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

// Xiaogang Zhang 1 , Xinsen Xu 1 , Yina Jiang 2 , Jianyu He 3 , Wenjing Wang 1 , Wei Li 1 , Xufeng Zhang 1 and Yi Lv 1 1 Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi’an 710061, China 2 Department of Pathology, First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi’an 710061, China 3 Department of Pharmacology, First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi’an 710061, China Correspondence to: Yi Lv, email: luyi169@126.com Keywords: hepatorenal syndrome; α1-adrenoceptor; hyperresponsiveness; renal artery; pathogenesis Received: February 17, 2017 Accepted: June 29, 2017 Published: November 25, 2017 ABSTRACT Objective: To investigate the potential role of alpha1-adrenoceptor (α1-AR) in the pathogenesis of hepatorenal syndrome. Methods: Hepatorenal syndrome was induced in male rats by intraperitoneal injection of D-galactosamine and orally treatment with α1-AR antagonist tamsulosin. Hyperresponsiveness of the renal artery contraction was evaluated by the laser-Doppler flowmetry and multimyograph system, while renal blood flow (cortical and medullary perfusion) was simultaneously measured. Renal artery ring segment tone was recorded with the myograph system, and concentration-response curves were obtained by cumulative administration of agonists. Results: This model developed acute renal and liver failure without renal damage in pathology, accompanied by significant hyperresponsiveness of renal artery contraction. After hepatorenal syndrome, plasma concentrations of tumor necrosis factor-α increased by two-fold, and α1-AR was significantly activated in the renal artery. Concentration-dependent vasoconstriction induced by noradrenaline was significantly decreased in the renal arteries of hepatorenal syndrome rat because of gradually decreased renal blood flow. Administration of tamsulosin prevented renal failure when given before the onset of liver injury, but it had no effect on liver injury by itself. Conclusion: α1-AR expression is positively associated with renal vasoconstriction induced by renal artery hyperresponsiveness in HRS. Therefore, α1-AR may be a potential target in the treatment of HRS.

Objective:This study aimed to define the characteristics and use of ocular and cervical vestibular evoked myogenic potentials for evaluating paediatric cochlear implant candidates.Methods:Ocular and cervical vestibular evoked myogenic potentials of 34 paediatric cochlear implant candidates were analysed. All patients also underwent a routine audiological examination, including computed tomography.Results:In all, 27 patients with normal inner-ear structures had absent or impaired vestibular evoked myogenic potential responses. In paediatric candidates with inner-ear malformations, ocular and cervical vestibular evoked myogenic potentials had lower thresholds and higher amplitudes. Vestibular evoked myogenic potential responses in this cohort were classified into three groups. There was significant concordance between vestibular evoked myogenic potentials and temporal bone computed tomography findings.Conclusion:Ocular and cervical vestibular evoked myogenic potential waveforms were different in paediatric candidates with normal and abnormal inner-ear structures. Therefore, vestibular evoked myogenic potential responses can indicate temporal bone structure.

// Xinsen Xu 1 , Lei Huang 2 , Chun Hei Chan 3 , Tao Yu 4 , Runchen Miao 1 , Chang Liu 1 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China 2 118 Lancaster Terrace, Brookline, MA, USA 3 Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 4 Department of Neurosurgery, Peking University First Hospital, Beijing, China Correspondence to: Chang Liu, email: liuchangdoctor@163.com Keywords: genome, cancer, expression, utility, prognosis Received: February 24, 2016 Accepted: May 29, 2016 Published: June 14, 2016 ABSTRACT Cancer molecular profiling provides better understanding of tumor mechanisms and helps to improve the existing cancer management. Here we present the gene expression signatures from ~9000 human tumors with clinical information across 32 malignancies from The Cancer Genome Atlas project (TCGA). Major predictors from the RNA sequencing data that were significantly correlated with cancer survival were identified. The expression level of these prognostic genes revealed significant genomic pathways that were clinically relevant to survival outcomes across human cancers. Furthermore, it is shown that in most cancer types, combinations of these genomic signatures with clinical information might yield improved predictions. Thus, with respect to clinical utility, our study reveals the promising values of genomic data from the pan-cancer perspective.

The relationship between telomere length and cancer survival has been widely studied. To gain a deeper insight, we reviewed the published studies. A total of 29 studies evaluated telomere length in the peripheral blood; 22 studies evaluated telomere length in the tumor tissue. First, in the peripheral blood studies, for solid tumor patients with shortened telomere length, the combined hazard ratios (HRs) for mortality and tumor progression were 1.21 (95%CI, 1.10-1.32) and 1.71 (95%CI, 1.37-2.13), respectively. Meanwhile, in hematology malignancy, the combined HRs for mortality and tumor progression were 2.83 (95%CI, 2.14-3.74) and 2.65 (95%CI, 2.18-3.22), respectively. Second, in the studies that use tumor tissue, for patients with shortened telomeres, the combined HRs for mortality and tumor progression were 1.26 (95%CI, 0.95-1.66) and 1.65 (95%CI, 1.26-2.15), respectively. In the studies that calculate the telomere length ratios of tumor tissue to adjacent normal mucosa, for patients with lower telomere length ratios, the combined HRs were 0.66 (95%CI, 0.53-0.83) and 0.74 (95%CI, 0.41-1.32) for mortality and tumor progression, respectively. In conclusion, shortened telomere in peripheral blood and tumor tissue might indicate poor survival for cancer patients. However, by calculating the telomere length ratios of tumor tissue to adjacent normal mucosa, the lower ratio might indicate better survival.

