The prognostic values of 12 cirrhosis-relative noninvasive models in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinogenesis is associated with the progression of cirrhosis, and the latter further aggravates tumor development and prognosis. The aim of the study was to investigate the prognostic values of 12 cirrhosis-relative noninvasive models in hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 363 HCC patients who either underwent partial hepatectomy (PH) or received transcatheter arterial chemoembolization (TCAE). Preoperative data were collected to calculate these indices using the original formulas. Diagnostic accuracy of these models in detection of cirrhosis was evaluated by area under receiver operating characteristic curve (AUC) analysis. Multivariate analyses were performed to assess the independent prognostic significance of the 12 indicators. RESULTS: Aspartate aminotransferase-platelet ratio index (APRI) and Goteborg University Cirrhosis Index (GUCI) were found to be significant in discriminating cirrhotic patients from non-cirrhotic individuals. When the indices were expressed as continuous variables, multivariate analyses indicated that APRI and GUCI were independent indices to predict overall survival in patients underwent PH, with a hazard ratio (HR) value 1.04 (p = 0.005) and 1.07 (p = 0.001), respectively. In the cohort of TACE, APRI and GUCI were independently associated with survival as well. CONCLUSION: Of the 12 indices, APRI and GUCI were relatively accurate predictors of cirrhosis status as well as outcome of HCC. As only a limited study population was enrolled in the current study, larger cohorts are needed to validate our results.

Liver transplantation versus liver resection for hepatocellular carcinoma: a meta-analysis.

BACKGROUND: Liver transplantation (LT) and liver resection (LR) are currently considered the standard treatment of patients with hepatocellular carcinoma (HCC). However, the outcomes of LT and LR are still inconclusive. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Library were searched for relevant studies. Surgical safety indices such as treatment-related morbidity and mortality, and efficacy indices such as overall and tumor-free survival outcomes were evaluated. Weighted mean differences and odds ratios (ORs) were calculated using a random-effects model. RESULTS: Seventeen studies were included in this meta-analysis. LT achieved significantly higher rates of surgery-related morbidity (OR=1.47; 95% CI: 1.02-2.13) and mortality (OR=2.12; 95% CI: 1.11-4.05). Likewise, the 1-year survival rate was lower in LT (OR=0.86; 95% CI: 0.61-1.20). However, the 3- and 5-year survival rates were significantly higher in LT than in LR and the ORs were 1.12 (95% CI: 0.96-1.30) in 3 years and 1.84 (95% CI: 1.49-2.28) in 5 years. Furthermore, the tumor-free survival rate in LT was significantly higher than that in LR in 1, 3, 5 years after surgery, with the ORs of 1.72 (95% CI: 1.24-2.41), 3.75 (95% CI: 2.94-4.78) and 5.64 (95% CI: 4.35-7.31), respectively. CONCLUSIONS: One-year morbidity and mortality are higher in LT than in LR for patients with HCC. However, long-term survival and tumor-free survival rates are higher in patients treated with LT than those treated with LR.

Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction.

AIM: To elucidate the molecular mechanisms underlying the immunosuppressive effects of emodin isolated from Rheum palmatum L. METHODS: Human T cells were isolated from the peripheral venous blood of 10 healthy adult donors. Cell viability was analyzed with MTT assay. AO/EB and Annexin V/PI staining and DNA damage assay were used to detect cell apoptosis. Fluorescence staining was used to detect the levels of ROS, the mitochondrial membrane potential and intracellular Ca(2+). Colorimetry was used to detect the levels of MDA and total SOD and GSH/GSSG ratio. The expression and activity of caspase-3, -4, and -9 were detected with Western blotting and a fluorometric assay. Western blotting was also used to detect the expression of Bcl-2, Bax, cytochrome C, and endoplasmic reticulum (ER) markers. RESULTS: Emodin (1, 10, and 100 µmol/L) inhibited the growth of human T cells and induced apoptosis in dose- and time dependent manners. Emodin triggered ER stress and significantly elevated intracellular free Ca(2+) in human T cells. It also disrupted mitochondrial membrane potential, and increased cytosolic level of cytochrome C, and the levels of activated cleavage fragments of caspase-3, -4, and -9 in human T cells. Furthermore, emodin significantly increased the levels of ROS and MDA, inhibited both SOD level and GSH/GSSG ratio in human T cells, whereas co-incubation with the ROS scavenger N-acetylcysteine (NAC, 20 µmol/L) almost completely blocked emodin-induced ER stress and mitochondrial dysfunction in human T cells, and decreased the caspase cascade-mediated apoptosis. CONCLUSION: Emodin exerts immunosuppressive actions at least partly by inducing apoptosis of human T cells, which is triggered by ROS-mediated ER stress and mitochondrial dysfunction.

