Aryl hydrocarbon receptor nuclear translocator is associated with tumor growth and progression of hepatocellular carcinoma.

bHLH/PAS proteins play important roles in tumor progression. Lost or reduced expression of single-minded homolog 2 (SIM) as well as aryl hydrocarbon receptor repressor (AHRR) has been observed in cancerous human tissues. Here, we investigated the role of aryl hydrocarbon receptor nuclear translocator (ARNT), another bHLH/PAS protein, in hepatocellular carcinoma (HCC). Using tissue microarray and immunohistochemistry, we found that intratumoral ARNT was inversely correlated with time to recurrence and overall survival of HCC patients after resection. Knockdown of ARNT in HepG2, HCCLM3 and HCCLM6 cells significantly shortened cell doubling time, increased S-phase cell populations and accelerated in vivo HCCLM6 growth and metastasis. After ARNT expression was rescued, prolonged cell doubling time and decreased S-phase cell populations were observed in HepG2, HCCLM3 and HCCLM6 cells. And, HCCLM6 growth and metastasis in vivo were remarkably inhibited. Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC. According to the results of immunoprecipitation assay, both ARNT/ARNT and ARNT/AHRR complexes were clearly formed in HCCLM6 xenograft with increased ARNT expression. In summary, ARNT is an important regulator of HCC growth and metastasis and could be a promising prognostic candidate in HCC patients.

[Evaluation of the efficacy and prognostic factors for colorectal liver metastases treated with transcatheter arterial chemoembolization].

OBJECTIVE: The aim of this study was to evaluate the therapeutic efficacy and to determine the prognostic factors of TACE in patients with colorectal liver metastases (CRLM). METHODS: The clinical data of 183 patients with unresectable CRLM treated with TACE from Jan. 2002 to Dec. 2008 were retrospectively reviewed. Log-rank method was used for univariate analysis and Cox proportional hazard model was used for multivariate analysis of the prognostic factors. RESULTS: The median survival time was 22 months, and the 0.5-, 1-, 2-, 3-, 5-year survival rates were 93.9%, 81.1%, 39.8%, 18.2%, and 3.9%, respectively. Multivariate analysis showed that tumor involved more than one lobe of the liver, and elevated CEA and CA19-9 levels were independent risk factors for the overall survival (P < 0.01). Females, more times of TACE, combination with regional therapy and received phase II resection were related with a good survival (P < 0.01) in CRLM patients after TACE treatment. CONCLUSIONS: Transcatheter arterial chemoembolization is an effective therapy for unresectable colorectal liver metastases. Patients with tumor spread more than one lobe of the liver, high CEA and CA19-9 levels are independent poor prognostic factors. Females, patients received more times of TACE, combined with regional therapy and received phase II resection may have a good survival.

[Expression and role of CXC chemokine 5 in liver cancer cells].