// Lei Zhou 1, 2, 3 , Zhixin Wang 2, 4 , Xinsen Xu 2 , Yong Wan 2 , Kai Qu 2 , Haining Fan 4 , Qiangpu Chen 1 , Xuejun Sun 3 , Chang Liu 2 1 Department of Hepatobiliary Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, China 2 Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, China 3 Department of General Surgery, The First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, China 4 Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining, China Correspondence to: Qiangpu Chen, e-mail: drcqp@hotmail.com Xuejun Sun, e-mail: sunxj@mail.xjtu.edu.cn Chang Liu, e-mail: liuchangdoctor@163.com Keywords: Nek7, hepatocellular carcinoma, cell proliferation, cyclin B1, prognosis Received: October 20, 2015 Accepted: January 24, 2016 Published: February 23, 2016 ABSTRACT NIMA-related kinase-7 (Nek7) is a serine/threonine kinase involved in cell-cycle progression via mitotic spindle formation and cytokinesis. In this study, we investigated whether Nek7 involves in hepatocellular carcinoma (HCC). Interestingly, we found that Nek7 was significantly overexpressed in HCC than in liver tissues. In HCC patients, high Nek7 expression was significantly correlated with tumor numbers, tumor diameter, adjacent organs invasion, tumor grade and TNM stage. Furthermore, Nek7 expression pattern showed close relationship with that of Ki-67, a well-stablished cell proliferation marker. More importantly, patients with higher expression levels of Nek7 had significantly lower 5-years survival rate. Likewise, Nek7 expression was significantly higher in HCC cell lines than normal hepatic cell line. By Nek7 silencing using lentivirus-mediated Nek7 interference approach, the growth of HCC cell lines was inhibited and the tumor growth in xenograft mouse model was also suppressed. Mechanistic studies showed that silencing of Nek7 resulted in decreasing cyclinB1 level both in vitro and in vivo . In conclusion, this study highlights for the first time the possible role of Nek7 in HCC progression. Nek7 would be a useful biomarker that early predicts HCC patients at higher risk of poor prognosis. Also, Nek7 could be a novel HCC therapeutic target.

Although overweight and obesity increase cancer risk, it is still controversial with respect to cancer mortality. In the current study, we enrolled 2670 patients of 14 tumor types from the Cancer Genome Atlas (TCGA) project, to identify the prognostic role of overweight and obesity in cancer patients. After dividing the patients into different groups by the body mass index (BMI), we found significant lower mortality in the obesity group. In addition, we also treat BMI value as a binary categorical variable or continuous variable, respectively. We found significant lower mortality in the higher BMI group. Furthermore, when focusing on each tumor type, cervical cancer and bladder cancer showed lower mortality in the patients with higher BMI values. Taken together, our results demonstrate that postdiagnosis obesity might indicate a better prognosis in cancer patients. However, these findings should be interpreted cautiously because of small sample size.

Aspirin as an antitumor drug has been studied in various malignancies with regards to its effects on apoptosis, proliferation, metastasis and senescence of tumor cells. However, the clinical application is limited by its side effects. Nutlin-3 is a novel antitumor compound, which has not been clinically approved. The present study investigated the value of combining aspirin and nutlin-3 on hepatocellular carcinoma (HCC) cells. MTT was performed to detect the proliferation of HepG2 cells treated with aspirin or/and nutlin-3. Transwell invasion assays were performed to estimate the invasion ability of HepG2 cells treated with aspirin or/and nutlin-3. Then the apoptotic analysis of HepG2 cells evaluated the synergistic effect of aspirin and nutlin-3. Apoptosis markers, including B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, caspase-8 and caspase-9 were estimated by western blot analysis at various time points. In addition, a Xenograft mouse model was established by infection with HepG2 cells, and aspirin and/or nutlin-3 was administrated to verify the anti-apoptotic effect of the two drugs in vivo. A high dose of aspirin and nutlin-3 inhibit the proliferation and apoptosis of HepG2 cells. The antitumor effect was enhanced with the combined treatment of the two drugs, particularly in the group with a low concentration of aspirin and nutlin-3. Nutlin-3 was able to increase the level of Bax in HepG2 cells treated with aspirin significantly after treatment for 8 h. When treated with a low concentration of aspirin and nutlin-3, the level of Bax in HepG2 cells was enhanced for 2 h. In the animal model, tumor volume and tumor angiogenesis were significantly decreased in combination group compared with other groups (P

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.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.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 P0.05). 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.The KS is an effective index for predicting OS and DFS in hepatitis B-associated HCC. Larger cohorts are needed to validate our finding.

Background and Aim Although the influence of cigarette smoking on the incident risk of liver cancer has been determined, the association between smoking and liver cancer mortality remains uncertain. Methods We searched Pubmed, EmBase, and Web of Science databases to obtain eligible studies. Hazard ratio (HR) value and 95% confidential intervals (CI) were pooled by using a random-effects model, and dose–response analyses were conducted to quantify associations between smoking and mortality from liver cancer. Results A total of 27 articles involving four million participants from seven countries by retrieval (published 1986–2014) were finally included. Pooled HR values for liver cancer mortality was 1.45 (95% CI: 1.33–1.59), 1.22 (95% CI: 1.11–1.34) and 1.16 (95% CI: 1.01–1.32) for current, former, and ever smokers, respectively, when compared with nonsmokers. The risk increased by 7.1% (95% CI: 1.4–13.2) for per additional 10 cigarettes per day and by 5.2% (95% CI: 0.02–11.2) for per additional 10 pack-years. In our population recruiting 597 patients with liver cancer, smoking status was further identified as a significant determinant factor of tumor size and serum level of gamma-glutamyl transpeptidase, but not a significant prognostic factor. Conclusions Cigarette smoking, especially current smoking, significantly increased mortality risk from liver cancer.