Correction to "Downregulation of FoxM1 inhibits the viability and invasion of gallbladder carcinoma cells, partially dependent on the induction of cellular senescence".

[This corrects the article on p. 9497 in vol. 20, PMID: 25071344.].

Simple models based on gamma-glutamyl transpeptidase and platelets for predicting survival in hepatitis B-associated hepatocellular carcinoma.

BACKGROUND: Several hepatic cirrhosis-derived noninvasive models have been developed to predict the incidence and outcomes of hepatocellular carcinoma (HCC). We aimed to investigate the prognostic significance of the two novel established cirrhosis-associated models based on gamma-glutamyl transpeptidase (GGT) and platelets in hepatitis B-associated HCC. METHODS: We retrospectively evaluated 182 HCC patients with positive hepatitis B surface antigen who received radical therapy at a single institution between 2002 and 2012. Laboratory data prior to operation were collected to calculate the GGT to platelets ratio (GPR) and the S-index. Predictive factors associated with overall survival and recurrence-free survival were assessed using log-rank test and multivariate Cox analysis. Additional analyses were performed after patients were stratified based on cirrhosis status, tumor size, therapy methods, and so forth, to investigate the prognostic significance in different subgroups. RESULTS: During a median follow-up time of 45.0 months, a total of 88 (48.4%) patients died and 79 (43.4%) patients recurred. The cut-off points for GPR and S-index in predicting death were determined to be 0.76 and 0.56, respectively. Compared with patients with a lower GPR, those with GPR ≥0.76 had a higher probability of cirrhosis and a larger tumor (both P<0.05). GPR and S-index were both found to be significantly associated with survival by univariate log-rank test. Multivariate analysis identified tumor size ≥5 and high level of GPR, but not high Barcelona Clinic Liver Cancer stage or S-index, as independent factors for predicting poor overall survival and recurrence-free survival. CONCLUSION: The GPR is an effective preoperative predictor for outcomes in hepatitis B-associated HCC.

FoxM1 as a novel therapeutic target for cancer drug therapy.

BACKGROUND: Current cancer therapy mainly focuses on identifying novel targets crucial for tumorigenesis. The FoxM1 is of preference as an anticancer target, due to its significance in execution of mitosis, cell cycle progression, as well as other signal pathways leading to tumorigenesis. FoxM1 is partially regulated by oncoproteins or tumor suppressors, which are often mutated, lost, or overexpressed in human cancer. Since sustaining proliferating signaling is an important hallmark of cancer, FoxM1 is overexpressed in a series of human malignancies. Alarge- scale gene expression analysis also identified FoxM1 as a differentially-expressed gene in most solid tumors. Furthermore, overexpressed FoxM1 is correlated with the prognosis of cancer patients, as verified in a series of malignancies by Cox regression analysis. Thus, extensive studies have been conducted to explore the roles of FoxM1 in tumorigenesis, making it an attractive target for anticancer therapy. Several antitumor drugs have been reported to target or inhibit FoxM1 expression in different cancers, and down-regulation of FoxM1 also abrogates drug resistance in some cancer cell lines, highlighting a promising future for FoxM1 application in the clinic.

