Antiviral and antifibrotic therapies reduce occurrence of hepatocellular carcinoma in patients with chronic hepatitis B and liver fibrosis: a 144-week prospective cohort study / 南方医科大学学报

OBJECTIVE@#To compare the efficacy and safety of different antiviral and antifibrotic regimens in patients with chronic hepatitis B (CHB) and hepatic fibrosis and the incidence of hepatocellular carcinoma (HCC) associated with these therapies.@*METHODS@#A total of 840 patients with CHB and concurrent hepatic fibrosis, who received antiviral therapy in Nanfang Hospital between June, 2010 and June, 2018, were enrolled in this follow-up cohort study. The patients were assigned to 3 cohorts matched for gender, age (difference≤5 years), HBeAg status and liver stiffness measurement (LSM) for treatment with one of the 3 antiviral drugs, namely entecavir, tenofovir dipivoxil and adefovir dipivoxil; each cohort was divided into 2 groups, with one of the groups having a combined treatment with Fufang Biejiaruangan tablet. The cumulative negative conversion rate of HBV DNA, normalization rate of ALT, hepatic fibrosis regression and the incidence of HCC were compared among the 3 cohorts and across the 6 groups at 144 weeks.@*RESULTS@#A total of 749 patients were available to follow-up at 144 weeks. Compared with the baseline data, the cumulative negative conversion rate of HBV DNA increased gradually and the abnormal rate of ALT decreased significantly over time during the treatment in all the 6 groups (all < 0.001). Compared with the any of the antiviral drugs used alone, the combined treatments all resulted in significantly better antifibrotic effects (χ=11.345, χ=10.160, χ=6.358; all < 0.05). At 144 weeks, the incidence of HCC were 2.2%, 1.7%, 1.7% and 3.3% in enecavir group, enecavir with Biejiaruangan tablet group, adefovir group, and adefovir with Biejiaruangan tablet group, respectively, showing no significant difference between the two cohorts (4 groups; χ=6.813, =0.138). None of the patients in the 2 groups with tenofovir treatment had HCC by the end of the observation.@*CONCLUSIONS@#Antiviral therapy combined with antifibrotic therapy can effectively reverse hepatic fibrosis and reduce the incidence of HCC in patients with CHB; among the 3 antiviral drugs, tenofovir dipivoxil can be a better option for reducing the incidence of HCC in these patients.

Expression of long noncoding RNA linc00261 in hepatocellular carcinoma and its association with postoperative outcomes / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the expression of long noncoding RNA linc00261 in hepatocellular carcinoma (HCC) and its correlation with the clinicopathological features and postoperative outcomes of the patients.</p><p><b>METHODS</b>Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression of linc00261 in surgical specimens of HCC and adjacent tissues from 74 patients. The correlation of the expression level of linc00261 in HCC with the clinicopathological parameters of the patients was analyzed using Chi-square test. The Cox's proportional hazards regression model was used to assess the value of linc00261 in predicting the prognosis of HCC patients after operation. The expression of linc00261 was also examined in 5 HCC cell lines using qRT-PCR. The HCC cell lines MHCC-LM3 and SNU-449 were transfected with small interfering RNAs targeting linc00261 for linc00261 knockdown, and the changes in the cell proliferation, migration and invasion abilities were observed using CCK-8 assay and Transwell assay.</p><p><b>RESULTS</b>The expression level of linc00261 in HCC was significantly correlated with AFP (=0.032), tumor size (=0.007), microscopic vascular invasion (MVI; =0.01), and TNM stage (=002). The patients with lowered expressions of linc00261 in HCC tissues had a significantly shortened tumor-free survival time ( < 0.05), and a lowered expression of linc00261 was identified as an independent risk factor affecting postoperative recurrence-free survival time of the patients ( < 0.05). In HCC cell lines MHCC-LM3 and SNU-449 cells, linc00261 knockdown obviously promoted the cell migration and invasion ( < 0.01) but did not significantly affect cell proliferation ( > 0.05).</p><p><b>CONCLUSIONS</b>Linc00261 may serve as a new prognostic biomarker for predicting the postoperative outcomes of the patients with HCC.</p>

Role and mechanism research on reversal of 5-fluorouracil resistance by epigallocatechin gallate in gastric cancer drug-resistance cells lines SGC-7901/5-FU / 中华胃肠外科杂志

