γ-glutamyl transferase-to-platelet ratio based nomogram predicting overall survival of gallbladder carcinoma.

BACKGROUND: Gallbladder carcinoma (GBC) carries a poor prognosis and requires a prediction method. Gamma-glutamyl transferase-to-platelet ratio (GPR) is a recently reported cancer prognostic factor. Although the mechanism for the relationship between GPR and poor cancer prognosis remains unclear, studies have demonstrated the clinical effect of both gamma-glutamyl transferase and platelet count on GBC and related gallbladder diseases. AIM: To assess the prognostic value of GPR and to design a prognostic nomogram for GBC. METHODS: The analysis involved 130 GBC patients who underwent surgery at Peking Union Medical College Hospital from December 2003 to April 2017. The patients were stratified into a high- or low-GPR group. The predictive ability of GPR was evaluated by Kaplan-Meier analysis and a Cox regression model. We developed a nomogram based on GPR, which we verified using calibration curves. The nomogram and other prognosis prediction models were compared using time-dependent receiver operating characteristic curves and the concordance index. RESULTS: Patients in the high-GPR group had a higher risk of jaundice, were older, and had higher carbohydrate antigen 19-9 levels and worse postoperative outcomes. Univariate analysis revealed that GPR, age, body mass index, tumor-node-metastasis (TNM) stage, jaundice, cancer cell differentiation degree, and carcinoembryonic antigen and carbohydrate antigen 19-9 levels were related to overall survival (OS). Multivariate analysis confirmed that GPR, body mass index, age, and TNM stage were independent predictors of poor OS. Calibration curves were highly consistent with actual observations. Comparisons of time-dependent receiver operating characteristic curves and the concordance index showed advantages for the nomogram over TNM staging. CONCLUSION: GPR is an independent predictor of GBC prognosis, and nomogram-integrated GPR is a promising predictive model for OS in GBC.

The emerging roles of non-coding competing endogenous RNA in hepatocellular carcinoma.

Accumulating evidence has emerged revealing that noncoding RNAs (ncRNAs) play essential roles in the occurrence and development of hepatocellular carcinoma (HCC). However, the complicated regulatory interactions among various ncRNAs in the development of HCC are not entirely understood. The newly discovered mechanism of competing endogenous RNAs (ceRNAs) uncovered regulatory interactions among different varieties of RNAs. In recent years, a growing number of studies have suggested that ncRNAs, including long ncRNAs, circular RNAs and pseudogenes, play major roles in the biological functions of the ceRNA network in HCC. These ncRNAs can share microRNA response elements to affect microRNA affinity with target RNAs, thus regulating gene expression at the transcriptional level and both physiological and pathological processes. The ncRNAs that function as ceRNAs are involved in diverse biological processes in HCC cells, such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. Based on these findings, ncRNAs that act as ceRNAs may be promising candidates for clinical diagnosis and treatments. In this review, we discuss the mechanisms and research methods of ceRNA networks. We also reviewed the recent advances in studying the roles of ncRNAs as ceRNAs in HCC and highlight possible directions and possibilities of ceRNAs as diagnostic biomarkers or therapeutic targets. Finally, the limitations, gaps in knowledge and opportunities for future research are also discussed.

Hepatobiliary case report and literature review of hepatic reactive lymphoid hyperplasia with positive anti-smooth muscle antibody and anti-nuclear antibody tests.

Hepatic reactive lymphoid hyperplasia (RLH) is a rare benign tumor of the liver that exhibits similar imaging characteristics to those of other hepatic malignant tumors; therefore, it requires novel biomarkers to be differentiated from the other tumors. A 69-year-old female was found to have a mass in the liver and was admitted to Peking Union Medical College Hospital for further evaluation. Most laboratory tests, including liver function tests, tumor biomarkers, and autoimmune markers were within normal range, except for positive antinuclear antibody and anti-smooth muscle antibody (SMA) tests. Diagnostic imaging, including ultrasonography, computerized tomography and magnetic resonance imaging displayed a small hepatic mass suggestive of hepatocellular carcinoma (HCC). Partial hepatectomy was performed, and histological diagnosis suggested RLH. Postoperative treatments included anti-infection, nutritional enhancement and liver protection. The suspicion of autoimmune hepatitis could not be confirmed. No recurrence or autoimmune disease was observed over 6-month follow-up. Positive anti-nuclear antibody (ANA) and anti-SMA may be potential biomarkers for hepatic RLH.

