Sushun Liu

The Prognostic Value of Platelet Count in Patients With Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Abstract Thrombocytopenia has been acknowledged to be a crucial risk factor for cirrhosis formation and hepatocarcinogenesis in chronic liver diseases. However, to date, the association between platelet count (PLT) and the prognosis of hepatocellular carcinoma (HCC) remains inconsistent and controversial. The aim of the present study was to determine whether PLT could be used as a useful predictor of survival in patients with HCC. We performed systematic review in online databases, including PubMed, EmBase, and Web of Science, from inception until 2014. Studies were included if a statistical relationship was investigated between PLT and survival for HCC, and hazard ratio (HR) and 95% confidence intervals (CIs) for overall survival (OS) or recurrence-free survival (RFS) were provided. The quality of each included study was assessed by Newcastle–Ottawa scale score. To synthesize these studies, a random-effects model or a fixed-effects model was applied as appropriate. Then, we calculated heterogeneity, performed sensitivity analysis, tested publication bias, and did subgrouped and meta-regression analysis. Finally, we identified 33 eligible articles (published from 1998 to 2014) involved 5545 patients by retrieval. A low level of preoperative PLT was found to be significantly associated with a poor survival of HCC. Irrespective of the therapy used, the pooled HRs for OS and RFS were 1.41 (95% CI, 1.14–1.75) and 1.44 (95% CI, 1.13–1.83), respectively. Specifically, in patients who underwent liver resection, the pooled HRs for OS and RFS were 1.67 (95% CI, 1.22–2.27) and 1.44 (95% CI, 1.04–1.99), respectively. Furthermore, patients with preoperative thrombocytopenia (PLT < 100 × 109/L) had a worse OS (HR: 1.73, 95% CI, 1.29–2.32) and RFS (HR: 1.57, 95% CI, 1.31–1.87) in comparison with patients without thrombocytopenia. All our findings showed no significant changes due to the removal of any study or the use of an opposite-effects model, and there was no significant publication bias. The limitations of this meat-analysis were nonuniform cut-off values of PLT, high between-study heterogeneities, potential confounders, and a bias of publication year. A low preoperative PLT level results in an unfavorable outcome in HCC. PLT is a simple, inexpensive, and useful predictor of survival in patients with HCC.

Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis

MicroRNAs play an important role in liver cancer genesis and progression. In this study, we identified down-regulation of miR-146b-5p associated with tumor growth, metastasis and poor survival in hepatocellular carcinoma (HCC) patients. miR-146b-5p could suppress proliferation, migration, and invasion and induced apoptosis in vitro and in vivo. Remarkably, TNF receptor associated factor 6 (TRAF6) was confirmed as a direct target of miR-146b-5p in HCC and miR-146b-5p exerted the tumor suppression roles through inhibiting the phosphorylation of Akt mediated by TRAF6. Furthermore, we identified long non-coding RNA MALAT1 as a molecular sponge of miR-146b-5p to down-regulate its expression in HCC. In general, our results indicate that miR-146b-5p inhibits tumor growth and metastasis of HCC by targeting TRAF6 mediated Akt phosphorylation.

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.

Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse

Acetaminophen (APAP) is widely used as a safety analgesic and antipyretic agent. Although considered safe at therapeutic doses, overdose of APAP can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. Luteolin is a naturally occurring flavonoid which is abundant in plants. The objective of this study was to investigate corresponding anti-oxidative and anti-inflammatory activities of luteolin, using acetaminophen-treated mice as a model system. Male C57BL/C mice were randomly divided into three groups (n=6 each). The control group was given phosphate buffered saline (PBS) orally. The APAP group was given APAP by intraperitoneal injection (i.p) at 300 mg/kg suspended in PBS. The luteolin-treated group was given APAP and luteolin (0-100 mg/kg/day, 1 or 3 days before APAP administration) suspended in PBS orally. 16 h after APAP administration, the liver and serum were collected to determine the liver injury. Luteolin administration significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) levels, as well as glutathione (GSH) depletion and decrease of superoxide dismutase (SOD). Luteolin restored SOD, GSH and GSH-px activities and depressed the expression of pro-inflammatory factors, such as inducible nitric oxide synthase (i-NOS), TNF-α, nuclear factor kappa B (NF-κB), and IL-6, respectively. Moreover, luteolin down-regulated acetaminophen-induced nitrotyrosine (NT) formation and endoplasmic reticulum (ER) stress. These results suggest the presence of anti-oxidative, anti-inflammatory and anti-ER stress properties of luteolin in response to acetaminophen-induced liver injury in mice.

