Cidan Capsule in Combination with Adjuvant Transarterial Chemoembolization Reduces Recurrence Rate after Curative Resection of Hepatocellular Carcinoma: A Multicenter, Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC). METHODS: A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded. RESULTS: As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P<0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P<0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P<0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug. CONCLUSIONS: Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511).

A novel scoring system predicts adjuvant chemolipiodolization benefit for hepatocellular carcinoma patients after hepatectomy.

Our aim in this study was to develop a prognostic scoring system with which to identify patients most likely to benefit from adjuvant chemolipiodolization (ACL) after liver resection for hepatocellular carcinoma (HCC). Data from 1150 HCC patients who underwent liver resection between 2002 and 2008 at the Eastern Hepatobiliary Surgery Hospital were used to develop the scoring system. Patients were stratified into prognostic subgroups using the new scoring system, and the outcomes of patients who received ACL and those who did not were compared in each subgroup. Using data from 379 patients operated on between 2008 and 2010 for validation, the scoring system had a concordance index (C-index) of 0.75 for predicting post-resectional overall survival (OS). It optimally stratified patients into three prognostic subgroups with scores of 0-5, 6-9 and ≥ 10, having better, medium and worse survival outcomes, respectively. A difference in OS between ACL and non-ACL patients was only detected in the subgroup with scores ≥ 10 (1-, 3-, and 5-year OS rates: 63.9%, 22.6%, and 9.0% vs. 33.8%, 5.6%, and 2.8%, p = 0.001). Our proposed scoring system provides an effective tool for selecting the patients most likely to benefit from ACL.

Multimodality Treatment for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Large-Scale, Multicenter, Propensity Mathching Score Analysis.

The optimal treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains controversial. We aimed to investigate the best treatment for patients with HCC with PVTT. From January 2002 to January 2014, the data from all consecutive patients with HCC with PVTT who underwent surgical treatment (ST),TACE,TACE combined with sorafenib (TACE-Sor), or TACE combined with radiotherapy (TACE-RT) in the 4 largest tertiary hospitals in China were analyzed retrospectively. The patients were divided into 3 subtypes according to the extent of PVTT in the portal vein (type I-III). The primary endpoint was overall survival (OS). A total of 1580 patients with HCC with PVTT were included in the study. The median survival times (MST) for ST (n = 745) for type I, II, and III patients (95% CI) were 15.9 (13.3-18.5), 12.5 (10.7-14.3), and 6.0 (4.3-7.7) months, respectively. The corresponding figures for patients after TACE (n = 604) were 9.3 (5.6-12.9), 4.9 (4.1-5.7), and 4.0 (3.1-4.9), respectively; for patients after TACE-Sor (n = 113) 12.0 (6.6-17.4), 8.9 (6.7-11.1), and 7.0 (3.0-10.9), respectively; and for patients after TACE-RT (n = 118) 12.2 (0-24.7), 10.6 (6.8-14.5), and 8.9 (5.2-12.6), respectively. Comparison among the different treatments for the 3 subtypes of PVTT patients after propensity score (PS) matching showed the effectiveness of ST to be the best for type I and type II PVTT patients, and TACE-RT was most beneficial for type III patients. Treatment was an independent risk factor of OS. ST was the best treatment for type I and II PVTT patients with Child-Pugh A and selected B liver function. TACE-RT should be given to type III PVTT patients.

Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial.

OBJECTIVE: A randomized controlled trial was conducted to find out whether antiviral therapy in patients with hepatitis B-related hepatocellular carcinoma (HCC) improves long-term survival after hepatic resection. BACKGROUND: Despite advances in surgery and in multidisciplinary treatment, there is still no effective adjuvant treatment to prevent HCC recurrence after R0 resection for HCC. Whether antiviral therapy is useful in reducing postoperative HCC recurrence is unclear. METHODS: Between May 2007 and April 2008, patients who received R0 hepatic resection for HBV-related HCC were randomly assigned to receive no treatment (the control group, n = 100) or antiviral therapy (adefovir 10 mg/d, the antiviral group, n = 100). RESULTS: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.0%, 50.3%, 46.1% and 84.0%, 37.9%, 27.1%, respectively. The corresponding overall survival rates for the 2 groups were 96.0%, 77.6%, 63.1% and 94.0%, 67.4%, 41.5%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.026, P = 0.001). After adjusting for the confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.651 [95% confidence interval (CI): 0.451-0.938; P = 0.021] and 0.420 (95% CI: 0.271-0.651; P < 0.001). Antiviral therapy was an independent protective factor of late tumor recurrence (HR = 0.348, 95% CI: 0.177-0.687; P = 0.002) but not of early tumor recurrence [hazard ratio (HR) = 0.949, 95% CI: 0.617-1.459; P = 0.810]. CONCLUSIONS: In patients with hepatitis B-related HCC, adefovir antiviral therapy reduced late HCC recurrence and significantly improved overall survival after R0 hepatic resection.