As the most important detoxifying enzymes in liver, glutathione S-transferases (GSTs) can protect hepatocytes against carcinogens. We conducted a large cohort study to investigate the prognostic value of single nucleotide polymorphisms (SNPs) in seven encoding genes of GSTs for hepatocellular carcinoma (HCC). Twelve SNPs were genotyped and correlated with overall survival in 469 HCC patients. The median follow-up time of all patients was 21 (range 3-60) months, and the median survival time was 22 months. By the end of the study, 135 (28.8 %) patients were alive. Only rs4147581 in GSTP1 gene exhibited a significant association with survival of HCC patients (P = 0.006), with its mutant allele bearing a significantly lower risk of death (hazard ratio, 0.71; 95 % confidence interval 0.53-0.90), compared with the homozygous wide-type. A longer median survival time in patients with rs4147581 mutant allele was noticed than those homozygous wide-type (P = 0.03), and there was a marked adverse effect on survival conferred by smoking exposure in these patients. Conclusively, our findings provide supporting evidence for a contributory role of GSTP1 rs4147581 polymorphism in predicting the prognosis of HCC.

Background and Aim It was commonly accepted that chemotherapeutic cytotoxicity was the main cause for hepatic failure in hepatocellular carcinoma patients after repeated transarterial chemoembolization (TACE). However, the effect of embolization-induced hypoxia on liver cirrhosis has rarely been concerned. Methods Serum levels of alanine aminotransferase, aspartate aminotransferase, and albumin were used to detect liver injury. Hepatic artery ligation was performed in carbon tetrachloride-induced rat hepatic fibrosis model to mimic the effect of hepatic hypoxia on liver fibrosis after TACE. Sirius Red staining and immunohistochemical analysis of alpha-smooth muscle actin (α-SMA) were used to detect the activation of hepatic stellate cells. Moreover, the expression of hypoxia and fibrosis-related molecules were analyzed at protein and/or mRNA level. Results Patients showed a significant increase in alanine aminotransferase and aspartate aminotransferase (P = 0.006), accompanied by a decrease in albumin (P = 0.005) after repeated TACE. Hepatic artery ligation significantly promoted carbon tetrachloride-induced rat liver fibrosis progression as indicated by Sirius Red and α-SMA staining, as well as increased expression of hypoxia-inducible factor (HIF)-1α, transforming growth factor (TGF)-β1, and vascular endothelial growth factor (VEGF). Conditioned media of hypoxia-treated L02 cells induced the expression of Collagen I and α-SMA in LX-2 cells, which was inhibited by HIF-1α small interfering RNA. Finally, HIF-1α inhibitor LW6 attenuated the hypoxia-induced fibrosis progression in vivo. Conclusion Our data demonstrate that TACE-induced hepatic hypoxia aggravates the fibrosis progression in peritumoral liver tissue, thus leads to the deterioration of liver function. Intervention of HIF-1α might be a valuable strategy to optimize the efficacy and reduce the complication of TACE.

Some genetic alterations of glutathione S-transferase omega 2 (GSTO2) have been reported to increase the risk of many malignancies, including hepatocellular carcinoma (HCC); however, their prognostic capability remained unresolved in HCC patients treated with transarterial chemoembolization (TACE). To fill this gap, we genotyped three well-defined polymorphisms in GSTO2 to assess whether they can predict overall survival among 228 HCC patients under TACE treatment. The median follow-up time and survival time were 22.0 months (range 3.0-60.0) and 19.2 months, respectively. Only one of three polymorphisms examined, rs157077, was significantly associated with overall survival of TACE-treated HCC (P = 0.003), and its mutant allele conferred a higher risk of death than its wild homozygotes (hazard ratio 1.58, 95 % confidence interval 1.17-2.14). Moreover, carriers of this mutant allele had higher tissue GSTO2 expression, reinforcing the prognostic capability of GSTO2 rs157077 for HCC, especially in combination with age and tumor-node-metastasis (TNM) stage. Taken together, we for the first time provided evidence supporting the prognostic role of GSTO2 in the progression of TACE-treated HCC.

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. Keywords

Aim: To explore the value and prospects of the combined vessel resection with reconstruction techniques in space-occupying lesion surgical treatment. Method: We collected and analyzed clinical data of patients received combined with vessel resection and reconstruction techniques surgery in department of hepatobiliary surgery in our hospital from May 2007 to November 2012, and concluded experience in application of vessel resection and artificial vessel reconstruction. Result: A total of 12 cases were collected. 9 of them were pancreatic lesion, and the other 3 were liver Echinococcus granulosus. The average operative time of 12 cases was 6.1 ± 1.8 h, and the average blood loss was 385 ± 202 ml. The average intraoperative portal vein occlusion time was 31 ± 13 min. 1 case suffered intraperitoneal hemorrhage within 48 h after surgery and other 2 suffered pancreatic fistula. All of them were treated and cured; there was no infection, thrombosis and other complications and perioperative deaths turned up before discharge. 4 cases of pancreatic cancer patients after 4, 9, 35 and 37 died of tumor recurrence and metastasis: 1 was lost and the rest are all alive. The follow-up time of these cases was 3 - 58 months with an average level of 22.4 months. Conclusion: Occupying lesions that cannot achieve traditional radical resection due to vessel invasion conventional radical resection may be cured by combining with vessel resection and reconstruction of the lesion resection surgery, and with good prospects worthy of promotion and application of clinic; this technique should be applied to lesion in hepatobiliary system.

