Traditional herbal medicine in preventing recurrence after resection of small hepatocellular carcinoma: a multicenter randomized controlled trial

BACKGROUND： Disease recurrence is a main challenge in treatment of hepatocellular carcinoma （HCC）. There is no generally accepted method for preventing recurrence of HCC after resection. OBJECTIVE： To compare the efficacy of a traditional herbal medicine （THM） regimen and transarterial chemoembolization （TACE） in preventing recurrence in post-resection patients with small HCC. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS： This is a multicenter, open- label, randomized, controlled study, which was undertaken in five centers of China. A total of 379 patients who met the eligibility criteria and underwent randomization were enrolled in this trial. One hundred and eighty-eight patients were assigned to the THM group and received Cinobufacini injection and Jiedu Granule, and the other 191 patients were assigned to the TACE group and received one single course of TACE. MAIN OUTCOME MEASURES： Primary outcome measures were the annual recurrence rate and the time to recurrence. Incidence of adverse events was regarded as the secondary outcome measure. RESULTS： Among the 364 patients who were included in the intention-to-treat analysis, 67 patients of the THM group and 87 of the TACE group had recurrence, with a hazard ratio of 0.695 （P = 0.048）. Median recurrence-free survival of the patients in the THM and TACE groups was 46.89 and 34.49 months, respectively. Recurrence rates at 1, 2 and 3 years were 17.7%, 33.0% and 43.5% for the THM group, and 28.8%, 42.5% and 54.0% for the TACE group, respectively （P = 0.026）. Multivariate analysis indicated that the THM regimen had a big advantage for prolonging the recurrence-free survival. Adverse events were mild and abnormality of laboratory indices of the two groups were similar. CONCLUSION： In comparison with TACE therapy, the THM regimen was associated with diminished risk of recurrence of small-sized HCC after resection, with comparable adverse events. TRIAL REGISTRTION IDENTIFIER： This trial was registered in the Chinese Clinical Trial Registry with the identifier ChiCTR-TRC-07000033.

Surgical treatment of hepatocellular carcinoma with inferior vena cava tumor thrombus: a new classification for surgical guidance

BACKGROUND: Hepatic resection is the main treatment modality for hepatic tumors. Advances in diagnostic technique, preoperative preparation, surgical technique, and postoperative management increased the success rate. The present study aimed to evaluate hepatectomy and resection of inferior vena cava tumor thrombus (IVCTT) in patients with hepatocellular carcinoma, and the relationship between IVCTT classification and selection of surgical technique. METHODS: We retrospectively reviewed 13 patients with hepatocellular carcinoma who had undergone hepatectomy with IVCTT resection between May 1997 and August 2009. Age, gender, diagnosis, findings of physical examination, results of preoperative laboratory investigations, radiological examination, criteria for resection, postoperative pathological results, incisions, operative technique, intraoperative transfusion, drains, and intraoperative and postoperative complications were evaluated for all patients. RESULTS: Type Ⅰ IVCTT (10 patients) was posterior to the liver and below the diaphragm; type Ⅱ IVCTT (2 patients) was above the diaphragm but still outside the atrium; and type Ⅲ IVCTT (1 patient) was above the diaphragm and in the right atrium. Type Ⅰ was treated by radical hepatectomy and removal of IVCTT with total hepatic vascular exclusion. Type Ⅱ was treated by radical hepatectomy and removal of IVCTT by incision of the diaphragm. Type Ⅲ was treated by hepatectomy and resection of the thrombus from the right atrium under cardiopulmonary bypass. There were no surgical complications and one patient has been survived for 4 years with cancer-free status. The median survival time was 18.2 months, and the 1-and 2-year survival rates were 53.8% and 15.4%, respectively. CONCLUSION: Surgical treatment is safe and feasible for treatment of IVCTT in patients with hepatocellular carcinoma, and surgical resectability can be judged according to the classification of tumor thrombus.