Inhibition of autophagy significantly enhances combination therapy with sorafenib and HDAC inhibitors for human hepatoma cells.

AIM: To clarify whether histone deacetylase inhibitors histone deacetylase inhibitors (HDACIs) can sensitize hepatocellular carcinoma (HCC) cells to sorafenib treatment. METHODS: Bax, Bcl-2, ATG5-ATG12, p21, and p27 protein levels in Hep3B, HepG2, and PLC/PRF/5 cells were examined by Western blot. CCK8 and a fluorometric caspase-3 assay were used to examine cellular viability and apoptosis levels. The effect of Beclin-1 on sensitization of HCC cells to sorafenib was examined by transfecting Beclin-1 siRNA into Hep3B, HepG2, and PLC/PRF/5 cells. RESULTS: Autophagy inhibition enhances the inhibitory effects of vorinostat and sorafenib alone or in combination on HCC cell growth. Vorinostat and sorafenib synergistically induced apoptosis and cell cycle alterations. Western blot data indicated that HDACIs and Beclin-1 knockdown increased the p53 acetylation level. The knockdown of Beclin-1 enhanced the synergistic effect of the combination of vorinostat with sorafenib. CONCLUSION: HDACIs can sensitize HCC cells to sorafenib treatment by regulating the acetylation level of Beclin-1.

All-trans retinoic acid potentiates the chemotherapeutic effect of cisplatin by inducing differentiation of tumor initiating cells in liver cancer.

BACKGROUND & AIMS: Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC. METHODS: In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo. RESULTS: ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone. CONCLUSIONS: These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation.

Sorafenib suppresses postsurgical recurrence and metastasis of hepatocellular carcinoma in an orthotopic mouse model.

UNLABELLED: Surgical resection is the first-line treatment for hepatocellular carcinoma (HCC) patients with well-preserved liver function. Nevertheless, the rate of postoperative recurrence at 5 years is as high as 70%, and this gravely jeopardizes the therapeutic outcome. Clearly, new approaches are needed for preventing the relapse of this deadly disease. Taking advantage of a luciferase-labeled orthotopic xenograft model of HCC, we examined the role of sorafenib, the first systemic drug approved for advanced HCC patients, in the prevention of HCC recurrence. We found that sorafenib suppressed the development of postsurgical intrahepatic recurrence and abdominal metastasis and consequently led to prolonged postoperative survival of mice in this model. Furthermore, hyperactivity of extracellular signal-regulated kinase signaling caused by elevated levels of growth factors associated with postoperative liver regeneration enhanced the sensitivity of HCC cells to sorafenib; this provides a plausible explanation for the observation that recurrent tumors are more responsive to growth inhibition by sorafenib. CONCLUSION: Our results strongly suggest that by effectively reducing postoperative recurrence, sorafenib has a potential application in early-stage HCC patients who have undergone hepatectomy with curative intention.

Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation.

AIM: to determine the efficacy and toxicities of sorafenib in the treatment of patients with multiple recurrences of hepatocellular carcinoma (HCC) after liver transplantation in a Chinese population. METHODS: twenty patients with multiple recurrences of HCC after liver transplantation were retrospectively studied. They received either transarterial chemoembolization (TACE) or TACE combined with sorafenib. RESULTS: the median survival times (MST) after multiple recurrences was 14 months (TACE+sorafenib group) and 6 months (TACE only group). The difference was significant in MST between the two groups (P=0.005). The TACE + sorafenib group had more stable disease (SD) patients than the TACE group. The most frequent adverse events of sorafenib were hand-foot skin reaction and diarrhea. In the univariate analysis, preoperative bilirubin and CHILD grade are found to be significantly associated with tumor-free survival time, the survival time after multiple recurrences and overall survival time. TACE+sorafenib group showed a better outcome than single TACE treatment group. In the multivariate COX regression modeling, the preoperative high CHILD grade was found to be a risk factor of tumor-free survival time. In addition, the preoperative high bilirubin grade was also found to be a risk factor of survival time after recurrence and overall survival time. Furthermore, survival time after recurrence and overall survival time were also associated with therapeutic schedule, which was indicated by the GROUP. CONCLUSION: Treatment with TACE and sorafenib is worthy of further study and may have more extensive application prospects.