Role of Serotonin in MODS: Deficiency of Serotonin Protects Against Zymosan-Induced Multiple Organ Failure in Mice.

ABSTRACT Zymosan-induced multiple organ dysfunction syndrome (MODS) is a multifactorial pathology that involves the deterioration of function of several organs. 5-Hydroxytryptamine (5-HT) is a small monoamine molecule that is primarily known for its role as a neurotransmitter. Previous studies have shown that 5-HT could serve as an important inflammatory mediator in the peripheral immune system. In the present study, we investigated the effect of 5-HT on the development of non–septic shock caused by zymosan in mice. Tryptophan hydroxylase 1–knockout mice (TPH1−/−, leading to the absence of 5-HT), TPH1−/− + 5-hydroxytryptophan (precursor of 5-HT) treatment mice, wild-type (TPH1+/+) mice, and wild-type plus p-chlorophenylalanine (PCPA, TPH1 inhibitor) treatment mice received zymosan intraperitoneally at a dose of 500 mg/kg. Organ failure and systemic inflammation in the mice were assessed 18 h after the administration of zymosan. Deficiency of 5-HT caused a significant reduction of the 1) peritoneal exudate formation, 2) neutrophil infiltration, 3) MODS, 4) nitrosative stress, and 5) cytokine formation. In addition, at the end of the observation period (7 days), deficiency of 5-HT in the mice was shown to be able to alleviate the severe illness characterized as systemic toxicity, significant loss of body weight, and high mortality caused by zymosan. In conclusion, the lack of 5-HT by genetic knockout or by pharmacologic inhibition of the TPH1 enzyme significantly attenuated zymosan-induced MODS.

Prognostic significance of pretreatment albumin/globulin ratio in patients with hepatocellular carcinoma

Background Pretreatment nutritional and immunological statuses play an indispensable role in predicting the outcome of patients with various types of malignancies. The purpose of this study is to evaluate the predictive value of albumin/globulin ratio (AGR) in overall survival (OS) and recurrence in patients with hepatocellular carcinoma (HCC) following radical hepatic carcinectomy. Patients and methods This retrospective study included a total of 172 patients with HCC with complete medical and follow-up information between 2002 and 2012. AGR was calculated according to the following formula: AGR = albumin/globulin. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff value. The associations of AGR with clinicopathological characteristics and prognosis were assessed. Further multivariate analysis using Cox regression model and subgroup analysis was performed to evaluate the predictive value. Results Receiver operating characteristic curve determined 37.65, 31.99, and 1.48 as the optimal cutoff values of albumin, globulin, and AGR in terms of 5-year OS or death, respectively. On the basis of the cutoff value of AGR, all the patients were divided, respectively, into low-AGR (n=105) and high-AGR (n=67) groups. AGR was found to be significantly correlated with age, cancer embolus, international normalized ratio, and postoperative outcome (P<0.05). Hepatitis B virus infection (hazard ratio [HR]: 2.125; 95% confidence interval [CI]: 1.285–3.153), tumor node metastasis stage (HR: 1.656; 95% CI: 1.234–2.223), serum albumin (HR: 0.546; 95% CI: 0.347–0.857), and AGR (HR: 0.402; 95% CI: 0.233–0.691) were independent predictors of OS via univariate and multivariate survival analyses. However, alpha-fetoprotein (HR: 1.708; 95% CI: 1.027–2.838), tumor node metastasis stage (HR: 1.464; 95% CI: 1.078–1.989), and AGR (HR: 0.493; 95% CI: 0.293–0.828) functioned as independent risk variables for predicting recurrence. Moreover, AGR showed superior prognostic value for OS and recurrence in the subgroups with normal level of albumin or survival time beyond 6 months. Conclusion Pretreatment AGR might serve as an effective biomarker to evaluate the prognosis of patients with a diagnosis of HCC. Based on the results, AGR, characterized with easy accessibility, objectivity, and noninvasiveness, should be included in the routine assessment of HCC.