Von Hippel-Lindau (VHL) disease is a rare, autosomal inherited tumor disorder caused by mutations or deletions of the VHL gene. Most of the previous research focused on the clinical features and molecular mechanisms of the disease, few concerned about the psychosocial impact on the patients and their family. We encountered a VHL family in the clinical work and attempted to assess the possible psychological effects of the disease on the members of the family. Three questionnaires including Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) and Revised Symptom Checklist (SCL-90-R) were used in the research. A total of 61 members participated in the investigation. The SAS and SDS tests showed that 13 members were affected by anxiety which was associated with age, and 19 members suffered from depression which was correlated with gender, marital status, age, being patients, occupation, education and close relative of the VHL patients. The SCL-90 results showed that the “total scores”, “interpersonal sensitivity”, “depression”, “anxiety” and “panic” scored higher in our study than Chinese average level. Meanwhile, the SCL-90 data revealed that: 1) age was associated with anxiety disorder; 2) marital status was related to higher prevalence of hostility; 3) Being VHL patients was related to bigoted symptoms; and 4) closer relationship with the VHL patients was associated with depressive and hostility symptoms in the family. The study revealed that susceptibility to psychiatric symptoms was correlated with certain sociodemographic and clinical characteristics. Depression and anxiety were the most prevalent psychiatric symptoms in the VHL family. This was the first study focusing on the psychological consequences of the VHL disease. An understanding of these factors would be helpful in providing appropriate mental health services to the VHL family.

// Xinsen Xu 1 , Wei Chen 1 , Runchen Miao 1 , Yanyan Zhou 1 , Zhixin Wang 1 , Lingqiang Zhang 1 , Yong Wan 1 , Yafeng Dong 2 , Kai Qu 1 , Chang Liu 1 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China 2 Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, KS 66160, USA Correspondence to: Chang Liu, e-mail: liuchangdoctor@163.com Kai Qu, e-mail: joanne8601@163.com Keywords: miR-34a, HCC, senescence, telomerase, telomere Received: October 07, 2014 Accepted: December 11, 2014 Published: January 09, 2015 ABSTRACT Increasing evidence suggests that miRNAs can act as either tumor suppressors or oncogenes in carcinogenesis. In the present study, we identified the role of miR-34a in regulating telomerase activity, with subsequent effect on cellular senescence and viability. We found the higher expression of miR-34a was significantly correlated with the advanced clinicopathologic parameters in hepatocellular carcinoma. Furthermore, tumor tissues of 75 HCC patients demonstrated an inverse correlation between the miR-34a level and telomere indices (telomere length and telomerase activity). Transient introduction of miR-34a into HCC cell lines inhibited the telomerase activity and telomere length, which induced senescence-like phenotypes and affected cellular viability. We discovered that miR-34a potently targeted c-Myc and FoxM1, both of which were involved in the activation of telomerase reverse transcriptase (hTERT) transcription, essential for the sustaining activity of telomerase to avoid senescence. Taken together, our results demonstrate that miR-34a functions as a potent tumor suppressor through the modulation of telomere pathway in cellular senescence.

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 χ 2 = 3.963, P = 0.047, hazard ratio [ HR ] =1.453, 95% confidence interval [ CI ]: 1.006-2.098), lower albumin (Wald χ 2 = 12.213, P HR = 1.982, 95% CI : 1.351-2.910), tumor size (Wald χ 2 = 8.179, P = 0.004, HR = 1.841, 95% CI : 1.212-2.797), and higher alpha-fetoprotein level (Wald χ 2 = 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 χ 2 = 14.491, P HR = 2.285, 95% CI : 1.493-3.496) and tumor size (Wald χ 2 = 21.662, P 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.

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 signifi cance of the 12 indicators. Results. Aspartate aminotransferase-platelet ratio index (APRI) and Goteborg University Cirrhosis Index (GUCI) were found to be signifi cant 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.

AIM: To investigate the effect of knockdown of Forkhead box M1 (FoxM1) on the proliferation and invasion capacities of human gallbladder carcinoma (GBC)-SD cells. METHODS: Four FoxM1 shRNAs were transfected into GBC-SD cells with Lipofectamine 2000 to select the appropriate shRNA for down-regulation of FoxM1. A recombinant lentivirus for shFoxM1 (Lv-shFoxM1), which expresses FoxM1-specific shRNA, and a negative control carrying green fluorescent protein, which expresses a scrambled RNA, were constructed. After transfection with the recombinant adenovirus and screened with puromycin, RT-PCR and Western blot were utilized to evaluate the inhibition efficiency. Cell viability was evaluated by MTT assay, and cell migration and invasion were assessed using the Transwell system. Cells were suspended in serum-free medium and seeded into Transwell inserts either uncoated (for migration assay) or coated (for invasion assay) with growth factor-reduced Matrigel. To verify the involvement of FoxM1 in the senescence of tumor cells, staining of senescence β-galactosidase (SA β-gal), the widely used biomarker of cellular senescence, was also performed. RESULTS: After successful transfection of four FoxM1 small interfering RNAs (shRNAs) with Lipofectamine 2000, the shF1822 was selected as the most appropriate shRNA according to its obvious inhibitory effect. The recombinant adenovirus was then constructed with the shF1822 and successfully transfected into the GBC-SD cells, resulting in the significant inhibition of FoxM1 expression at both the mRNA and protein levels, compared with the negative control (P < 0.05). After transfection, down-regulation of FoxM1 significantly inhibited cell viability according to the MTT assay (P < 0.05). In addition, Transwell migration and invasion assays also suggested the suppression of invasion ability of the transfected cells. SA β-gal staining showed that down-regulation of FoxM1 could induce more senescent GBC cells (P < 0.05), suggesting the possible involvement of the senescence process of the FoxM1-deficient cells in GBC. CONCLUSION: FoxM1 is functionally involved in viability of GBC cells, partially dependent on the inducement of cellular senescence, and is a potential target for GBC therapy.