OBJECTIVE: To explore the expression of CXC chemokine 5 (CXCL5) in liver cancer cells and its effect on cell proliferation, migration and invasion. METHODS: Real-time (RT)-PCR and enzyme-linked immunosorbent assay (ELISA) were used to detect the mRNA and protein levels of CXCL5 in 4 liver cancer cell lines with different metastatic potentials (in ascending order: HepG2, SMMC7721, MHCC97L and MHCC97H). HepG2 with a low expression of CXCL5 was treated with CXCL5. There were four groups: 0 nmol/L CXCL5, 0.1 nmol/L CXCL5, 1.0 nmol/L CXCL5 and 10.0 nmol/L CXCL5. Cell proliferation was evaluated by cell counting kit-8 (CCK-8) assay. Transwell chambers and basement membrane matrix (Matrigel) were used to observe the cellular migration and invasion. Statistical analysis was performed with SPSS 16.0. Statistical comparison of the results was made by analysis of variance (ANOVA). RESULTS: The relative mRNA expression levels of CXCL5 in HepG2, SMMC7721, MHCC97L and MHCC97H were 0.002% ± 0.000%, 0.005% ± 0.000%, 1.030% ± 0.070% and 0.980% ± 0.190% (F = 33.88, P < 0.01) while their protein levels 14.3 ± 0.4, 25.7 ± 1.4, 82.8 ± 3.2 and 98.9 ± 1.7 respectively (F = 447.08, P < 0.01). The CCK-8 results showed that cell proliferation increased with the treatment of CXCL5, but no significant difference existed (F < 1.00, P > 0.05), cell numbers of migration of 0, 0.1, 1.0, 10.0 nmol/L CXCL5 groups were 29 ± 3, 56 ± 16, 113 ± 7 and 130 ± 15 (F = 51.94, P < 0.01), while cell numbers of invasion 17.3 ± 1.8, 33.0 ± 3.2, 65.7 ± 4.4 and 94.3 ± 3.5 respectively (F = 104.13, P < 0.01). CONCLUSIONS: Liver cancer cells with high metastatic potential have a higher expression of CXCL5. And exogenous CXCL5 can increase the proliferation, migration and invasion of liver cancer cells with low metastatic potential. Thus CXCL5 may be associated with the metastasis of liver cancer.

[Effect of let-7c on the proliferation of human hepatocellular carcinoma cell HCCLM3].

OBJECTIVE: To investigate let-7c's effect on the proliferation of human hepatocellular carcinoma cell HCCLM3 by transient transfection and the mechanism inside. METHODS: Lipofectamine 2000 was used to transfect miRNAs into HCCLM3 cells. The cells were divided into three groups, let-7c group: let-7c was transfected, negative control group: negative control miRNA was transfected, blank control group: nothing was transfected. The proliferation of HCCLM3 cells was evaluated using Cell Counting Kit-8 (CCK-8). The cell cycles of each group were assayed by flow cytometry. Western blot and Real time PCR were used to analyze the protein and mRNA expressions of cyclin D1. Statistical analysis was performed with SPSS 17.0. RESULTS: The absorbances of let-7c group were 0.70 ± 0.05, 0.77 ± 0.09 at 48 h and 72 h after transfection, lower than that of blank control group (0.97 ± 0.10, 1.21 ± 0.12) and negative control group (0.91 ± 0.07, 1.12 ± 0.09), 48 h: F = 14.431, P < 0.05, 72 h: F = 21.146, P < 0.05. The flow cytometry at 72 h after transfection revealed that let-7c increased the percentage of cells in G1 phase. The percentage of blank control group was 43.53% ± 0.86%, the negative control group was 44.82% ± 0.77%, and the let-7c group was 54.52% ± 0.13%, F = 240.739, P < 0.05. let-7c suppressed expressions of cyclin D1 at both protein and mRNA levels. The protein levels of cyclin D1 were 0.48 ± 0.09, 0.47 ± 0.06 and 0.23 ± 0.06 (F = 11.316, P < 0.05) in blank control group, negative control group and let-7c group, respectively. The mRNA levels were 1.03% ± 0.29%, 1.01% ± 0.11% and 0.63% ± 0.14% (F=6.315, P < 0.05) in the above three groups, respectively. CONCLUSION: Let-7c can inhibit proliferation of HCCLM3 cells and increase the proportion of cells in G1 phase. The mechanism may be that let-7c represses the expressions of cyclin D1 at both protein and mRNA levels.

[TNFα induced IL-8 production through p38 MAPK- NF-kB pathway in human hepatocellular carcinoma cells].