King's score as a novel prognostic model for patients with hepatitis B-associated hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: King's score (KS) has been developed to predict the presence of cirrhosis and hepatocellular carcinoma (HCC) in patients with chronic liver diseases. We aimed to investigate the prognostic significance of the KS in hepatitis B-associated HCC. PATIENTS AND METHODS: We retrospectively analyzed 319 hepatitis B-associated HCC patients. Preoperative data were collected to calculate the KS (age × aspartate aminotransferase × international normalized ratio/platelet count). The primary outcomes were overall survival (OS) and disease-free survival (DFS), which was estimated using the Kaplan-Meier method. Then, we carried out a multivariate Cox analysis to assess the independent significance of the KS. Additional analyses were carried out after patients were stratified on the basis of cirrhosis status and therapy methods to investigate the significance of KS in different subgroups. RESULTS: During a median follow-up period of 44 months, 199 (62.4%) patients died and 144 (45.1%) experienced recurrence. The cut-off value for the KS was determined to be 33.31 with 56.8% sensitivity and 66.7% specificity. Compared with patients with low KS, the high group showed a higher probability of cirrhosis and worse Child-Pugh class (both P<0.05). Multivariate analysis identified older age, tumor size 5 or more, palliative therapy, high Barcelona Clinic Liver Cancer stage, and high KS as significant factors for predicting poor OS and DFS. A combination of the KS and tumor size showed better discrimination ability for survival than Barcelona Clinic Liver Cancer stage. CONCLUSION: The KS is an effective index for predicting OS and DFS in hepatitis B-associated HCC. Larger cohorts are needed to validate our finding.

Model Based on Alkaline Phosphatase and Gamma-Glutamyltransferase for Gallbladder Cancer Prognosis.

PURPOSE: To evaluate the prognostic value of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in gallbladder cancer (GBC). MATERIALS AND METHODS: Serum ALP and GGT levels and clinicopathological parameters were retrospectively evaluated in 199 GBC patients. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values of ALP and GGT. Then, associations with overall survival were assessed by multivariate analysis. Based on the significant factors, a prognostic score model was established. RESULTS: By ROC curve analysis, ALP≥210 U/L and GGT≥43 U/L were considered elevated. Overall survival for patients with elevated ALP and GGT was significantly worse than for patients within the normal range. Multivariate analysis showed that the elevated ALP, GGT and tumor stage were independent prognostic factors. Giving each positive factor a score of 1, we established a preoperative prognostic score model. Varied outcomes would be significantly distinguished by the different score groups. By further ROC curve analysis, the simple score showed great superiority compared with the widely used TNM staging, each of the ALP or GGT alone, or traditional tumor markers such as CEA, AFP, CA125 and CA199. CONCLUSIONS: Elevated ALP and GGT levels were risk predictors in GBC patients. Our prognostic model provides infomration on varied outcomes of patients from different score groups.

Survival Analysis of Hepatocellular Carcinoma: A Comparison Between Young Patients and Aged Patients.

BACKGROUND: To compare the clinicopathological features and prognosis between younger and aged patients with hepatocellular carcinoma (HCC). METHODS: We analyzed the outcome of 451 HCC patients underwent liver resection, transcatheter arterial chemoembolization and radiofrequency ablation, respectively. Then risk factors for aged and younger patients' survival were evaluated by multivariate analysis, respectively. RESULTS: The patients who were older than 55 years old were defined as the older group. The overall survival for aged patients was significantly worse than those younger patients. The younger patients had similar liver functional reserve but more aggressive tumor factors than aged patients. Cox regression analysis showed that the elevated levels of aspartate aminotransferase (AST) (Wald χ2 = 3.963, P = 0.047, hazard ratio [HR] =1.453, 95% confidence interval [CI]: 1.006-2.098), lower albumin (Wald χ2 = 12.213, P < 0.001, HR = 1.982, 95% CI: 1.351-2.910), tumor size (Wald χ2 = 8.179, P = 0.004, HR = 1.841, 95% CI: 1.212-2.797), and higher alpha-fetoprotein level (Wald χ2 = 4.044, P = 0.044, HR = 1.465, 95% CI: 1.010-2.126) were independent prognostic factors for aged patients, while only elevated levels of AST (Wald χ2 = 14.491, P < 0.001, HR = 2.285, 95% CI: 1.493-3.496) and tumor size (Wald χ2 = 21.662, P < 0.001, HR = 2.928, 95% CI: 1.863-4.604) were independent prognostic factors for younger patients. CONCLUSIONS: Age is a risk factor to determine the prognosis of patients with HCC. Aged patients who have good liver functional reserve are still encouraged to receive curative therapy.

Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index.

AIM: To investigate whether central obesity is associated with nonalcoholic fatty liver disease (NAFLD) formation after adjusting for general obesity. METHODS: The online databases PubMed, EMBASE, and ISI Web of Science were searched for studies estimating the influence of central obesity on NAFLD occurrence published through April 2014. Studies that did not adjust for body mass index (BMI) were excluded. In addition, the independent effect of BMI was also assessed with the included studies. The pooled effect sizes and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models based on the degree of heterogeneity. Furthermore, subgroup analyses, meta-regression, sensitivity analyses, and publication bias were performed. RESULTS: Twenty eligible studies were identified. The summary odds ratio (OR) values per-unit increase in waist circumference (WC) and BMI for NAFLD formation were 1.07 (95%CI: 1.03-1.10, I (2) = 73.9%, n = 11 studies) and 1.25 (95%CI: 1.13-1.38, I (2) = 88.7%, n = 11 studies), respectively. When the indices were expressed as binary variables (with the non-obesity group as reference), the pooled OR in WC, waist-to-hip ratio, and BMI were 2.34 (95%CI: 1.83-3.00, I (2) = 41.8%, n = 7 studies), 4.06 (95%CI: 1.53-10.79, I (2) = 65.7%, n = 3 studies), and 2.85 (95%CI: 1.60-5.08, I (2) = 57.8%, n = 5 studies), respectively. Using the same studies as the latter (n = 5), pooled OR in WC was 3.14 (95%CI: 2.07-4.77), which is greater than that in BMI. CONCLUSION: Central obesity may pose a greater threat to national health than general obesity, although both are independently associated with increased risk of NAFLD.

Platelet to lymphocyte ratio as a novel prognostic tool for gallbladder carcinoma.

AIM: To preliminarily investigate the prognostic significance of the platelet to lymphocyte ratio (PLR) in patients with gallbladder carcinoma (GBC). METHODS: Clinical data of 316 surgical GBC patients were analyzed retrospectively, and preoperative serum platelet and lymphocyte counts were used to calculate the PLR. The optimal cut-off value of the PLR for detecting death was determined by the receiver operating characteristic (ROC) curve. The primary outcome was overall survival, which was estimated by the Kaplan-Meier method. The log-rank test was used to compare the differences in survival. Then, we conducted multivariate Cox analysis to assess the independent effect of the PLR on the survival of GBC patients. RESULTS: For the PLR, the area under the ROC curve was 0.620 (95%CI: 0.542-0.698, P = 0.040) in detecting death. The cut-off value for the PLR was determined to be 117.7, with 73.6% sensitivity and 53.2% specificity. The PLR was found to be significantly positively correlated with CA125 serum level, tumor-node-metastasis (TNM) stage, and tumor differentiation. Univariate analysis identified carcinoembryonic antigen (CEA), CA125 and CA199 levels, PLR, TNM stage, and the degree of differentiation as significant prognostic factors for GBC when they were expressed as binary data. Multivariate analysis showed that CA125 > 35 U/mL, CA199 > 39 U/mL, PLR ≥ 117.7, and TNM stage IV were independently associated with poor survival in GBC. When expressed as a continuous variable, the PLR was still an independent predictor for survival, with a hazard ratio of 1.018 (95%CI: 1.001-1.037 per 10-unit increase, P = 0.043). CONCLUSION: The PLR could be used as a simple, inexpensive, and valuable tool for predicting the prognosis of GBC patients.

Prognostic significance of preoperative platelet count in patients with gallbladder cancer.