A modified staging of early and intermediate hepatocellular carcinoma based on single tumour >7 cm and multiple tumours beyond up-to-seven criteria.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used staging system for hepatocellular carcinoma (HCC). However, the classifications of early (BCLC-A) and intermediate (BCLC-B) stage HCC remain controversial. AIM: To refine the staging of BCLC-A and -B. METHODS: A total of 986 patients with HCC undergoing liver resection from two institutions formed the training cohort, and 694 from another institution were the validation cohort. Time-dependent receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance of tumour size in predicting overall survival (OS), and determined the optimised cut-off. Discriminatory performance was evaluated using Harrell's concordance index (C-index). RESULTS: Patients with multiple tumours exceeding Milan criteria but within up-to-seven criteria had similar OS and disease-free survival (DFS) to those with multiple tumours meeting Milan criteria, and were assigned to the modified BCLC-A stage. The area under the ROC curve of tumour size for predicting OS was 0.778, and the diameter of 7 cm was the optimal cut-off to identify patients with single tumours who had higher OS than BCLC-B stage patients. Due to the similar OS, patients with single HCCs >7 cm were assigned to the modified BCLC-B stage. The C-indexes of the modified BCLC classification for OS and DFS were higher compared to the original version. The findings were supported by the validation cohort. CONCLUSIONS: The modified staging of BCLC-A and -B, based on single tumour >7 cm and multiple tumours beyond up-to-seven criteria, could be more accurate to predict the prognosis of HCC patients. Liver resection could benefit patients with resectable multifocal HCCs beyond the Milan criteria.

Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition).

BACKGROUND: Hepatocellular carcinoma (HCC) (about 85-90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people. SUMMARY: This guideline presents official recommendations of the National Health and Family Planning Commission of the People's Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations. KEY MESSAGES: The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.

Safety and efficacy for laparoscopic versus open hepatectomy: A meta-analysis.

BACKGROUND: Laparoscopic hepatectomy (LH) is growing in popularity, but its efficacy and safety are still controversial. Few multicenter, large, population-based, prospective, randomized studies have compared LH with open hepatectomy (OH). We performed a meta-analysis to compare the treatment outcome of patients undergoing LH versus OH. METHODS: We searched PubMed, EMBASE, Cochrane Central Register, CNKI, and WanFang Med Online databases to November 30th, 2016 for randomized controlled trials (RCTs) that compared treatment outcome for LH and OH. Eligibility criteria included evaluation of operation time, blood loss, complications, and hospital stay after surgery for adult patients who underwent LH or OH. Reviewers in pairs independently screened the studies, extracted data and assessed the risk of bias of included studies. Agreement was achieved. RevMan 5.3 was used to conduct meta-analysis. Complete case analysis was used as primary analysis. Predefined subgroup analysis includes benign and malignant disease. RESULTS: Eight RCTs with a total of 554 patients were included in the meta-analysis, 275 types of LH and 279 types of OH. LH reduced the hospital stay after surgery (8 trials, 554 patients, MD = -3.84 days, 95%CI: -5.05 to -2.63, P < 0.0001, I2 = 88%) and the complication rate (8 trials, 554 patients, RR = 0.29, 95%CI: 0.17-0.50, P < 0.0001, I2 = 0%, absolute 13 to 40 fewer), shortened the time to first flatus (3 trials, 264 patients, MD = -1.41 days, 95%CI: -1.98 to -0.83, P < 0.0001, I2 = 92%), and had less blood loss (8 trials, 554 patients, MD = -164.31 ml, 95%CI: -220.91 to -107.72, P < 0.0001, I2 = 98%) without increasing the operation time (MD = -7.96 min, 95%CI: -24.99 to 9.07, P = 0.36, I2 = 91%) compared with OH. CONCLUSIONS: Laparoscopy is more effective in terms of hospital stay after surgery and time to first flatus with fewer blood loss and complication rate for hepatic resection compared with open surgery.

Multimodality Treatment for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Large-Scale, Multicenter, Propensity Mathching Score Analysis.