Acupuncture versus metoclopramide in treatment of postoperative gastroparesis syndrome in abdominal surgical patients: a randomized controlled trial.

BACKGROUND: Postoperative gastroparesis syndrome (PGS) is a common complication after abdominal surgery in patients with primary liver cancer. However, surgeons usually do not have effective treatment for them. OBJECTIVE: To explore the effects of acupuncture applied to Zusanli and other acupoints on PGS in patients after abdominal surgery. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Sixty-three PGS patients of abdominal surgery, from Eastern Hepatobiliary Surgical Hospital, were randomized into acupuncture group (32 cases) and metoclopramide group (31 cases). The patients in acupuncture group were treated with acupuncture applied to Zusanli and other acupoints once a day, while the patients in metoclopramide group were intramuscularly injected 20 mg metoclopramide three times a day. MAIN OUTCOME MEASURES: Volume of gastric drainage, number of treatment and cure rate in the two groups were measured and evaluated. RESULTS: Acupuncture and metoclopramide could significantly reduce gastric drainage volume. In acupuncture group, the cure rate was 90.6% and the number of treatment was 6.58+/-4.26, while in metoclopramide group, the cure rate and the number of treatment were 32.3% and 10.13+/-3.60 respectively. There were significant differences in gastric drainage volume, cure rate and number of treatment between the two groups (P<0.05, P<0.01). CONCLUSION: Acupuncture is a good treatment for PGS, with fewer treatments, high cure rate and rapid effect.

Cerebral lipiodol embolism following transcatheter arterial chemoembolization for hepatocellular carcinoma.

Cerebral lipiodol embolism (CLE) is an extremely rare complication of transcatheter arterial chemoembolization for hepatocellular carcinoma (HCC). The authors present a case of CLE that occurred after the second hepatic arterial chemoembolization for HCC, and attempt to introduce several plausible mechanisms of CLE, after reporting the clinical and radiological findings and reviewing the medical literature.

[Transcatheter hepatic arterial chemoembolization and thymosin alpha1 in postoperative treatment of hepatocellular carcinoma].

OBJECTIVE: To observe the effect of postoperative transcatheter hepatic arterial chemoembolization (TACE) and thymosin alpha(1) (T(alpha1)) treatment on recurrence of hepatocellular carcinoma (HCC). METHODS: From Jan 2000 to Dec 2002, 57 patients with HCC were randomly divided into three groups: group A (n = 18) received hepatectomy plus postoperative TACE and T(alpha1), group B (n = 23) received hepatectomy plus postoperative TACE and group C (n = 16) received hepatectomy only. The recurrence rate, the time to tumor recurrence and the median survival for the three groups were investigated. RESULTS: For group A, B and C, the 1 year recurrence rate was 83.3%, 87.0% and 87.5% (P = 0.926), respectively. The time to tumor recurrence was 7.0, 5.0 and 4.0 months (P = 0.039), respectively. The median survival was 10.0, 7.0 and 8.0 months (P = 0.002), respectively. CONCLUSION: Postoperative TACE plus Talpha(1) treatment for HCC patients does not decrease the recurrence rate but may delay its occurrence and prolong surviving time.

Patients with advanced primary hepatocellular carcinoma treated by melatonin and transcatheter arterial chemoembolization: a prospective study.

OBJECTIVE: To observe the clinical efficacy of transcatheter arterial chemoembolization (TACE) and TACE+MLT (melatonin) on inoperable advanced primary hepatocellular carcinoma. METHODS: From January 1997 to January 1998, one hundred patients with inoperable advanced primary hepatocellular carcinoma were treated separately by TACE (50) and TACE+MLT (20 mg/d at 8:00 PM orally, 7 days before TACE)(50). RESULTS: The effective rates (WHO standards) of TACE and TACE+MLT were 16% and 28% respectively (P<0.05). After TACE or TACE+MLT, the resection rate at two-stage of TACE was 4% or 14% (P<0.01). The 0.5-, 1- and 2-year survival rates in the TACE group were 82%, 54% and 26% respectively; in the TACE+MLT group 100%, 68% and 40% respectively. The results were significantly better in the TACE+MLT group than in the TACE group. MLT could protect liver function from the damage caused by TACE. The IL-2 levels of all patients significantly increased, whereas sIL-2R expressions decreased after TACE+MLT as compared with the TACE group (P<0.01). CONCLUSIONS: With definite protection and treatment effect on the liver function damage caused by TACE, MLT can enhance the immunological activities of patients. It also can improve the effect of TACE by increasing the survival and resection rate after two-stage operation.