Effect of chromium substitution on structural, electrical and magnetic properties of NiZn ferrites

Ni0.5Zn0.5Fe2-xCrxO4(0≤x≤0.5)ferrites were successfully prepared by conventional solid state reaction method to investigate the effect of chromium substitution on the structural,electrical and magnetic properties.X-ray powder diffraction results demonstrate that all the prepared samples are well crystallized single-phase spinel structures without secondary phase.As chromium concentration increases,the lattice parameter and crystallite size gradually decrease.The magnetic measurement indicates that saturation magnetization is substantially suppressed by Cr3+doping,changing from 73.5 A·m2/kg at x=0 to 46.3 A·m2/kg at x=0.5.While the room-temperature electrical resistivity is more than four orders of magnitude enhanced by Cr3+substitution,reaching up to 1.1×108Ω·cm at x=0.5.The dielectric constant monotonously decreases with rising frequency for these ferrites,showing a normal dielectric dispersion behavior.The compositional dependence of dielectric constant is inverse with that of electrical resistivity,which originates from the reduced Fe2+/Fe3+electric dipole number by doping,indicating inherent correlation between polarization and conduction mechanism in ferrite.

Replication of hepatitis B virus in primary duck hepatocytes transfected with linear viral DNA

AIM: To explore the expression and replication of hepatitis B virus (HBV) DNA in primary duck hepatocytes (PDHs).METHODS: Complete HBV genome was transfected into PDHs by electroporation (transfected group, 1.19×1012copies of linear HBV DNA/1×107 PDHs). After 1-5 d of transfection, HBsAg and HBeAg in the supernatant and lysate of PDHs were measured with the IMX System.Meanwhile, replicative intermediates of HBV DNA were analyzed by Southern blotting and Dot blotting. PDHs electroporated were used as control group.RESULTS: HBsAg in the hepatocyte lysates of transfected group was 15.24 (1 d), 14.55 (3 d) and 5.13 (5 d; P/N values, positive≥2.1) respectively. HBeAg was negative (＜2.1). Both HBsAg and HBeAg were negative in the supernatant of transfected group. Dot blotting revealed that HBV DNA was strongly positive in the transfected group and negative in the control group. Southern blot analysis of intracellular total DNA indicated that there were relaxed circular (rc DNA), covalently closed circular (ccc DNA), and single-stranded (ss DNA) HBV DNA replicative intermediates in the transfected group, there was no integrated HBV DNA in the cellular genome. These parameters were negative in control group.CONCLUSION: Expression and replication of HBV genes can occur in hepatocytes from non-mammalian species.HBV replication has no critical species-specificity, and yet hepatic-specific regulating factors in hepatocytes may be essential for viral replication.

The natural history of chronic hepatitis B:a retrospective study

OBJECTIVE: To clarify the natural history, of chronic hepatitis B so as to evaluate its long-term therapeutic outcome of the patients and the efficacy of antiviral drugs. METHODS: A cohort of 183 biopsy-proven chronic hepatitis B patients (mean age of 31.75±8.03 years, male/female ratio: 152:31) and 247 controls were followed up retrospectively for 11.81±4.08 years. This study was focused on long-term clinical outcome including the rates of liver cirrhosis, hepatocellular carcinoma and death, apart from the long-term effect of antiviral drugs and prognostic factors. RESULTS: In the 183 chronic hepatitis B patients, 22 (12.02%) developed liver cirrhosis, 12 (6.56%) developed hepatocellular carcinoma, and 20 (10.93%) died. The 5-, 10- and 15-year survival rates were 97. 27%, 91.62%, and 84.47%, respectively. The 5-, 10- and 15-year incidence rates of HCC were O, 3.19%, and 11.56%, respectively. In the 247 controls, 6 (2.43%) died; none of them developed cirrhosis or HCC. The rates of death, liver cirrhosis, and HCC in the hepatitis B patients were markedly different (P<0. 005) compared with the controls. The overall mortality of hepatitis B patients was 4.5-fold higher than the general population. Cox multiple regression analysis showed that old age, severe histological injury, and positive HBeAg were closely related to liver cirrhosis; old age, severe histological injury, and male were major factors leading to death. The independent variable of predicted HCC was not found. CONCLUSION: The long-term outcome of hepatitis B patients is poor and the efficacy of antiviral drugs needs further study.