AIM: To investigate the prognostic value of preoperative platelet count (PLT) in patients with primary gallbladder cancer (GBC). METHODS: The clinical data of 223 GBC patients after surgery was retrospectively reviewed. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cutoff point for PLT. Univariate and multivariate survival analyses were performed to identify the factors associated with the prognosis. RESULTS: The ROC curve showed that the optimum cutoff point for PLT was 178 × 10(9)/L, and the entire cohort was stratified into group A with PLT > 178 × 10(9)/L and group B with PLT ≤ 178 × 10(9)/L. Group A had a better survival than group B (P < 0.001). There was an obvious difference between the two groups in terms of the differentiation degree, advanced tumor stage, lymph node metastasis (P < 0.001) and pathological type (P < 0.05). The univariate analysis demonstrated that tumor location, differentiation degree, TNM stage, Nevin stage, lymph node metastasis and PLT were associated with overall survival (P < 0.001). In the multivariate analysis, PLT (P = 0.032), lymph node metastasis (P = 0.007), tumor location (P < 0.001) and TNM stage (P = 0.005) were independent prognostic factors. CONCLUSION: PLT is closely correlated with GBC prognosis and could be used to identify the population with a poorer prognosis after surgery.

Significance of platelet count and platelet-based models for hepatocellular carcinoma recurrence.

AIM: To explore the effects of platelet count (PLT) and 11 platelet-based indices on postoperative recurrence of hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 172 HCC patients who were treated by partial hepatectomy. Preoperative data, including laboratory biochemical results, were used to calculate the 11 indices included in the analysis. We performed receiver operating characteristic curve analysis to determine the optimal cut-off values for predicting recurrence. Cumulative rates of HCC recurrence were calculated using Kaplan-Meier survival curves and differences were analyzed by log-rank tests. Multivariate analyses were performed to identify independent predictors of recurrence, early recurrence (within one year after surgery), and late recurrence in HCC. To obtain better prognostic models, PLT-based indices were analyzed separately after being expressed as binary and continuous variables. Two platelet-unrelated, validated HCC prognostic models were included in the analyses as reference indices. Additional analyses were performed after patients were stratified based on hepatitis B virus infection status, cirrhosis, and tumor size to investigate the significance of platelets in different subgroups. RESULTS: In the study cohort, 44.2% (76/172) of patients experienced HCC recurrence, and 50.6% (87/172) died during a median follow-up time of 46 mo. PLT and five of the 11 platelet-related models were significant predisposing factors for recurrence (P < 0.05). Multivariate analysis indicated that, among the clinical parameters, presence of ascites, PLT ≥ 148 × 10(9)/L, alkaline phosphatase ≥ 116 U/L, and tumor size ≥ 5 cm were independently associated with a higher risk of HCC recurrence (P < 0.05). Independent and significant models included the aspartate aminotransferase/PLT index, fibrosis index based on the four factors, fibro-quotient, aspartate aminotransferase/PLT/γ-glutamyl transpeptidase/alpha-fetoprotein index, and the PLT/age/alkaline phosphatase/alpha-fetoprotein/aspartate aminotransferase index. There were different risk factors between early and late recurrences, and PLT and these indices were more inclined to influence late recurrence. PLT was only predictive of recurrence in non-cirrhotic HCC patients, and was not influenced by tumor size, which was a critical confounder in our study. CONCLUSION: PLT and PLT-based noninvasive models are effective tools for predicting postoperative recurrence, especially late recurrence. Larger cohorts are needed to validate our findings.

Prognostic implications of estrogen receptor 1 and vascular endothelial growth factor A expression in primary gallbladder carcinoma.