OBJECTIVE: To identify the role of p38 MAPK- NF-kB signaling pathway in TNF-α induced IL-8 production in human hepatocellular carcinoma cells. METHODS: The concentrations of IL-8 from MHCC-97H cells were measured by an enzyme-linked immunosorbent assay (ELISA). The phosphorylation of p38 MAPK was analyzed by Western blot and immunofluorescence. NF-kB p65 protein nuclear translocation was determined by non-radioactive NF-kB p50 / p65 transcription factor activity kit and immunofluorescence. RESULTS: The IL-8 production from MHCC-97H cells challenged with TNFa significantly increased in a time-dependent (F = 144.04, P < 0.01) and dose-dependent (F = 364.14, P < 0.01) manners, as compared with those without TNFa challenge. TNFa up-regulated the phosphorylation levels of p38 MAPK and increased the translocation of NF-kB p65 protein into the nucleus, also proved by immunofluorescence staining. p38 MAPK inhibitor (SB203580) could significantly inhibit IL-8 production in a dose-dependent manners (F = 65.47, P < 0.01), and partially inhibited NF-kB p65 nuclear translocation in a dose-dependent manner (F=141.20, P < 0.05). CONCLUSION: TNF-α could increase the production of IL-8 in MHCC-97H cells and p38 MAPK- NF-kB pathways seem to play a central role in the regulation of IL-8 production.

[The establishment of a systematic site-specific metastasis model of human hepatocellular carcinoma in nude mouse].

To establish a systematic site-specific metastatsis model of human hepatocellular carcinoma (HCC) in nude mouse. HCCLM3-R cells were seeded into mice liver to establish xenograft mouse models. With the help of RFP, metastasis foci in lungs and lymph nodes in mice were detected using fluorescent stereomicroscopy and were removed. Cells derived from the metastasis foci were named HCCLM3-R-LM1 and HCCLM3-R-LnM1 respectively. HCCLM3-R-LM1 and HCCLM3-R-LnM1 cells were seeded into mice livers to analyze the lung and lymph node metastasis. Lungs of all tested mice were collected, examined by pathological evaluation and counted lung metastasis. Both lung and lymph node metastasis were found in HCCLM3-R-LM1, HCCLM3-R and HCCLM3-R-LnM1 cells and a significant difference was found between the lung and the lymph node metastasis levels in the three cells. The fluorescent areas (pixels) of lung and lymph node metastasis were 8687.00+/-1844.63 versus 2570.00+/-318.20 (P = 0.0031) in HCCLM3-R-LM1 cells, 6457.67+/-832.62 versus 10 994.33+/-2 212.31 (P = 0.0036) in HCCLM3-R cells, and 2968.67+/-2571.00 versus 24 416.00+/-7 186.13 (P = 0.0094) in HCCLM3-R-LnM1 cells, respectively. The middle numbers of microscopic lung metastatic foci were 775, 430 and 310 in HCCLM3-R-LM1, HCCLM3-R and HCCLM3-R-LnM1 cells (P less than 0.001), respectively, consist with the results quantified by RFP. We established the systematic site-specific metastasis models which demonstrates lung- and lymph node-specific metastasis potential in nude mice and can be used as a model for researches on site-specific metastasis of HCC.

A positive feedback loop between Periostin and TGFß1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation.

BACKGROUND: Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. METHODS: Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-ß1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. RESULTS: The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvß3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFß1 from the extracellular matrix and initiated POSTN/TGFß1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. CONCLUSIONS: The POSTN/TGFß1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

[Effect of postoperative adjuvant transarterial chemoembolization upon early recurrence after radical resection of hepatocellular carcinoma].