<p><b></b>To study the role and molecular mechanism of epigallocatechin gallate (EGCG) in reversing drug-resistance to 5-fluorouracil (5-FU) in gastric cancer drug-resistant cell line SGC-7901/5-FU.</p><p><b>METHODS</b>Drug-resistance gastric cancer cell line (SGC-7901/5-FU) was established by high doses of repeated impact joint drug concentration increment methods. The cell viability of the parent cell line and the drug-resistance cell line were determined by standard MTT assay. Cell survival rate of drug-resistance was calculated by the formula [(Aof the treatment group / Aof the control group) × 100%]. Cell half inhibitory concentration (IC) and resistance index (RI) were calculated by the Graphpad prime 6.0 software(RI=ICvalue of drug-resistance cells / ICvalue of parent cells). The apoptosis rate of SGC-7901/5-FU cells was quantified by flow cytometry after staining with annexin-V and PI. Western blot was used to detect the protein expression of drug-resistance-related proteins (ABCG2, P-gp, MDR-1 and GST-π) and apoptosis-related proteins (PARP, Survivin, Bax and bcl-2).</p><p><b>RESULTS</b>ICvalue was significantly increased in drug-resistant cells compared with parental cells [(64.7±3.9) mg/L and (4.1±0.3) mg/L, respectively, t=26.46, P=0.000], and the RI was 15.6. Proliferation activity in the drug-resistant cells was higher than that in parental cells at different 5-FU concentrations (all P<0.05). In drug-resistant cells, the ICvalue of 5-FU combined with EGCG group obviously decreased compared with 5-FU group [(7.3±0.1) mg/L and (63.1±1.4) mg/L respectively, t=40.84, P=0.000], and the RI was 0.12. Proliferation activity in drug-resistant cells was significantly decreased after EGCG treatment at different 5-FU concentrations (all P<0.05). Cell apoptosis rates in control group, 5-FU group, EGCG group and 5-FU combined with EGCG group were (3.0±1.0)%, (7.0±1.3)%, (6.0±1.2)% and (18.0±1.4)%, while apoptosis rate in 5-FU combined with EGCG group was significantly higher than those of other 3 groups(F=129.5, P=0.000). Western blot revealed that after EGCG treatment, the expression levels of drug-resistance-related proteins (ABCG2, P-gp, MDR-1 and GST-π) in the drug-resistant cell line SGC-7901/5-FU decreased significantly; the expression levels of apoptosis marker protein PARP and pro-apoptotic protein Bax increased significantly; and the expression levels of anti-apoptotic protein Survivin and Bcl-2 decreased significantly (all P<0.05).</p><p><b>CONCLUSION</b>EGCG can reduce the resistance of gastric cancer resistant cell line SGC-7901/5-FU, whose role may be via the inhibition of the expression of drug-resistance-related proteins, and the elevation of the protein expression ratio of PARP/Survivin and Bax/Bcl-2.</p>

Evaluation of TAZ and KLF5 expression and their clinical significance in hepato-cellular carcinoma / 中国免疫学杂志

Objective:To investigate the expression of TAZ and KLF5 and their clinical significance in hepatocellular carcinoma ( HCC).Methods:We freshly collected 76 samples of surgically resected HCC and matched normal tumor-adjacent tissues and detected TAZ and KLF5 expression in these samples using immunohistochemical staining.The clinical significance of TAZ and KLF5 protein expression were analysed.Results:The protein expression of TAZ and KLF5 in HCC tissues was significantly higher than those in matched normal tumor-adjacent tissues ( P=0.001;P=0.035 ).Clinicopathological analysis suggested that TAZ and KLF5 protein expression were associated with histopathological differentiation ( P=0.007;P=0.047 ) and TNM stage ( P=0.009;P=0.040).TAZ was positively correlated with KLF5 protein in HCC tissues (r=0.651,P=0.003).Conclusion:The high-expression of TAZ and KLF5 are correlated with poor clinicopathological characteristics,and TAZ is positively associated with KLF5 in HCC tissues, suggesting that TAZ may promote tumor progression through inhibition of KLF5 protein degradation in HCC.