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.

Accelerated senescence is important because this process is involved in tumor suppression and has been induced by many chemotherapeutic agents. The platinum-based chemotherapeutic agent cisplatin displays a wide range of antitumor activities. However, the molecular mechanism of cisplatin-induced accelerated senescence in hepatocellular carcinoma (HCC) remains unclear. In the present study, the growth inhibitory effect of cisplatin on HepG2 and SMMC-7721 cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cellular senescence was then assessed by β-galactosidase assay. Senescence-related factors, including p53, p21, and p16, were evaluated by quantitative reverse transcription-polymerase chain reaction. Reactive oxygen species (ROS) was analyzed by flow cytometry. Our results revealed that cisplatin reduced the proliferation of HepG2 and SMMC-7721 cells in a dose- and time-dependent manner. Senescent phenotype observed in cisplatintreated hepatoma cells was dependent on p53 and p21 activation but not on p16 activation. Furthermore, cisplatininduced accelerated senescence depended on intracellular ROS generation. The ROS scavenger N-acetyl-L-cysteine also significantly suppressed the cisplatin-induced senescence of HepG2 and SMMC-7721 cells. In conclusion, our results revealed a functional link between intracellular ROS generation and cisplatin-induced accelerated senescence, and this link may be used as a potential target of HCC.

Intensive care unit (ICU) is important in the rehabilitation of critically ill patients. In the past decades, many patients who received aggressive treatment in ICU developed sclerosing cholangitis in multiple centers. Sclerosing cholangitis in critically ill patients (SC-CIP) is a relatively new issue. To investigate the causes, clinical manifestation, treatment, and prognosis of SC-CIP, we searched for published cases in the databases of PubMed, Highwire, and Elsevier from 2001 to 2012. Data were extracted using a standard form and retrospectively analyzed. Twelve eligible studies covering 88 patients, with 64 men and 24 women, were enrolled in this analysis. The mean age was 49.8 years. All of the patients recovered from critical illnesses, such as trauma, infection, burn, and major surgeries. High pressure positive end-expiratory pressure (PEEP, peak level at 12.8 cm H₂O) was utilized for all patients, with the average duration of 36.3 d. In addition, vasopressor agents were administered in approximately 60%of SC-CIP. A rapid increase in cholestasis and irregular strictures in the intrahepatic bile ducts was observed in the following months. With an average follow-up period of 17.9 months, poor outcomes were observed in 54 patients, including 34 deaths. In conclusion, ischemic injury of the biliary tree, which may be affected by PEEP and/or vasopressor administration, affects cholangiopathic procedure. As a newly discovered type of secondary sclerosing cholangitis, SC-CIP is a severe progressive complication of patients in ICU and should be carefully monitored by clinicians.

Objective: To discuss the etiology, diagnosis and treatment of central pontine myelinolysis (CPM) by analyzing 4 cases of our center and 26 cases reported by others in our country. Methods: We analyzed the clinical feature, diagnosis and treatment of 4 CPM cases and then compared them with 26 CPM cases reported between 2000 and 2010. Results: The average age of our 4 cases (3 men and 1 woman) was 47.5 years old. All cases were diagnosed by MRI scan. The patients all had been diagnosed as liver cirrhosis and most of the CPM related symptoms were observed within 2 weeks after surgery, including neural and psychic symptoms and physical impairment. Rapid correction of hyponatremia during perioperative period and high blood concentration of FK506 may be the main causes. All cases received etiological and symptomatic combination treatment and were continued with neural function training after hospital discharge. A long-term follow-up (29.5 ± 15.0 months) showed an improvement of neural function to different degrees. Conclusion: CPM after liver transplantation is a severe complication, of which the etiology and pathogenesis were not clear. MRI scan is the main method for confirmative diagnosis. Etiological prevention and timely treatment may improve the prognosis.

von Hippel-Lindau (VHL) disease is a rare, inherited neoplastic disease characterized by hemangioblastomas (HBL) of the central nervous system (CNS), retinal angiomas, renal cell carcinomas (RCC), pancreatic endocrine tumors (PETs), pheochromocytomas, paragangliomas, and visceral cysts. We encountered a large VHL family in northwest China and conducted a systematic screening of the family members based on their epidemiological and clinical characteristics. A self-designed questionnaire was used to collect the general sociodemographic and health information of the family members. For the preliminary family screening, physical examination and abdomen B ultrasonography were performed. The suspected patients were subjected to cranial computerized tomography and fundus examination. The clinical data of the patients with confirmed VHL disease were collected from hospital records. A total of 63 lineal descendants in six generations were observed in the family (generations O, A, B, C, D, E), including 9 dead suspected cases (6 males, 3 females) and 10 living cases (2 males, 8 females). Among the 10 living cases, 4, 2, 1, 3, 4, 8, and 2 manifested HBLs of the CNS, PETs, RCC, pancreatic cysts, renal cysts, pheochromocytomas (4 hemi and 4 bilateral), and paragangliomas, respectively. Data showed that the morbidity of VHL disease in generation C was lower than that in generation B, but the age of onset was younger. This study is the first to report VHL disease in northwest China and VHL-associated PET cases in Chinese. Therefore, follow-up checkups of the family should be focused on younger generations. Proper family screening protocols should be followed for the treatment of patients with VHL disease.