OBJECTIVE: To explore the effect of postoperative adjuvant transarterial chemoembolization (TACE) upon early recurrence of hepatocellular carcinoma (HCC) patients after radical resection. METHODS: Between November 2000 and December 2007, 2591 HCC patients undergoing radical resection were retrospectively recruited. Patients undergoing resection alone were selected as control group while those receiving post-operative adjuvant TACE as intervention group. The patients were further stratified into tumor < or = 5 cm with low or high risk factors for residual tumor and tumor > 5 cm with low or high risk factors for residual tumor. A low risk factor for residual tumor was defined as single tumor and without microscopic tumor thrombus while a high risk factor for residual tumor was defined as 2 - 3 nodules or with the presence of microscopic tumor thrombus. The effect of adjuvant TACE upon early (< or = 2 years) recurrence was evaluated. RESULTS: Recurrent rates of tumor < or = 5 cm with low or high risk factors for residual tumor and tumor > 5 cm with low or high risk factors for residual tumor at Month 3 post-resection were 1.34%, 3.17%, 5.33% and 8.43% in the control group versus 4.14% (P = 0.002), 8.15% (P = 0.011), 12.88% (P = 0.002) and 14.29% (P = 0.045) respectively in the intervention group; recurrence rates at Month 6 post-resection were 4.63%, 8.73%, 11.50% and 19.46% in the control group versus 6.71% (P = 0.133), 13.48% (P = 0.070), 21.02% (P = 0.052) and 23.94% (P = 0.210) respectively in the intervention group. For patients remaining recurrence free within the first 6 months post-resection, there were no significant differences in recurrence rates at Months 9, 12, 18 and 24 post-operation between each intervention group and control group. CONCLUSION: Postoperative adjuvant TACE has no preventive effect upon early recurrence, but may be of benefit to detect residual tumor and early recurrence.

[Effect of postoperative adjuvant transarterial chemoembolization on late recurrence of hepatocellular carcinoma after radical resection].

OBJECTIVE: To identify the effect of postoperative adjuvant transarterial chemoembolization (TACE) on late recurrence of hepatocellular carcinoma (HCC) patients after radical resection. METHODS: From year 2001 to 2007, 2436 HCC patients underwent radical resection were retrospectively selected. Patients underwent resection only were classified into control group, while those received adjuvant TACE within 2 months after operation were classified into intervention group. Patients were further stratified into those with tumor5 cm and presenting low or high risk factors for recurrence. Patients with single tumor and without microscopic tumor thrombus were defined as low risk for recurrence; otherwise they were defined as high risk. The effect of adjuvant TACE on late (>2 years) recurrence was evaluated. RESULTS: Recurrence rates of tumor5 cm and presenting low, high risk factors for recurrence at 2-year after resection were 20.38%, 33.06%, 30.54% and 50.82%, respectively in the control group, compared with 25.41%, 39.61%, 40.55% and 51.57%, respectively in the intervention group; there were no significant differences between intervention group and control group in each stratum. For patients recurred or died within the first 2 years after resection, the median survival of tumor>5 cm and presenting high risk factors for recurrence was 24 months in the intervention group and 12 months in the Control group. Only in this subgroup, the survival curve of the intervention group was significantly higher than that compared to the control group. For patients who remained recurrence free and survived within the first 2 years after resection, there were no significant differences in the recurrence curves between the intervention group and control group in each stratum; while cumulative survival rates in the subgroup of patients with tumor size is less than or equal to 5 cm and presenting low risk factors for recurrence were 93.95%, 91.50% and 88.42% respectively in the control group, compared with 91.70%, 81.32% and 78.19% respectively in the intervention group at 3-, 4- and 5-year after resection (P=0.0062); for other subgroups, there were no significant differences in the survival curves between the intervention group and the control group in each stratum. Cox regression model suggested adjuvant TACE was not an independent risk factor for late recurrence; however, it might have negative effect on survival [hazard ratio (HR)=1.50, P=0.062] for those patients (especially patients with tumor is less than or equal to 5 cm and presenting low risk factors for recurrence). CONCLUSIONS: The value of adjuvant TACE was mainly due to its therapeutic actions on residual tumor or early recurrence. It had no effect on postponing or eliminating late recurrence; moreover, it could be a risk rather than a benefit in patients at low risk for recurrence (especially those with tumor is less than or equal to 5 cm and presenting low risk factors for recurrence).

Sulfiredoxin-1 is a promising novel prognostic biomarker for hepatocellular carcinoma.