The current status of sorafenib treatment in hepatocellular carcinoma / 实用肿瘤学杂志

Hepatocellular carcinoma(HCC)has high incidence rate,recurrence rate after surgecal treat-ment,as well as fatality rate in China .HCC is not sensitive to radiotherapy or chemotherapy and no effective treat-ment is available for HCC patients at advanced stage .Sorafenib is the first effective molecularly targeted drug for the treatment of HCC,which represents a milestone in the treatment of HCC .However,it also shows drug resist-ance during clinical application .Therefore,it is important to investigate the mechanism of drug resistance and its molecular markers for HCC .In this review ,we summarize the current status of the studies in these fields .

Expression of miR-126/miR-126* in hepatocelluar carcinoma and its correlation with clinical outcomes / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the expression of miR-126/miR-126* in hepatocellular carcinoma (HCC) tissues and its clinical significance.</p><p><b>METHODS</b>The expressions of miR-126/miR-126* in the tumor tissues and non-cancer tissues from 74 HCC cases were detected using real-time quantitative PCR. The correlation between miR-126/miR-126* expression and the clinicopathological features of the patients was analyzed.</p><p><b>RESULTS</b>Compared with the non-cancer tissues, HCC tissues showed significantly lowered expression levels of miR-126/miR-126*. A positive correlation was found between the expressions of miR-126 and miR-126* in the tumor tissues. Lower expressions of miR-126/miR-126* were significantly correlated with tumor recurrence and poor survival of the HCC patients.</p><p><b>CONCLUSION</b>The down-regulation of miR-126/miR-126* may play an important role in HCC metastasis and contributes to poor survival of HCC patients.</p>

The association of the SNP in miRNA146a with genetic prediposion and the earlier recurrence after resection for hepatocellular carcinoma / 中华肝胆外科杂志

Objective To investigate the association of the SNP in miRNA146A with genetic prediposion and earlier recurrence after resection for hepatocellular carcinoma (HCC).Methods In the casecontrol study including 173 HCC cases,DNA were exacted from cancer tissue embedded with paraffin and were amplificated by PCR,SNP was explored in gene sequence of miRNA146a (385 base pair including extron).The outcome were analyzed with genetic prediposion and clinical features.Result Only hsa-mir-146a rs2910164 was found.The genetype frequence of C/C 、G/G and C/G at rs2910164 gene locus were separately 61 (35.3％),21 (15％) and 86(49.7％) in cases.Compared to G/G genetype,C/C and C/G genetype were danger factor to onset risk of HCC (OR =3.086,95％ CI:1.289-7.390) ; C/G was danger factor to earlier recurrence after resection(OR =8.179,95％ CI:2.248-29.759).Conclusion rs2910164 may be associated with genetic prediposion and earlier recurrence after resection of HCC in Jiangxi hans

Surgical techniques and perioperative management for improving the success rate of orthotopic liver transplantation in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the surgical techniques and appropriate perioperative management for ensuring successful orthotopic liver transplantation (ROLT) in rats.</p><p><b>METHODS</b>Based on the double-cuff technique of Kamada, we modified the surgical techniques of separation, perfusion and cold preservation of the donor liver, shearing and anastomosis of the suprahepatic vena cava with optimized postoperative infusion protocols and animal care.</p><p><b>RESULTS</b>Two hundred and seventy rats underwent ROLT and a learning curve of the success rate was built to reflect the improvement of techniques. The learning curve showed steep improvements over the exploration stage, breakthrough stage and maturation stage, and the success rates increased sharply over time (0%, 71.1%, and 94.5%, respectively) until finally reaching over 90%. The shearing and anastomosis of the suprahepatic vena cava remained the most critical and difficult techniques in ROLT modeling.</p><p><b>CONCLUSION</b>Proficient microsurgical techniques and meticulous nursing can reduce postoperative complications, enhance operational success rate and extend the survival time after ROLT.</p>

Expression of Nusap1 in the surgical margins of hepatocellular carcinoma and its association with early recurrence / 南方医科大学学报

<p><b>OBJECTIVE</b>To detect the expression of Nusap1 of surgical margins in hepatocellular carcinoma (HCC) and investigate its association with early tumor recurrence.</p><p><b>METHODS</b>The expression of Nusap1 in the surgical margins of HCC, which were histopathologically negative for tumor cells, was examined using immunohistochemistry in 61 HCC cases.</p><p><b>RESULTS</b>Fifteen of 21 (71.4%) cases with immunohistochemical positivity for Nusap1 expression in the surgical margins had early recurrence of HCC, a rate significantly higher than that in patients with negative Nusap1 expression (12/40, 30%) (P<0.05).</p><p><b>CONCLUSIONS</b>Nusap1 expression in the surgical margins of HCC is closely correlated to early postoperative recurrence and can serve as an indicator for predicting early recurrence of HCC.</p>