Numerous literature suggest that the preoperative neutrophil to lymphocyte ratio (NLR) is correlated to the prognosis of various cancers. However, the prognostic significance of NLR in gallbladder carcinoma (GBC) remains to be determined.Data from 316 GBC patients with surgical treatment were reviewed retrospectively. A receiver operating characteristic (ROC) curve was performed to determine an optimal cut-off value for NLR. The Kaplan-Meier method and Cox regression proportional hazard model were performed to evaluate prognostic factors.The optimal cut-off point for NLR was 2.61 according to the ROC curve. According to the univariable analysis, NLR, differentiation and TNM stage were associated with GBC prognosis. GBC patients with NLR 2.61 have worsened 5-year overall survival (OS) compared to patients with NLR ≤ 2.61 (P 0.001). Multiple analyses indicated that NLR (hazard ratio (HR) 1.65; 95 percent confidence interval (95% CI) 1.25-2.17), differentiation (HR 1.25; 95% CI 0.97-1.62) and TNM stage (HR 3.79; 95% CI 2.09-6.87) were independent prognostic factors for GBC. GBC patients in stage III/IV, NLR 2.61 exhibited worse OS compared to patients with NLR ≤ 2.61 (P 0.05). A prognostic evaluation model based on the independent prognostic factors was established.NLR is associated with GBC prognosis and is a potential prognostic marker for GBC, not only preoperatively but also postoperatively.

Qing Pang, Jian-Bin Bi, Zhi-Xin Wang, Xin-Sen Xu, Kai Qu, Run-Chen Miao, Wei Chen, Yan-Yan Zhou, Chang Liu Department of Hepatobiliary Surgery, the First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Shaanxi Province, People’s Republic of China 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

Objective: To evaluate the prognostic factors of gallbladder carcinoma. Methods: Presentation, operative data, complications, and survival outcome were examined for 132 gallbladder carcinoma patients who underwent gallbladder surgery in our unit during 2002-2007, and follow-up results were obtained from every patient for univariate and multivariate survival analysis. Results: The univariate analysis showed that gallbladder lesion history, tumor cell differentiation, Nevin staging, preoperative lymph node metastasis and the surgical approach significantly correlated with the prognosis of the patients (p

Biliary tract cancers, broadly described as malignancies that arise from the biliary tract epithelia, are usually divided into two major clinical phenotypes: cholangiocarcinoma and gallbladder cancer, differing in etiopathogenesis, risk factors, and perhaps molecular and genetic signatures. Atypical symptoms and lack of tumor biomarkers make it difficult to diagnose in early stages. At the time of presentation, few patients are candidates for potentially curative surgical resection. We here assessed and compared features of a total of 150 cases divided into extra- and intrahepatic cholangiocarcinomas and gallbladder cancers (GBC). Althought there were no significant differences in serum tumour marker levels, GBC patients had the poorest prognosis. Furthermore, gallbladder cancer respond poorly to chemotherapy or radiation therapy and approximately half of untreated patients died within 10 months. Therefore, treatment for patients with gallbladder cancer is still in challenge. Outcomes and survival of these patients had improved little over the past three decades - a period in which new successful treatments have greatly contributed to the prolonged patient survival for many other cancers.

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.

We performed weighted gene coexpression network analysis (WGCNA) to gain insights into the molecular aspects of hepatocellular carcinoma (HCC). Raw microarray datasets (including 488 samples) were downloaded from the Gene Expression Omnibus (GEO) website. Data were normalized using the RMA algorithm. We utilized the WGCNA to identify the coexpressed genes (modules) after non-specific filtering. Correlation and survival analyses were conducted using the modules, and gene ontology (GO) enrichment was applied to explore the possible mechanisms. Eight distinct modules were identified by the WGCNA. Pink and red modules were associated with liver function, whereas turquoise and black modules were inversely correlated with tumor staging. Poor outcomes were found in the low expression group in the turquoise module and in the high expression group in the red module. In addition, GO enrichment analysis suggested that inflammation, immune, virus-related, and interferon-mediated pathways were enriched in the turquoise module. Several potential biomarkers, such as cyclin-dependent kinase 1 (CDK1), topoisomerase 2α (TOP2A), and serpin peptidase inhibitor clade C (antithrombin) member 1 (SERPINC1), were also identified. In conclusion, gene signatures identified from the genome-based assays could contribute to HCC stratification. WGCNA was able to identify significant groups of genes associated with cancer prognosis.

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 × 109/L, and the entire cohort was stratified into group A with PLT > 178 × 109/L and group B with PLT ≤ 178 × 109/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.

To investigate whether central obesity is associated with nonalcoholic fatty liver disease (NAFLD) formation after adjusting for general obesity.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.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.Central obesity may pose a greater threat to national health than general obesity, although both are independently associated with increased risk of NAFLD.