Identifying novel prognostic biomarkers for hepatocellular carcinoma (HCC) and then, develop an effective individualized treatment strategy remain extremely warranted. The prognostic role of sulfiredoxin-1(SRXN1), an antioxidant enzyme, remains unknown in HCC. This study aimed to explore the prognostic implications of SRXN1 in HCC patients after partial hepatectomy. The expression of SRXN1 in HCC and normal tissue were analyzed using the patients from the public databases and Zhongshan Hospital. The Cox regression, Kaplan-Meier survival analysis, and time-dependent receiver operating characteristic curves were performed to identify the predictive role of SRXN1 expression on HCC patients. A prognostic nomogram based on SRXN1 expression was constructed and validated to further confirm the predictive power of SRXN1 as a prognostic biomarker. Finally, functional enrichment analysis and protein-protein interaction network analysis of SRXN1 and its associated genes were conducted. The results showed that SRXN1 was upregulated in HCC samples compared with the normal liver tissues. Patients with SRXN1 upregulation had shorter survival time. SRXN1 overexpression was significantly correlated with advanced clinicopathological parameters. The prognostic nomogram based on SRXN1 expression was proved to be more accurate than routine staging systems for the prediction of overall survival. Protein-protein interaction network analysis demonstrated the first neighbor genes of SRXN1 mainly participated in response to oxidative stress. In brief, SRXN1 could be a prognostic biomarker for the management of HCC.

[Treatment of postoperative recurrence of hepatocellular carcinoma with radiofrequency ablation comparing with repeated surgical resection].

OBJECTIVE: To evaluate the efficacy of radiofrequency ablation for the treatment of postoperative recurrence of hepatocellular carcinoma and whether radiofrequency ablation can be used as first line treatment for recurrent hepatocellular carcinoma. METHODS: There were 213 patients with small recurrent hepatocellular carcinoma (tumor size of 3 cm or less and no more than 3 nodules) who treated in Liver Cancer Institute, Fudan University from January 2000 to December 2005. Among these patients 68 were treated with radiofrequency ablation and 145 were treated with repeated surgical resection. Kaplan-Meier method was used to evaluate the overall survival or disease free survival. Log-rank used to determine the survival difference between groups and COX proportional hazard was used for multivariate analysis to evaluate the risk factors for prognosis. The overall survival or disease free survival was calculated from the time treated with radiofrequency or repeated surgical resection. RESULTS: The 1-, 3-, 5-years overall survival rates were 94.7%, 65.1%, 37.3% and 88.1%, 62.6%, 41.0% in radiofrequency ablation group and surgical repeated resection group, respectively. There was no significant difference between two groups (P = 0.693). However, the disease free survival was better in repeated surgical resection than in radiofrequency ablation, which were 79.4%, 48.1%, 34.4% and 58.0%, 27.8%, 12.4% in repeated surgical resection and radiofrequency ablation, respectively (P = 0.001). The interval between recurrence and initial hepatectomy with more than 2 years was independent factor favor to good prognosis. CONCLUSIONS: Radiofrequency ablation seems to be as effective as repeated surgical resection owing to comparable overall survival and can be considered as alternative therapy for surgical resection treatment of small recurrent hepatocellular carcinoma.

HOXB7 promotes tumor progression via bFGF-induced activation of MAPK/ERK pathway and indicated poor prognosis in hepatocellular carcinoma.

The homeobox-containing gene HOXB7 plays an important role in the pathogenesis and progression of many cancers, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study comprehensively analyzed the expression and clinical significance of HOXB7 in HCC and explored its potential mechanism in tumor progression. We found HOXB7 was highly expressed in HCC cell lines with highly metastatic potential and cancerous tissues from patients with tumor recurrence. The abilities of proliferation, migration, and invasion were notably decreased by depletion of HOXB7, and were enhanced by its enforced expression in vitro. HOXB7 expression was positively correlated with tumor progression and lung metastasis in vivo. The gene microarray data implied that HOXB7 affects biological functions of HCC cells through MAPK/ERK pathway activation. Further study confirmed that the effect of HOXB7 in activating MAPK/ERK pathway via induction of basic fibroblast growth factor (bFGF) secretion, and the inhibition of bFGF secretion could abolish MAPK/ERK pathway activation after ectopic expression of HOXB7. Chromatin immunoprecipitation experiments and luciferase reporter assays confirmed that HOXB7 promoted bFGF secretion via binding its promoter directly. Furthermore, the clinical significance of HOXB7 expression was confirmed using tissue microarrays containing 394 HCC tissue specimens. Patients with high HOXB7 expression showed shorter survival times and higher recurrence rates, and HOXB7 was an independent indicator for survival and recurrence. Overall, HOXB7 promotes HCC cell proliferation, migration, and invasion through the bFGF-induced MAPK/ERK pathway activation. It might be a novel prognostic factor in HCC and a promising therapeutic target for tumor metastasis and recurrence.

VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2.

The von Hippel-Lindau (VHL) is deficient in ∼70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. Here we show that VHL-deficient ccRCC cells present enhanced cytotoxicity of anthracyclines in a hypoxia-inducible factor-independent manner. By subtractive proteomic analysis coupling with RNAi or overexpression verification, aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in ccRCC cells. Furthermore, VHL regulates ALDH2 expression by directly binding the promoter of -130 bp to -160 bp to activate the transcription of hepatocyte nuclear factor 4 alpha (HNF-4α). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4α and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients.

The association between BMI and gallbladder cancer risk: a meta-analysis.

Obesity is a known cause of gallstone formation and gallstones increases the risk of gallbladder cancer (GBC), but the relation of body mass index (BMI) to GBC remains incompletely understood. To help elucidate the role of obesity in GBC, we performed a meta-analysis of the relationship between BMI and GBC risk. PUBMED and EMBASE databases were searched up to April 17, 2016. Fifteen articles with 5902 cases were identified. Random-effects models and dose-response meta-analyses were used to pool study results. Compared to normal weight, the pooled relative risks (RRs) and the corresponding 95% confidence intervals (CI) of GBC for overweight and obesity is 1.10 (0.98-1.23) and 1.58 (1.43-1.75) respectively. The RRs and 95% CI of overweight and obesity in man are 0.98 (0.90-1.08) and 1.43 (1.19-1.71), while the corresponding RRs in woman are 1.29 (1.08-1.55) and 1.68 (1.41-2.00) when compared to normal weight. A nonlinear dose-response relationship between BMI and risk of GBC was found (P=0.001), and the risk increased by 4% for each 1 kg/m2 increment in BMI. When adjusted for sex, at the point of BMI=25 kg/m2, the RRs (95% CIs) for women and men were 1.13 (1.01-1.25) and 0.98 (0.90-1.07) respectively. The corresponding RRs (95%CIs) at the point of BMI=30 kg/m2 were 1.56(1.39-1.75) vs. 1.24(1.06-1.44). These results suggest that association of obesity and risk of GBC is stronger in woman. Furthermore, overweight is only associated with GBC in woman. A even stricter weight control might be necessary for woman to prevent GBC.

[Transcatheter hepatic arterial chemoembolization on recurrent hepatocellular carcinoma after resection].

OBJECTIVE: To investigate the effect of transcatheter hepatic arterial chemoembolization (TACE) therapy on the survival and prognosis of recurrent hepatocellular carcinoma (HCC) after surgical resection. METHODS: The data of 130 surgically resected but recurrent HCC patients treated by TACE were reviewed retrospectively. The survival and influencing factors on the prognosis were analyzed. RESULTS: The overall 1-, 3-, 5-year survival rates of these 130 patients were 83.0%, 45.5% and 17.6% respectively (median survival time 2.4 years). Ninty-four of the series were treated with TACE alone, which gave the 1-, 3- year survival rates of 76.4% and 37.1%, respectively (median survival time 2.1 years). Thirty-six out of 130 patients treated with TACE plus percutaneous ethanol injection (PEI), the 1-, 3-year survival rates were 100.0% and 66.5% respectively with a median survival time (MST) of 3.5 years. The survival of TACE plus PEI group was significantly better, and the mortality risk was significantly lower than that of TACE alone group (P < 0.05). The mortality risk of those with > 5 cm diameter recurrent tumor or with distant metastasis was significantly higher than those with < or = 5 cm diameter tumor or without metastasis (P < 0.05). CONCLUSION: TACE combined with PEI may improve the survival of recurrent HCC patients.