Expression of nucleolar spindle-associated protein 1 in hepatocellular carcinoma and its clinical significance / 中华肝胆外科杂志

Objective To investigate the expression of nucleolar spindle-associated protein 1(NuSAP1) in hepatocellular carcinoma (HCC) and in non-cancerous tissues,and to study the correlation between NuSAP1 and early recurrence and prognosis of HCC.Methods The expression of NuSAP1 in 61 cases of HCC and non-cancerous tissues were assessed by RT-PCR,quantitative PCR and immunohistochemistry.The relationship between the expression and the clinicopathological features was studied.Results The levels of mRNA and protein in HCC were higher than the non-cancerous tissues (P＜0.05).On univariate analysis,the expression levels of NuSAP1,mRNA and protein in HCC were significantly associated with TNM classification,lymphatic metastasis,early recurrence,tumor thrombosis and histological differentiation (P＜0.05).Multivariate analysis showed early recurrence was associated with the expression of NuSAP1 protein in HCC (P＜0.05).Overexpression of NuSAP1 protein was correlated with poor outcome of the patients with HCC (x2=15.846,P＜0.001).Conclusions NuSAP1 was overexpressed in hepatocellular carcinoma.Overexpression of NuSAP1 was associated with early postoperative HCC recurrence and bad prognosis.

Expression and clinical signiifcance of Nusap1 in hepatical carcinoma / 中南大学学报(医学版)

Objective:To investigate the expression and clinical significance of Nusap1 in hepatical carcinoma. Methods:The expression of Nusap1 protein in 61 specimens of hepatical carcinoma was examined by immunohistochemistry. Based on the levels of Nusap1 expression, the 61 specimens were divided into a high Nusap1 expression group and a low Nusap1 expression group. The correlation between Nusap1 expression with clinicopathologic features and prognosis of hepatical carcinoma was analyzed. Results:TherateofhighNusap1expressionwas54.1%inhepaticalcarcinoma.TherateofhighNusap1 expression was 21.3%in noncarcinoma, with signiifcant difference between the 2 groups (P0.05).Survivalanalysissuggested thatthe6monthand12monthnoncarcinomasurvivalratewassignificantlylowerinthehighNusap1 expression group [33.3%(11/33), 17.9%(5/33)] than that in the low Nusap1 expression group [89.3%(25/28), 53.6%(15/28);P<0.005]. Conclusion:Nusap1 is overexpressed in hepatical carcinoma and is a valuable prognostic factor for hepatical carcinoma.

Expression of SATB1 in hepatocellular carcinoma cell lines with different invasive capacities / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the expression of special AT-rich sequence binding protein 1 (SATB1) in hepatocellular carcinoma (HCC) cell lines with different invasive capacities.</p><p><b>METHODS</b>SATB1 expression was detected using real-time fluorescence quantitative PCR, RT-PCR, Western blotting and immunofluorescence in immortalized liver cell line HL-7702, noninvasive HCC cell lines HepG2 and SMMC-7721, MHCC97L cells with low invasiveness, and highly invasive cell lines MHCC97H and HCCLM3.</p><p><b>RESULTS</b>In comparison with HL-7702 cells, all the 5 HCC cell lines showed overexpression of SATB1 mRNA, which was the highest in the highly invasive HCCLM3 and MHCC97H cells, followed by MHCC97L cell line, and then by SMMC-7721 and HepG2 cell lines (P<0.001). The relative expression quantity of SATB1 protein in HepG2, SMMC-7721, MHCC97L, MHCC97H, and HCCLM3 cell lines was 0.271±0.002, 0.351±0.023, 0.621±0.026, 0.878±0.026, and 1.236±0.006, respectively. SATB1 expression level in HCCLM3 cell line was 4.6-fold higher than that in HepG2 cell line (P<0.001). SATB1 was found to localize in the cytoplasm and cell nuclei of the 5 HCC cell lines, and the highly invasive HCCLM3 and MHCC97H cell lines showed a strong positive staining for SATB1 in immunofluorescence assay.</p><p><b>CONCLUSION</b>SATB1 expression levels differ distinctly between the HCC cell lines with different invasive capacities and are possibly associated with the metastatic potentials of the cells.</p>

