CRP expression with overall survival (OS) and recurrence-free survival (RFS) in HCC patients by meta-analysis. Moreover, the correlation between high serum CRP and tumor clinicopathological parameters was also assessed. Hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. RESULTS: Our pooled results showed that high expression level of serum CRP (≥ 10 mg/L) was associated with poor OS (HR: 2.15, 95% CI: 1.76-2.63) and RFS (HR: 2.66, 95% CI: 1.54-4.58) in HCC. Serum CRP overexpression (≥ 10 mg/L) was also significantly associated with the presence of tumor vascular invasion (OR: 3.05, 95% CI: 1.79-5.23), multiple tumor (OR: 2.36, 95% CI: 1.36-4.10), larger tumor size (OR: 3.41, 95% CI: 1.04-11.18), and advanced TNM stage (OR: 3.23, 95% CI: 2.29-4.57). In addition, serum CRP overexpression (≥ 10 mg/L) tended to be correlated with poor differentiation (OR: 1.58, 95% CI: 0.74-3.39), though not significantly. CONCLUSION: The present systematic review and meta-analysis demonstrate that high serum level of CRP (≥ 10 mg/L) denotes a poor prognosis of patients with HCC.

Reduced expression of DACT2 promotes hepatocellular carcinoma progression: involvement of methylation-mediated gene silencing.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. Many advances have been made to understand the pathogenesis of HCC; however, the molecular mechanisms that lead to hepatocarcinogenesis and progression are still not clearly understood. METHODS: The expression of DACT2 in specimens from 30 paired HCCs and an additional 61 HCC patients after liver transplantation was evaluated by quantitative RT-PCR and immunohistochemical analysis. We investigated the methylation status of the DACT2 promoter region. We also analyzed the alterations of the cell cycle, migration and invasion after DACT2 knockdown. RESULTS: The expression level of DACT2 was significantly lower in HCC tissues than in non-cancerous tissues. Reduced DACT2 expression was associated with large tumor size. DACT2 transcripts were at low levels in hypermethylated liver cancer cells and were restored by exposure to a demethylating agent. Reduced expression of DACT2 in MHCC97L cells induced G1/S arrest, increased cell proliferation, and promoted cell invasion. CONCLUSIONS: Our study suggests that DACT2 is silenced by promoter hypermethylation, and reduced DACT2 can promote liver cancer progression. DACT2 may serve as a novel tumor suppressor gene in HCC.

Doxorubicin-eluting bead versus conventional TACE for unresectable hepatocellular carcinoma: a meta-analysis.

BACKGROUND/AIMS: Doxorubicin-eluting bead TACE (DEB-TACE) has recently been developed as a novel therapy option for HCC. However, the clinical efficacy of DEB-TACE is still unclear. Herein, we performed a meta-analysis to evaluate the efficacy of DEB-TACE compared with conventional TACE (cTACE). METHODOLOGY: We inlcuded seven studies (a total of 693 patients) to compare DEB-TACE with cTACE. The pooled odds ratios (OR) were calculated using a random or fixed effects model. MEDLINE, EMBASE and the Cochrane Database were searched for articles published from dates of inceptions up to February 20, 2012. Sensitivity analysis and publication bias estimate were also performed to evaluate the potential risk bias in the overall results of pooled analysis. RESULTS: The pooled estimates for tumor response of DEB-TACE were not significantly different from those of cTACE, with CR (OR: 1.18; 95%CI: 0.81-1.71; p=0.394), PR (OR: 1.37; 95%CI: 0.94-1.99; p=0.101), SD (OR: 0.88; 95%CI: 0.51-1.51; p=0.637), PD (OR: 0.85; 95%CI: 0.52-1.38; p=0.512), DC (OR: 1.37, 95%CI: 0.95-1.98; p=0.089) and OR (OR: 1.40; 95%CI: 0.97-2.000; p=0.070). CONCLUSIONS: The current evidence suggests that DEB-TACE is able to accomplish the same tumor response as cTACE. Although this analysis provides a comprehensive look at published data involving the clinical efficacy of DEB-TACE compared with conventional TACE, additional large scale of randomized-control studies are still needed.