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.

Thrombocytopenia as an inexpensive, valuable predictor for survival in patients with hepatocellular carcinoma

Platelets are involved in liver regeneration and hepatic diseases via releasing several cytokines, including 5-hydroxytryptamine, platelet-derived growth factors and so forth. Due to splenic breakdown, a decrease in thrombopoietin production, and a capture of platelets by the liver [1], platelet count (PLT) generally reduces in cirrhotic patients. Furthermore, a PLT < 160 10/l significantly increased the risk of cirrhosis in patients with known/suspected liver disease [2]. In addition, thrombocytopenia/a low PLT was independently associated with hepatic carcinogenesis [3,4]. However, the association between PLT and prognosis of hepatocellular carcinoma (HCC) remains inconsistent and controversial. To explore the predictive significance of thrombocytopenia on survival of HCC patients who received surgical resection, we systematically searched PubMed, Embase and Web of Science until July 2014. We only included the studies whose PLT was expressed as binary variable. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS) (or disease-free survival). Finally, we identified nine eligible publications, which consisted of 1434 men and 519 women (Table I). Among these, six reported hazard ratio (HR) value for OS and six studies were available to assess RFS. The cutoff value of PLT ranged from 100 to 150 ( 10/l). By pooling these studies (with adjusted HR, if available) using a random effects model, we found that preoperative thrombocytopenia was a significant predictor of short postoperative survival, with a HR value 1.51 (95% CI, 1.15–1.97, I 43.4%, p = 0.116) for OS and 1.44 (95% CI, 1.04–1.99, I 72.1%, p = 0.003) for RFS. By contrast, a significant relation was also observed between thrombocytopenia and outcome of HCC when we used a fixed effects model. Impact analysis was carried out, and it suggested that no single study could affect the results. In addition, we found no significant evidence of publication bias (a p value for OS and RFS 0.188, 0.133 in Begg’s test and 0.624, 0.201 in Egger’s test, respectively). We suggested that preoperative thrombocytopenia was an unfavorable factor for the prognosis of HCC. However, Buergy et al. [5] emphasized that thrombocytosis at the time of diagnosis was associated with a shorter survival in several solid tumors, including HCC. Shen et al. [6] suggested that patients with a preoperative PLT level ‡300 10/l had a worse OS (p = 0.020) as well as RFS (p = 0.009) compared with patients with a low level. In vitro, platelets could stimulate cell growth, migration and invasion, as well as increase AFP levels in several HCC cell lines [7]. These findings indicated that excessive platelets might induce a poor prognosis as well. Therefore, not only was thrombocytopenia a crucial predisposing factor for HCC occurrence, but it was also a helpful, readily available and inexpensive indictor to predict survival in individuals with HCC. However, more studies are needed to elucidate the exact mechanism of the relationship between PLT and HCC outcome.

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.

5-HT Drives Mortality in Sepsis Induced by Cecal Ligation and Puncture in Mice

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation. The aim of this study is to investigate the role of 5-HT on cecal ligation and puncture- (CLP-) induced sepsis in the mouse model. CLP was performed on C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout (KO) mice. The results showed that the 5-HT-sufficient group mice had a significantly lower survival rate than the 5-HT-deficient group in CLP-induced sepsis and septic shock. The KO-CLP sepsis group received a lower clinical score than the WT-CLP sepsis group. Meanwhile, the body temperature of mice in the KO-CLP sepsis group was higher than that in the WT-CLP sepsis group and was much closer to the normal body temperature 24 hours after CLP. The tissue histopathology analysis revealed that 5-HT markedly exacerbated histological damages in the peritoneum, lung, liver, kidney, intestinal tissue, and heart in sepsis. Moreover, significant lower levels of TNF-α, IL-6, bacterial loads, MPO, and ROS were discovered in the KO-CLP sepsis group in contrast to the WT-CLP sepsis group. In conclusion, 5-HT drives mortality and exacerbates organ dysfunction by promoting serum cytokines and bacterial loads as well as facilitating oxidative stress in the process of sepsis.