The optimal treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains controversial. We aimed to investigate the best treatment for patients with HCC with PVTT. From January 2002 to January 2014, the data from all consecutive patients with HCC with PVTT who underwent surgical treatment (ST),TACE,TACE combined with sorafenib (TACE-Sor), or TACE combined with radiotherapy (TACE-RT) in the 4 largest tertiary hospitals in China were analyzed retrospectively. The patients were divided into 3 subtypes according to the extent of PVTT in the portal vein (type I-III). The primary endpoint was overall survival (OS). A total of 1580 patients with HCC with PVTT were included in the study. The median survival times (MST) for ST (n = 745) for type I, II, and III patients (95% CI) were 15.9 (13.3-18.5), 12.5 (10.7-14.3), and 6.0 (4.3-7.7) months, respectively. The corresponding figures for patients after TACE (n = 604) were 9.3 (5.6-12.9), 4.9 (4.1-5.7), and 4.0 (3.1-4.9), respectively; for patients after TACE-Sor (n = 113) 12.0 (6.6-17.4), 8.9 (6.7-11.1), and 7.0 (3.0-10.9), respectively; and for patients after TACE-RT (n = 118) 12.2 (0-24.7), 10.6 (6.8-14.5), and 8.9 (5.2-12.6), respectively. Comparison among the different treatments for the 3 subtypes of PVTT patients after propensity score (PS) matching showed the effectiveness of ST to be the best for type I and type II PVTT patients, and TACE-RT was most beneficial for type III patients. Treatment was an independent risk factor of OS. ST was the best treatment for type I and II PVTT patients with Child-Pugh A and selected B liver function. TACE-RT should be given to type III PVTT patients.

Three-dimensional printing: review of application in medicine and hepatic surgery.

Three-dimensional (3D) printing (3DP) is a rapid prototyping technology that has gained increasing recognition in many different fields. Inherent accuracy and low-cost property enable applicability of 3DP in many areas, such as manufacturing, aerospace, medical, and industrial design. Recently, 3DP has gained considerable attention in the medical field. The image data can be quickly turned into physical objects by using 3DP technology. These objects are being used across a variety of surgical specialties. The shortage of cadaver specimens is a major problem in medical education. However, this concern has been solved with the emergence of 3DP model. Custom-made items can be produced by using 3DP technology. This innovation allows 3DP use in preoperative planning and surgical training. Learning is difficult among medical students because of the complex anatomical structures of the liver. Thus, 3D visualization is a useful tool in anatomy teaching and hepatic surgical training. However, conventional models do not capture haptic qualities. 3DP can produce highly accurate and complex physical models. Many types of human or animal differentiated cells can be printed successfully with the development of 3D bio-printing technology. This progress represents a valuable breakthrough that exhibits many potential uses, such as research on drug metabolism or liver disease mechanism. This technology can also be used to solve shortage of organs for transplant in the future.

Magnesium isoglycyrrhizinate inhibits inflammatory response through STAT3 pathway to protect remnant liver function.

AIM: To investigate the protective effect of magnesium isoglycyrrhizinate (MgIG) on excessive hepatectomy animal model and its possible mechanism. METHODS: We used the standard 90% hepatectomy model in Sprague-Dawley rats developed using the modified Emond's method, in which the left, middle, right upper, and right lower lobes of the liver were removed. Rats with 90% liver resection were divided into three groups, and were injected intraperitoneally with 3 mL saline (control group), 30 mg/kg (low-dose group) and 60 mg/kg (high-dose group) of MgIG, respectively. Animals were sacrificed at various time points and blood was drawn from the vena cava. Biochemical tests were performed with an automatic biochemical analyzer for the following items: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl endopeptidase, total bilirubin (TBil), direct bilirubin (DBil), total protein, albumin, blood glucose (Glu), hyper-sensitivity C-reactive protein, prothrombin time (PT), and thrombin time (TT). Postoperative survival time was observed hourly until death. Hepatocyte regeneration was analyzed by immunohistochemistry. Serum inflammatory cytokines (IL-1, IL-6, IL-10, and iNOS) was analyzed by ELISA. STAT3 protein and mRNA were analyzed by Western blot and quantitative reverse-transcription PCR, respectively. RESULTS: The high-dose group demonstrated a significantly prolonged survival time, compared with both the control and the low-dose groups (22.0 ± 4.7 h vs 8.9 ± 2.0 vs 10.3 ± 3.3 h, P = 0.018). There were significant differences among the groups in ALT, Glu and PT levels starting from 6 h after surgery. The ALT levels were significantly lower in the MgIG treated groups than in the control group. Both Glu and PT levels were significantly higher in the MgIG treated groups than in the control group. At 12 h, ALT, AST, TBil, DBil and TT levels showed significant differences between the MgIG treated groups and the control group. No significant differences in hepatocyte regeneration were found. Compared to the control group, the high-dose group showed a significantly increase in serum inflammatory cytokines IL-1 and IL-10, and a decrease in IL-6. Both STAT3 protein and mRNA levels were significantly lower in the MgIG treated groups than in the control group at 6 h, 12 h, and 18 h after surgery. CONCLUSION: High-dose MgIG can extend survival time in rats after excessive hepatectomy. This hepatoprotective effect is mediated by inhibiting the inflammatory response through inhibition of the STAT3 pathway.