Oxaliplatin and 5-fluorouracil hepatic infusion with lipiodolized chemoembolization in large hepatocellular carcinoma.

AIM: To investigate transarterial chemoembolization (TACE) with hepatic infusion of oxaliplatin and 5-fluorouracil and Lipiodol chemoembolization in large hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 132 patients with unresectable HCCs larger than 10 cm were treated with hepatic infusion of oxaliplatin and 5-fluorouracil followed by Lipiodol chemoembolization. The primary endpoint was overall survival (OS). Sixteen-week disease-control rate, time to progression (TTP), and major complications were also studied. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP. RESULTS: A total of 319 procedures were performed in the 132 patients. Eleven (8.3%) patients received radical resection following TACE treatment (median time to initial TACE 4.3 ± 2.3 mo). The median OS and TTP were 10.3 and 3.0 mo respectively, with a 50.0% 16-wk disease-control rate. Major complications were encountered in 6.0% (8/132) of patients following TACE and included serious jaundice in 1.5% (2/132) patients, aleukia in 1.5% (2/132), and hepatic failure in 3.0% (4/132). One patient died within one month due to serious hepatic failure and severe sepsis after receiving the second TACE. The risk factor associated with TTP was baseline alpha-fetoprotein level, and vascular invasion was an independent factor related to OS. CONCLUSION: Hepatic infusion of oxaliplatin and 5-fluorouracil followed by lipiodolized-chemoembolization is a safe and promising treatment for patients with HCCs larger than 10 cm in diameter.

Postoperative adjuvant arterial chemoembolization improves survival of hepatocellular carcinoma patients with risk factors for residual tumor: a retrospective control study.

AIM: To evaluate the effect of postoperative adjuvant transcatheter arterial chemoembolization (TACE) on the prognosis of hepatocellular carcinoma (HCC) patients with or without risk factors for the residual tumor. METHODS: From January 1995 to December 1998, 549 consecutive HCC patients undergoing surgical resection were included in this research. There were 185 patients who underwent surgical resection with adjuvant TACE and 364 patients who underwent surgical resection only. Tumors with a diameter more than 5 cm, multiple nodules, and vascular invasion were defined as risk factors for residual tumor and used for patient stratification. Kaplan-Meier method was used to analyze survival curve and Cox proportional hazard model was used to evaluate the prognostic significance of adjuvant TACE. RESULTS: In the patients without any risk factors for the residual tumor, the 1-, 3-, 5-year survival rates were 93.48%, 75.85%, 62.39% in the control group and 97.39%, 70.37%, 50.85% in the adjuvant TACE group, respectively. There was no significant difference in the survival between two groups (P = 0.3956). However, in the patients with risk factors for residual tumor, postoperative adjuvant TACE significantly prolonged the patients' survival. There was a statistically significant difference in survival between two groups (P = 0.0216). The 1-, 3-, 5-year survival rates were 69.95%, 49.86%, 37.40% in the control group and 89.67%, 61.28%, 44.36% in the adjuvant TACE group, respectively. Cox proportional hazard model showed that tumor diameter and cirrhosis, but not the adjuvant TACE, were the significantly independent prognostic factors in the patients without risk factors for residual tumor. However, in the patients with risk factors for residual tumor adjuvant TACE, and also tumor diameter, AFP level, vascular invasion, were the significantly independent factors associated with the decreasing risk for patients' death from HCC. CONCLUSION: Postoperative adjuvant TACE can prolong the survival of patients with risk factors for residual tumor, but can not prolong the survival of patients without risk factors for residual tumor.