AIM: To investigate the prognostic significance of estrogen receptor 1 (ER1) and vascular endothelial growth factor A (VEGF-A) expression in primary gallbladder carcinoma (GBC) to identify new prognostic markers for this malignancy. METHODS: Using immunohistochemistry, we investigated ER1 and VEGF-A expression in 78 GBC and 78 cholelithiasis (CS) tissues. The results were correlated with clinicopathological features. Univariate and multivariate analyses were performed to evaluate the relationship between ER1 and VEGF-A expression and patients' prognosis. Further Kaplan-Meier survival analysis was also performed. RESULTS: ER1 and VEGF-A expression was significantly higher in GBC compared with CS (47/78 vs 28/78, P<0.05; 51/78 vs 33/78, P<0.05). ER1 expression was correlated with gender (P<0.05) and VEGF-A expression was correlated with tumor differentiation in GBC patients (P<0.05). In univariate analysis, age and tumor node metastasis (TNM) stage were factors associated with GBC prognosis (P<0.05). Although there was no statistical difference between the expression of ER1 or VEGF-A and overall survival, the high expression of ER1 combined with VEGF-A predicted a poor prognosis for GBC patients (16.30±1.87 vs 24.97±2.09, log-rank P<0.05). In multivariate analysis, combined expression of ER1 and VEGF-A and TNM stage were independent prognostic factors for GBC patients (P<0.05). CONCLUSION: Combined expression of ER1 and VEGF-A is a potential prognostic marker for GBC patients. Clinical detection of ER1 and VEGF-A in surgically resected GBC tissues would provide an important reference for decision-making of postoperative treatment programs.

Polymorphisms of glutathione S-transferase genes and survival of resected hepatocellular carcinoma patients.

AIM: To investigate the effects of single nucleotide polymorphisms (SNPs) in glutathione S-transferase (GST) genes on survival of hepatocellular carcinoma (HCC) patients. METHODS: Twelve tagging SNPs in GST genes (including GSTA1, GSTA4, GSTM2, GSTM3, GSTO1, GSTO2 and GSTP1) were genotyped using Sequenom MassARRAY iPLEX genotyping method in a cohort of 214 Chinese patients with resected HCC. The Cox proportional hazards model and log-rank test were performed to determine the SNPs related to outcome. Additionally, stratified analysis was performed at each level of the demographic and clinical variables. An SNP-gene expression association model was further established to investigate the correlation between SNP and gene expression. RESULTS: Two SNPs (GSTO2: rs7085725 and GSTP1: rs4147581) were significantly associated with overall survival in HCC patients (P = 0.035 and 0.042, respectively). In stratified analysis, they were more significantly associated with overall survival in patients with younger age, male gender and cirrhosis. We further investigated cumulative effects of these two SNPs on overall survival in HCC patients. Compared with the patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 1.70-fold increased risk of death (P < 0.001). The cumulative effects were more significant in those patients with younger age, male gender and cirrhosis (HR = 2.00, 1.94 and 1.97, respectively; all P < 0.001). Additionally, we found that heavy smoking resulted in a significantly worse overall survival in those patients carrying variant alleles of rs7085725 (HR = 2.07, 95%CI: 1.13-3.76, P = 0.018). The distributions of GSTO2: rs7085725 and GSTP1: rs4147581 genotypes were associated with altered gene expression and contributed to influences on overall survival. CONCLUSION: Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.

Thrombocytopenia for prediction of hepatocellular carcinoma recurrence: Systematic review and meta-analysis.

AIM: To investigate the association between thrombocytopenia and relapse after treatment for hepatocellular carcinoma (HCC). METHODS: We searched the PubMed, EMBASE, and Web of Science databases to obtain eligible studies. The hazard ratios (HRs) values and 95% confidence intervals (CIs) were pooled by random effects model. Subsequently, we estimated the heterogeneity, performed a sensitivity analysis, determined the publication bias, and performed subgroup and meta-regression analyses. Study quality was assessed by using the Oxford Center for Evidence Based Medicine tool. RESULTS: We identified 18 eligible studies by retrieval (published during 2000-2014). Out of the 4163 patients with HCC who were recruited, 2746 (66.0%) experienced recurrence. In general, our meta-analysis suggested that low platelet count (PLT) before therapy significantly increased the probability of postoperative recurrence (HR = 1.53, 95%CI: 1.29-1.81). PLT was also valuable in the prediction of intrahepatic distant recurrence (HR = 1.49, 95%CI: 1.25-1.77). Subgroup and meta-regression analyses identified various therapeutic modalities as the source of a high degree of heterogeneity. The pooled HR values showed no obvious change when a single study was removed, but otherwise, an opposite-effects model was used. In addition, no significant publication bias was detected. CONCLUSION: Thrombocytopenia before treatment might be an inexpensive and useful predictor of postoperative recurrence in patients with HCC.