Diagnosis and Treatment of Cholangiocarcinoma: A Consensus from Surgical Specialists of China

Cholangiocarcinoma refers to malignant tumors that develop in epithelial lining of biliary system, and it is divided into two categories according to tumor location, intrahepatic cholangiocarcinoma （ICC） and extrahepatic cholangiocarcinoma （ECC）. ICC occurs from the epithelial cells of the intrahepatic bile duct, its branches and interlobular biliary tree; and ECC is divided into hilar cholangiocarcinoma and distal cholangiocarcinoma by the circumscription at the confluence of cystic duct and the common hepatic duct.

Space debris tracking based on fuzzy running Gaussian average adaptive particle filter track-before-detect algorithm

Although tracking with a passive optical telescope is a powerful technique for space debris observation, it is limited by its sensitivity to dynamic background noise. Traditionally, in the field of astronomy, static background subtraction based on a median image technique has been used to extract moving space objects prior to the tracking operation, as this is computationally efficient. The main disadvantage of this technique is that it is not robust to variable illumination conditions. In this article, we propose an approach for tracking small and dim space debris in the context of a dynamic background via one of the optical telescopes that is part of the space surveillance network project, named the Asia- Pacific ground-based Optical Space Observation System or APOSOS. The approach combines a fuzzy running Gaussian average for robust moving-object extraction with dim-target tracking using a particle- filter-based track-before-detect method. The performance of the proposed algorithm is experimentally evaluated, and the results show that the scheme achieves a satisfactory level of accuracy for space debris tracking.

Development of preoperative prognostic models including radiological features for survival of singular nodular HCC patients

Background:Early singular nodular hepatocellular carcinoma(HCC)is an ideal surgical indication in clinical practice.However,almost half of the patients have tumor recurrence,and there is no reliable prognostic prediction tool.Besides,it is unclear whether preoperative neoadjuvant therapy is necessary for patients with early singular nodular HCC and which patient needs it.It is critical to identify the patients with high risk of recurrence and to treat these patients preoperatively with neoadjuvant therapy and thus,to improve the outcomes of these patients.The present study aimed to develop two prognostic models to preoperatively predict the recurrence-free survival(RFS)and overall survival(OS)in patients with singular nodular HCC by integrating the clinical data and radiological features.Methods:We retrospective recruited 211 patients with singular nodular HCC from December 2009 to January 2019 at Eastern Hepatobiliary Surgery Hospital(EHBH).They all met the surgical indications and underwent radical resection.We randomly divided the patients into the training cohort(n=132)and the validation cohort(n=79).We established and validated multivariate Cox proportional hazard models by the preoperative clinicopathologic factors and radiological features for association with RFS and OS.By analyzing the receiver operating characteristic(ROC)curve,the discrimination accuracy of the models was compared with that of the traditional predictive models.Results:Our RFS model was based on HBV-DNA score,cirrhosis,tumor diameter and tumor capsule in imaging.RFS nomogram had fine calibration and discrimination capabilities,with a C-index of 0.74(95%CI:0.68-0.80).The OS nomogram,based on cirrhosis,tumor diameter and tumor capsule in imaging,had fine calibration and discrimination capabilities,with a C-index of 0.81(95%CI:0.74-0.87).The area under the receiver operating characteristic curve(AUC)of our model was larger than that of traditional liver cancer staging system,Korea model and Nomograms in Hepatectomy Patients with Hepatitis B VirusRelated Hepatocellular Carcinoma,indicating better discrimination capability.According to the models,we fitted the linear prediction equations.These results were validated in the validation cohort.Conclusions:Compared with previous radiography model,the new-developed predictive model was concise and applicable to predict the postoperative survival of patients with singular nodular HCC.Our models may preoperatively identify patients with high risk of recurrence.These patients may benefit from neoadjuvant therapy which may improve the patients’outcomes.