Changed clinical aspects of primary liver cancer in China during the past 30 years.

BACKGROUND: Primary liver cancer (PLC) is one of the most frequently seen tumors in China. Thirty years ago, patients with PLC were often detected at relatively late stage, with a palpable mass or marked clinical symptoms and poor prognosis. In the past 30 years, the diagnosis and treatment of PLC have been greatly improved with better prognosis. METHODS: In order to study the changes of PLC during the 30 years, the clinical data of 3250 patients with PLC from 10 medical institutions of China were collected, analyzed, and compared with those of 3254 PLC patients before the 30 years. RESULTS: In the 3250 patients aged 1-80 years, with an average age of 49.1 years, the male to female ratio (2.3:1) was lower than that before the 30 years. 73.5% of the 3250 patients sought medical advice within 3 months after the onset of the disease in contrast to 63.8% before the 30 years. Compared with those patients before the 30 years the symptoms and signs were alleviated generally. The HBsAg positive rate was 81.0%, but the HCV-Ab positive rate was 13.2%. The AFP level in 75% of patients was elevated, but in the remaining 25% was normal. 1912 patients (58.8%) were confirmed pathologically. Among them 1755 patients (91.8%) had hepatocellular carcinoma. The overall resection rate was 46.3%. Those who had early, middle, late stage carcinoma accounted for 29.9%, 51.5%, and 18.6% respectively in contrast to 0.4%, 47.0%, and 52.6% reported before the 30 years. The 1-, 3-, 5-year survival rates of the patients were 66.1%, 39.7%, and 32.5% respectively, whereas 93.5%, 70.1%, and 59.1% for the early stage patients, and 65.3%, 30.5%, and 23.5% for the middle stage patients. The half and 1-year survival rates of the late stage patients were 52.5%, and 14.7%, respectively. CONCLUSION: Comparison with the clinical data before and after the 30 years show that PLC can be diagnosed early. More PLC patients tend to undergo resection while receiving a better conservative treatment, which ensures a prognosis.

[Prospective randomized trial of RFA and chemotherapy for unresectable small hepatocellular carcinoma].

OBJECTIVE: To study the clinical safety and effect on local recurrence in unresectable small hepatocellular carcinoma treated by radiofrequency ablation (RFA) with and without chemotherapy through a prospective randomized trial. METHODS: Thirty-eight unresectable small hepatocellular carcinoma patients with diameter

[Three-grade criteria of curative resection for primary liver cancer].

OBJECTIVE: To clarify three-grade criteria of curative resection for primary liver cancer (PLC) and evaluate their clinical significance. METHODS: Criteria of curative resection of PLC were summed up to three grades. Grade I: complete removal of all gross tumors with no residual tumor at the excision margin. Grade II: on the basis of Grade I, there was no extrahepatic metastasis, no hilar lymph node metastasis, no tumor thrombus in the main trunks and their primary tributaries of the portal vein, common hepatic duct, hepatic vein and vena cava inferior, and the tumor was not more than two in number. Grade III: in addition to the above criteria, AFP dropped to normal level (in patients with elevated AFP before surgery) within 2 months after operation, and no residual tumor upon diagnostic imaging. A total of 354 cases with PLC who had their liver resected was reviewed. Patients in each grade were divided into two portions depending on whether the treatment was curative or palliative. RESULTS: The survival of patients receiving curative treatment was better than those receiving palliative treatment (P < 0.01). This was true for patients whose treatment belonged to anyone of the three-grade criteria. The survival was improved along with the promotion of curative criteria used. The 5-year survival rate of Grade I, II and III patients undergone curative resection was 43.2%, 51.2% and 64.4%, respectively (P < 0.01). CONCLUSION: 1. The three-grade criteria may be used for judging the radicality of tumor resection for PLC. 2. The more stringent the criteria used, the better the survival would be. 3. Adopting high-grade criteria to select cases, to guide operation and postoperative follow-up would improve the results of liver resection for PLC.