Association of cellular inhibitor of apoptosis protein-2 expression with clinical outcomes of hepatocellular carcinoma / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the expression of cellular inhibitor of apoptosis protein-2 (C-IAP2) mRNA and protein in hepatocellular carcinoma (HCC) and its relationship with the clinical outcomes.</p><p><b>METHODS</b>Quantitative PCR and immunohistochemical staining were used to detect the expression of C-IAP2 mRNA and protein in the tumor tissues and corresponding adjacent non-cancerous tissues from HCC patients.</p><p><b>RESULTS</b>The expression of C-IAP2 mRNA in HCC tissues was 2.70 folds higher than that in the non-cancerous tissues (P<0.001). The expression rate of C-IAP2 protein in HCC tissues was 70.8%, significantly higher than that in the non-cancerous tissues (27.8%, P=0.001). The expression of C-IAP2 mRNA and protein was associated with the tumor emboli, lymph node metastasis, AFP level, histological differentiation, TNM stage, postoperative recurrence and metastasis (P<0.05), but not with the patients' gender, age, HbsAg positivity, number of tumors, cirrhosis or the presence of tumor encapsulation (P>0.05).</p><p><b>CONCLUSION</b>The expression of C-IAP2 in HCC is associated with tumor recurrence and metastasis, and can be a biological marker for prognostic evaluation of HCC.</p>

Arantius ligament approach to left hepatic vein in partial hepatectomy: experience in 43 patients / 中华肝胆外科杂志

Objective To investigate the maneuver of dividing Arantius duct to expose the posterior of left hepatic vein.Methods Based on the anatomy of Arantius duct on 33 cadavers,exposure of posterior of left hepatic vein was carried out in 43 patients by dividing the Arantius ligament.Results The posterior of left hepatic vein was dissected to expose the left hepatic vein in 43 patients.The operations and the recovery of the patients were smooth and uneventful.Conclsion Cutting the Arantius ligament allows safe exposure and extrahepatic division of left hepatic vein.

Relation of criteria of hepatoceilular carcinoma for liver transplantation to prognosis / 中华肝胆外科杂志

Objective To assess the efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) and the effect of recipient selection on postoperative survival. Methods The clinical data of 63 patients with primary HCC receiving OLT in this hospital from June 2000 to February 2007 were retrospectively analyzed. The cumulative survival rate after transplantation was analyzed by the Kaplan-Meier method. Results The 1-, 3- and 5-year cumulative survival rates of the 63 patients were 77.4%, 59.3%, 48. 9%, respectively. The rates in conformation with Milan criteria, UCSF criteria and beyond UCSF criteria were 93.8%, 80.8%, 80.8%; 92.1%, 79.2%,79.2%; 29.2%, 8.3%, 0, respectively. The 1-, 3-, 5-year cumulative recurrent rate of patients meeting Milan criteria, UCSF criteria and beyond UCSF criteria was 6.2%, 15.5%, 19. 2%; 7. 9%,15.9%, 20. 8% ; 70. 8%, 87. 5%, 91.7%, respectively (P＜0.01). However, tumor recurrence and survival rates were similar for patients meeting UCSF and Milan criteria (P＞0. 05). Conclusion Expansion of OLT criteria is justified for HCC and does not adversely impact the posttransplant prognosis by the UCSF criteria as compared with the Milan criteria.

Detection of ascarid ITS-2 sequence out of intrahepatic bile duct stones by PCR technique / 中国普通外科杂志

Objective To search for the molecular figngerprint of ascaris lumbricoides in intrahepatic stones. Methods In 56 cases deoxyribonucleic acid (DNA) was exstracted from intrahepatic stones and surgically obtained bile duct tissues, stool and sercum examinations were performed. Based on the sequence and designed primers of ITS-2 of ascaris lumbricoides, polymerase chain reaction ( PCR) was performed. Results There were 12 positive results in 56 (21.4% ) cases of intrahepatic stones. Positive reaction appeared on the examinations of the stool on ascaris lumbricoides and the blood serum among 12 cases. Conclusions Ascaris lumbricoides DNA was found in human of intrahepatic stones, indicating that ascaris lumbricoides infection may play a role in the formation of intrahepatic stones.