Clinical practice guidelines for the treatment of primary liver cancer with integrative traditional Chinese and Western medicine

Traditional Chinese medicine （TCM） is an important part of the treatment of primary liver cancer （PLC） in China; however, the current instructions for the integrative use of traditional Chinese and Western medicine for PLC are mostly based on expert opinion. There is no evidence-based guideline for clinical prac-tice in this field. Therefore, the Shanghai Association of Chinese Integrative Medicine has established a multidisciplinary working group to develop this guideline, which focuses on the most important questions about the use of TCM during PLC treatment. This guideline was developed following the method- ological process recommended by the World Health Organization Handbook for Guideline Development. Two rounds of questionnaire survey were performed to identify clinical questions; published evidence was searched; the Grading of Recommendations Assessment, Development and Evaluation approach was used to evaluate the body of evidence; and recommendations were formulated by combining the quality of evidence, patient preferences and values, and other risk factors. The guideline was written based on the Reporting Items for Practice Guidelines in Healthcare tool. This guideline contains 10 recommendations related to 8 questions, including recommendations for early treatment by TCM after surgery, TCM combined with transcatheter arterial chemoembolization for advanced PLC, TCM drugs for external use, and acupuncture and moxibustion therapy.

Associating liver partition and portal vein ligation for staged hepatectomy versus sequential transarterial chemoembolization and portal vein embolization in staged hepatectomy for HBV-related hepatocellular carcinoma:a randomized comparative study

Background:Both portal vein embolization(PVE)and associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)have merits and demerits when used in patients with unresectable liver cancers due to insufficient volumes in future liver remnant(FLR).Methods:This study was a single-center,prospective randomized comparative study.Patients with the diagnosis of hepatitis B related hepatocellular carcinoma(HCC)were randomly assigned in a 1:1 ratio to the 2 groups.The primary endpoints were tumor resection and three-year overall survival(OS)rates.Results:Between November 2014 to June 2016,76 patients with unresectable HBV-related HCC due to inadequate volume of FLR were randomly assigned to ALPPS groups(n=38)and TACE+PVE groups(n=38).Thirty-seven patients(97.4%)in the ALPPS group compared with 25 patients(65.8%)in the TACE+PVE group were able to undergo staged hepatectomy(risk ratio 1.48,95%CI:1.17-1.87,P<0.001).The three-year OS rate of the ALPPS group(65.8%)(95%CI:50.7-80.9)was significantly better than the TACE+PVE group(42.1%)(95%CI:26.4-57.8)(HR 0.50,95%CI:0.26-0.98,two-sided P=0.036).However,no significant difference in the OS rates between patients who underwent tumor resection in the 2 groups of patients was found(HR 0.80,95%CI:0.35-1.83,two-sided P=0.595).Major postoperative complications rates after the stage-2 hepatectomy were 54.1%in the ALPPS group and 20.0%in the TACE+PVE group(risk ratio 2.70,95%CI:1.17-6.25,P=0.007).Conclusions:ALPPS resulted in significantly better intermediate-term OS outcomes,at the expenses of a significantly higher perioperative morbidity rate compared with TACE+PVE in patients who had initially unresectable HBV-related HCC.