Presently, no effective markers are available to facilitate gallbladder cancer (GBC) diagnosis. This study aims to explore available markers for GBC diagnosis. Clinical data of 144 GBC and 116 cholelithiasis patients were retrospectively reviewed. Logistic regression analysis was performed to evaluate GBC risk factors. A receiver operating characteristic (ROC) curve was used to assess the diagnosis value of the risk factors. By comparing the characteristic of GBC and cholelithiasis patients, the following factors exhibited statistical difference: age, gender, gallstones, total bilirubin (TB), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count (PLT), CA125 (carcinoembryonic antigen 125), and CA199 (carbohydrate antigen 199). Logistic regression analysis indicated that age [odds ratio (OR), 1.032; 95%confidence interval (95% CI), 1.004 to 1.061; P = 0.024], gender (OR, 0.346; 95% CI, 0.167 to 0.716; P = 0.004), gallstones (OR, 0.027; 95% CI, 0.007 to 0.095; P < 0.001), ALP (OR, 1.003; 95% CI, 1.000 to 1.006; P = 0.032), TB (OR, 1.004; 95% CI, 1.000 to 1.009; P = 0.042), and CA125 (OR, 1.007; 95% CI, 1.002 to 1.013; P = 0.011) were independent risk factors for GBC. According to the ROC curve, CA125 [area under curve (AUC), 0.720], ALP (AUC, 0.713), TB (AUC, 0.636), and age (AUC, 0.573) were valuable diagnosis markers. Additionally, based on the independent risk factors, the GBC diagnosis model was established. Age, TB, ALP, and CA125 can be used as auxiliary diagnosis factors of GBC. The diagnosis model provides a quantitative tool for GBC diagnosis when comprehensively considering various risk factors.

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.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.ER1 and VEGF-A expression was significantly higher in GBC compared with CS (47/78 vs 28/78, P0.05; 51/78 vs 33/78, P0.05). ER1 expression was correlated with gender (P0.05) and VEGF-A expression was correlated with tumor differentiation in GBC patients (P0.05). In univariate analysis, age and tumor node metastasis (TNM) stage were factors associated with GBC prognosis (P0.05). 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 P0.05). In multivariate analysis, combined expression of ER1 and VEGF-A and TNM stage were independent prognostic factors for GBC patients (P0.05).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.

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.

Although previous evidence indicates close involvement of CD147 in the pathogenesis of liver fibrosis, the underlying molecular mechanisms and its therapeutic value remain largely unknown. In the present study, we investigated the biological roles of CD147 in liver fibrosis and assessed its therapeutic value as a target molecule in the CCl4-induced liver fibrosis mouse model. We found that CD147 was highly expressed in both hepatocytes and SECs (sinusoidal endothelial cells) in fibrotic liver tissues. Additionally, it was significantly associated with the fibrosis stage. TGF-β1 (transforming growth factor β1) was found to be mainly responsible for the up-regulation of CD147. Bioinformatic and experimental data suggest a functional link between CD147 expression and VEGF-A (vascular endothelial growth factor A)/VEGR-2 (VEGF receptor 2) signalling-mediated angiogenesis in fibrotic liver tissues. Furthermore, we observed that the CD147-induced activation of the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway promotes the production of VEGF-A in hepatocytes and expression of VEGFR-2 in SECs, which was found to enhance the angiogenic capability of SECs. Finally, our data indicate that blocking of CD147 using an mAb (monoclonal antibody) attenuated liver fibrosis progression via inhibition of VEGF-A/VEGFR-2 signalling and subsequent amelioration of microvascular abnormality in the CCl4-induced mouse model. Our findings suggest a novel functional mechanism that CD147 may promote liver fibrosis progression via inducing the VEGF-A/VEGFR-2 signalling pathway-mediated cross-talk between hepatocytes and SECs. New strategies based on the intervention of CD147 can be expected for prevention of liver fibrosis.

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.

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 breakd...

To determine the prognostic value of alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) for hepatocellular carcinoma (HCC) .We analyzed the outcome of 172 HCC patients who underwent liver resection. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of ALP and GGT. Then, preoperative risk factors for survival were evaluated by multivariate analysis. Based on the significant factors, a prognostic score model was established.By ROC curve analysis, ALP120 U/L and GGT115 U/L were considered elevated. Overall survival (OS) and tumor-free survival (TFS) for patients with elevated ALP and GGT were significantly worse than for patients with ALP and GGT within the normal range. Multivariate analysis showed that the elevated levels of ALP, GGT and tumor size were independent prognostic factors. Giving each positive factor as a score of 1, we established a preoperative prognostic score model. The 5-year OS for patients with a score of 0, 1, 2 and 3 were 84.0%, 45.9%, 44.1% and 0%, respectively, while the TFS was 80.6%, 40.0%, 38.8% and 0%, respectively. When combining patients with scores of 1 and 2 into the middle risk group, and patients with scores of 0 and 3 into the low-risk and high-risk groups, respectively, different outcomes would be significantly distinguished by the risk groups.Elevated ALP and GGT levels were risk predictors in HCC patients. Our prognostic model might vary the outcomes of patients from different risk groups.

Background Hepatitis B virus (HBV)–related chronic liver disease is one of the most common indications for liver transplantation (LT). Patient data in our unit were collected to evaluate the impact of liver tumor on outcomes in patients with HBV-related cirrhosis who underwent LT. Methods HBV transplantation patients in our hospital from August 2002 to March 2012 were analyzed and compared according to LT indications: decompensated cirrhosis (DEC) or hepatocellular carcinoma (HCC). For HCC patients, receiver operating characteristic (ROC) curve analysis was used to determine the cutoff tumor size for prognosis, namely the maximum tumor diameter. According to the cutoff size, patients were divided into 2 groups: large-size HCC and small-size HCC. The correlations among other clinicopathologic factors were also investigated. Potential prognostic factors were evaluated with the use of Cox proportional hazards model analysis. Results The 1-, 3-, and 5-year overall survival rates of the 111 HBV-related patients were 76.2%, 43.2%, and 32.9%, respectively. Patients with HCC had significantly poorer overall survival than those with only DEC (P < .05). The mean tumor size was 5.97 cm, and ROC analysis indicated that the cutoff tumor size for prognosis was 4.25 cm, with sensitivity and specificity of 62.8% and 81.0%, respectively (area under the ROC curve, 0.760; 95% CI, 0.644–0.877; P < .001). According to this cutoff point, 31 patients had large tumor size (≥4.25 cm) and 33 had small tumor size (