[Potential Clinical Implications of Circulating Tumor Cells].

The circulating tumor cells (CTCs) are derived from primary or metastatic tumor lesions and can be detected in the peripheral blood. With certain specific features, CTCs can,to certain extent, reflect the progression and invasiveness of tumors. Detection of CTCs may provide a powerful and noninvasive approach for diagnosing neoplastic disease, identifying drug sensitivity, and enabling real-time treatment monitoring and prognosis prediction. Improvements in cell isolation and molecular identification will enable a broad range of clinical applications.

The response of Golgi protein 73 to transcatheter arterial chemoembolization in patients with hepatocellular carcinoma may relate to the influence of certain chemotherapeutics.

BACKGROUND: Golgi protein 73 (GP73) is a promising biomarker of hepatocellular carcinoma (HCC). It decreases after surgical resection, and resumes upon recurrence, indicating a potential indicator for the effectiveness of the treatment. But changes of GP73 after transcatheter arterial chemoembolization (TACE) have not been reported so far. This study was to investigate the dynamic changes of GP73 in HCC patients after TACE treatment, and the possible underlying mechanisms in the cell cultures. METHODS: Blood samples were collected from 72 HCC patients, before TACE, at day 1 and day 30 after TACE. GP73 levels were measured by Western blotting. The dynamic changes of GP73 were analyzed and compared with image changes and clinical data. The effects of chemotherapeutic agents (5-FU and pirarubicin) on GP73 expression were tested in three HCC cell lines (HepG2, HCCLM3 and MHCC97H). RESULTS: The GP73 level was significantly elevated at day 1 and day 30 after TACE in HCC patients compared with that before the procedure (P<0.05). There was no statistical difference between the two time points after TACE, nor correlation between GP73 levels and clinicopathological features, tumor metastasis, and patient survival. Pirarubicin, not 5-FU, significantly increased GP73 expression in three cell lines. CONCLUSIONS: Unlike surgical resection which decreases the GP73 level, TACE significantly increased GP73 expression in patients with HCC. No correlations were observed among GP73 levels, tumor characteristics and prognosis of patients with HCC.

Regulatory Effects of Long Non-coding RNA on Tumorigenesis.

Long non-coding RNAs(LncRNA)may play a key role in tumorigenesis by regulating gene expression and intervening transcription. Recent studies have demonstrated that a series of patterns including protein modification,chromosomal reconstruction,regulation of target gene expression,transcription intervention,epigenetic modification,and natural antisense transcript are involved in this process. This article reviews recent research advances in this aspect with an attempt to better understand the role of LncRNA in tumorigenesis.

Advances in preoperative assessment of liver function.

BACKGROUND: Postoperative liver failure remains a life-threatening complication. Preoperative evaluation of liver function is essential in reducing the complications after hepatectomy. However, it is difficult to accurately evaluate liver function before surgery because of the limitations of the liver function tests available. Recent advances in liver function tests improved the ability to assess liver function. The present review was to analyze these methods and their advantages. DATA SOURCES: MEDLINE was searched using the terms of "liver function test", "liver function evaluation" and "galactosyl serum albumin". Relevant articles published in English and Chinese from 1961 to 2014 were reviewed. RESULTS: Although serological tests are used frequently in practice, they reflect the degree of total liver damage or function, not the remnant of liver function. Child-Pugh score and model for end-stage liver disease (MELD) score assess whole liver function, and are particularly useful in determining whether patients with hepatocellular carcinoma and cirrhosis are candidates for resection or transplantation, but cannot determine the safe extent or removal. The indocyanine green and other metabolic quantitative liver function tests can evaluate functional hepatocytes, making them more accurate in predicting liver function. Computed tomography (CT) volumetry can provide anatomic information on the remnant liver volume but not on functional volume. 99mTc-galactosyl serum albumin scintigraphy, combined with single photon emission computed tomography, CT and three-dimensional reconstruction, may be a better quantitative measure of liver function, especially of remnant liver function. CONCLUSIONS: Tests used to evaluate liver functional reserve and to predict surgical risk have limitations. 99mTc-galactosyl serum albumin scintigraphy, which can more accurately evaluate the whole and regional liver function, may be promising in predicting resection margins and risks of liver failure.