One-versus two-stage partial hepatectomy for large resectable solitary hepatocellular carcinomas determined preoperatively to have a narrow resection margin:a propensity score matching analysis

Background:For patients with a large but resectable solitary hepatocellular carcinoma(HCC)of>5 cm in diameter,it is often difficult to achieve a sufficient resection margin.There is still no study on whether a two-stage hepatectomy to increase a narrow resection margin would be beneficial.Methods:From August 2014 to February 2017,patients with a large but resectable solitary HCC of>5 cm and a preoperative estimated resection margin of<1.0 cm were retrospectively studied.They were divided into one-and two-stage resection groups.A retrospective analysis was performed,followed by propensity score matching(PSM)analysis.Disease recurrence,survival,intraoperative and postoperative data were compared.Results:Before PSM,the 1-,2-,3-and 4-year recurrence-free survival rates for the one-and two-stage groups were 44.3%,31.7%,24.3%,19.2%versus 60.6%,45.4%,43.5%,32.3%,respectively(P=0.007).The corresponding OS rates were 61.0%,45.2%,43.8%,38.4%versus 69.6%,62.5%,60.7%,57.3%,respectively(P=0.029).After PSM,the 1-,2-,3-and 4-year recurrence-free survival rates for the one-and two-stage groups were 44.0%,31.5%,27.3%,21.0%versus 60.6%,45.4%,43.5%,32.3%,respectively(P=0.013).The corresponding OS rates were 62.5%,41.1%,41.1%,37.5%versus 69.6%,62.5%,60.7%,57.3%,respectively(P=0.038).Differences in the resection margins between the one-and two-stage groups before[0.3(0-0.5)versus 1.2(0.8-2.2)cm]and after[0.2(0-0.5)versus 1.2(0.8-2.2)cm]PSM were also significant.Conclusions:Two-stage hepatectomy allowed a wider resection margin for patients with a resectable but solitary HCC of>5 cm,and resulted in significantly better long-term survival outcomes after partial hepatectomy.

Multiple hepatocellular carcinomas: liver resection or transcatheter arterial chemoembolization?

The article by Fukami et al.published in the Annals ofSurgery is a detailed study using a very large samplesize to discuss on the treatment strategies for multiplehepatocellular carcinoma(HCC)(1).Although thisis a retrospective study,the authors used propensityscore matching and other methods to draw interestingconclusions.

The liver tissue bank and clinical database in China

To develop a standardized and well-rounded material available for hepatology research,the National Liver Tissue Bank(NLTB)Project began in 2008 in China to make well-characterized and optimally preserved liver tumor tissue and clinical database.From Dec 2008 to Jun 2010,over 3000 individuals have been enrolled as liver tumor donors to the NLTB,including 2317 cases of newly diagnosed hepatocellular carcinoma(HCC)and about 1000 cases of diagnosed benign or malignant liver tumors.The clinical database and sample store can be managed easily and correctly with the data management platform used.We believe that the high-quality samples with detailed information database will become the cornerstone of hepatology research especially in studies exploring the diagnosis and new treatments for HCC and other liver diseases.

Novel insights of HBV RNA in hepatitis B virus pathogenesis and clinical application

Hepatitis B virus(HBV)infection is still a severe health problem in the world,and chronic hepatitis B(CHB)is the major cause of serious HBV-related complications,including fibrosis,hepatic failure,and hepatocellular carcinoma.It is difficult for CHB patients to achieve complete cure as the currently available antiviral drugs can hardly eradicate covalently closed circular DNA(cccDNA)in the infected liver.Since detecting intrahepatic cccDNA needs invasive procedure,it is urgent to find a noninvasive indicator to reflect the activity of cccDNA.Recently,growing numbers of studies have indicated that serum HBV RNA could be regarded as a new biomarker for CHB activity.In order to illustrate the molecular biology and clinical characteristics of HBV RNA,we systematically reviewed the latest research to summarize the role of HBV RNA in HBV replication and pathogenicity,and to better estimate its potential function as a remarkable biomarker in clinical application.Meanwhile,we will also point out the deficiencies of current research,and discuss the future direction of HBV RNA study.