Previous studies have demonstrated the involvement of transcriptional factor forkhead box M1 (FoxM1) in cellular senescence of hepatocellular carcinoma (HCC). In the present study, we revealed that oxaliplatin could induce senescence in HCC cells, since advanced HCC patients with lower expression of FoxM1 were more sensitive to oxaliplatin therapy. Our data indicated that due to the repression by p53, FoxM1 played a critical role in oxaliplatin-induced senescence via regulating cycle-related proteins p21, p27, cyclins B1 and D1. Furthermore, inhibition of FoxM1, combined with oxaliplatin treatment, could significantly promote the senescence of HCC cells. Taken together, our findings suggest that FoxM1 may represent a promising therapeutic target for the medication of the chemosensitivity to oxaliplatin in HCC patients.

Gallbladder carcinoma (GC) is generally considered as a relatively rare malignancy with poor prognosis. In order to guide clinicians in selecting suitable treatment for GC patients, reliable markers predictive of poor clinical outcome are desirable. This study analyzed the expression of Polo-like kinase 1 (Plk1), Nima related kinases 7 (Nek7) and Forkhead box M1 (FoxM1) in GC tissues and their relationship to clinicopathologic features and survival. We immunohistochemically investigated the 76 specimens of gallbladder carcinoma, pericarcinoma and normal tissues using Nek7, FoxM1 and Plk1 antibodies and analyzed the overall survival time of these 76 patients. There were significant correlations between the high level expression of Nek7, FoxM1 and Plk1 and the tumor differentiation, Nevin staging and metastasis. The high level expression of Nek7, FoxM1 and Plk1 was significantly associated with shorter overall survival time in univariate analysis (log-rank test), also identified as an independent prognostic factor in multivariate analysis. Nek7, FoxM1 and Plk1 were significantly associated with certain clinicopathologic indices in GC. Evaluation of Nek7, FoxM1 and Plk1 expression may be an important factor in identifying a group of poor GC prognosis.

AIM: To elaborate the clinicopathologic features of colorectal cancer-related pyogenic liver abscess (PLA). METHODS: Reported cases of colorectal cancer-related PLAs were collected from the literature published up to October 2011 and evaluated for their clinicopathologic features. Data of collected cases included demographics, clinical presentation, microbial findings and treatment. Categorical variables were compared by χ2 analysis and continuous variables were evaluated using Student’s t test. RESULTS: A total 96 cases of colorectal cancer-related PLA were collected from the previous literature. Most patients (60%) were male and 40% cases occurred in the age group of 61-70 years. Apart from some special types of PLA, there were significant differences in the microbiological spectrum between Eastern Asia and non-Eastern Asian countries, which implied different risk factors and courses of the disease. Gram negative bacteria especially Klebsiella pneumoniae (K. pneumoniae) PLA was predominant in Eastern Asia (80.0%) in contrast to non-Eastern Asian countries (P < 0.01). Meanwhile, most of the Eastern Asian patients exhibited smaller size of liver abscess and atypical presentation. Sigmoid colon and rectum (72.73%) were the main sites of tumor in Eastern Asian patients, whereas tumor sites were uneven among most of the non-Easter Asian PLA patients. CONCLUSION: K. pneumoniae PLA was strongly associated with colorectal cancer, especially those occurring in sigmoid colon and rectum, in elderly Eastern Asian male patients.

Objective: To improve the diagnosis of primary gallbladder carcinoma (GBC) with/without hepatic metastases by analyzing our experience of different GBC treatment in our patients. Methods: A retrospective study was carried out to analyze the clinical data of the 139 patients with GBC who underwent hepatic resection in our unit from January 2003 to December 2007. Patients were divided into two groups according to whether they demonstrated hepatic invasion. Tumor presentation, surgical modes, and prognosis of each patient were retrospectively reviewed. Kaplan-Meier curves and log-rank tests were employed to compare the survival rates of those patients undergoing different surgical procedures. Results: Of the 139 patients, 46 were men and 93 were women with the male to female ratio of 1:2.0. Their ages were ranged from 35 to 86 years with a mean age of 62.8±10.4 years. There were 73 patients complicated with hepatic invasion (group A), and no hepatic invasion occurred in the other 66 patients (group B). Compared with the group B, the patients with hepatic invasion suffered lower differentiation of tumor (p=0.000), more advanced Nevin staging (p=0.008) and poorer prognosis (p=0.013). Radical resection were more frequently performed in group B (75.76%) than in group A (45.20%) with better outcomes (p=0.000). Conclusion: GBC patients complicated with hepatic invasion had poorer prognosis than those without invasion in long-term follow-ups. Radical resection might result in a satisfied prognosis in patients without hepatic invasion, but appears less favorable than palliative resection in those who were complicated with hepatic invasion.

To explore the effects of platelet count (PLT) and 11 platelet-based indices on postoperative recurrence of hepatocellular carcinoma (HCC).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.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 (P0.05). 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 (P0.05). 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.PLT and PLT-based noninvasive models are effective tools for predicting postoperative recurrence, especially late recurrence. Larger cohorts are needed to validate our findings.