New evidence: Metformin unsuitable as routine adjuvant for breast cancer: a drug-target mendelian randomization analysis.

PURPOSE: The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. METHODS: Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. RESULTS: The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. CONCLUSION: The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.

Down-regulation of ALDOB during metabolic reprogramming mediates malignant behavior in hepatocellular carcinoma and insensitivity to postoperative adjuvant transarterial chemoembolization.

BACKGROUND: Postoperative transarterial chemoembolization (PA-TACE) is an effective adjuvant therapy for preventing early postoperative recurrence of hepatocellular carcinoma (HCC); however, many patients are insensitive to it. Therefore, the present study aimed to explore the in-depth reasons for PA-TACE resistance and provide a reliable basis for selecting patients who will benefit the most from PA-TACE. METHODS: The unique gene expression profiles of primary tumors from PA-TACE-sensitive or -insensitive patients were analyzed using microarray data. Combined differential expression analysis, gene set enrichment analysis (GSEA), and weighted correlation network analysis (WGCNA) were used to screen for potential drivers of PA-TACE insensitivity. The expression of ALDOB was silenced or overexpressed in hepatoma cell lines, and changes in glycolytic activity, cycle, apoptosis, and malignant biological phenotypes were observed under normoxia and hypoxia. Finally, an animal model was constructed to verify the effects of ALDOB dysregulation on the tumorigenic ability of HCC cells in vivo. RESULTS: The inhibition of ALDOB promoted the up-regulation of Ki67 expression, and glycolytic activity was significantly enhanced. Moreover, the proliferation, invasion, and migration capabilities were increased in HCC cells and even worse in hypoxia. This advantage of malignant behavior was also validated using in vivo models. CONCLUSION: Down-regulation of ALDOB may underlie the metabolic reprogramming observed in HCC by promoting the malignant behavior of HCC cells. Hypoxia and ALDOB down-regulation acted additively, which was closely related to PA-TACE insensitivity. The use of ALDOB and Ki67 as a combined marker has the potential to identify the 'PA-TACE beneficiary population'.

Clinical implications and biological features of a novel postoperative recurrent HCC classification: A multi-centre study.

BACKGROUND & AIMS: The multiplicity of hepatocellular carcinoma (HCC) recurrence patterns is the most important determinant of patients' postsurgical survival. A systematic HCC recurrence classification is needed to help prevent and treat postoperative HCC recurrence in the era of precision medicine. METHODS: A total of 1319 patients with recurrent HCC from four hospitals were enrolled and divided into a development cohort (n = 916), internal validation cohort (n = 225) and external validation cohort (n = 178). A comprehensive study of patients' clinicopathological factors and biological features was conducted. RESULTS: Four subtypes of recurrence were identified, which integrated recurrence features, survival, effects on systemic and liver function and potential therapeutics after recurrence: type I (solitary-intrahepatic oligorecurrence); type II (multi-intrahepatic oligorecurrence); type III (progression recurrence) and type IV (hyper-progression recurrence). Type III~IV recurrence indicated exceptionally poor prognosis. Subsequently, two nomogram models were established for type III~IV recurrence prediction, and both demonstrated excellent predictive performance and applicability of pre and postoperative strategy formulation. Multiple biological analyses revealed that HCC cases with type III~IV recurrence were characterized by enrichment in p53 mutations, CCND1 amplification, high proliferation/metastasis potential, inactive metabolism and immune exhaustion features. Over-expression of high mobility group protein 2 (HMGA2) enhanced the highly malignant behaviour of HCC through multiple molecular pathways, making it a potential prognostic predictor and therapeutic target. CONCLUSIONS: This 'recurrent HCC classification' has important potential value in identifying patients with surgical benefit, predicting postsurgical survival and guiding treatment strategies. Multidimensional biological insights also increased knowledge of factors associated with HCC recurrence.

Outcomes of postoperative adjuvant transarterial chemoembolization for hepatocellular carcinoma according to the Ki67 index.

Aim: To assess whether Ki67 is related to the efficacy of postoperative adjuvant transarterial chemoembolization (PA-TACE) in hepatocellular carcinoma patients at high risk of postsurgical recurrence. Methods: A total of 716 patients undergoing surgical resection with or without PA-TACE were retrospectively enrolled. Immunohistochemistry was used to analyze Ki67 expression. Results: There was no significant difference in tumor-free survival between patients who underwent resection with or without chemoembolization. However, chemoembolization was associated with significantly higher tumor-free survival rates among patients with 'low' (<30%) or 'moderate' (30-59%) levels of Ki67. Patients highly expressing Ki67 displayed higher rates of overall recurrence, earlier recurrence, multiple intrahepatic recurrence and extrahepatic metastasis. Conclusion: In patients with relatively high Ki67 levels, PA-TACE does not appear to improve outcomes.

Postoperative adjuvant transarterial chemoembolization (PA-TACE), as an adjuvant treatment to surgery, is widely recommended in patients with high-risk factors for recurrence. Nevertheless, some studies challenge whether it actually improves prognosis, thus the influence of PA-TACE on prognosis remains controversial. The present research indicated that the ability of PA-TACE to help inhibit hepatocellular carcinoma recurrence is conditionally restrictive, and it appears to be beneficial only in those patients with a low or moderate Ki67 index (<60%). For patients with high Ki67 expression, compared with PA-TACE, 'adjuvant immunotherapy' may be a potential alternative option. This finding suggests a valuable reference to identify the best beneficiaries of PA-TACE for individualized treatment.

The potential mechanism of miR-130b on promotion of the invasion and metastasis of hepatocellular carcinoma by inhibiting Notch-Dll1.

Introduction: This study aimed to elucidate the regulatory role and molecular regulation mechanism of miR-130b gene in the process of invasion and metastasis of hepatocarcinoma, and provide a theoretical basis for seeking of effective prevention and treatment of new targets for hepatocellular carcinoma.Materials and methods: The expression level of miR-130b gene in hepatocarcinoma tissues was determined by qRT-PCR. The biological function and mechanism of miR-130b gene were verified by cell and animal models, and the target gene was verified by double luciferase assay.Results: In the liver cancer tissues of patients with metastasis, the expression level of miR-130b gene was increased, and the difference was significantly significant (p < 0.05). Evaluation of independent risk factors for overall survival showed significant difference (p < 0.01). Up-regulation of miR-130b in MHCC97L- subpopulation cells significantly enhanced the invasion and migration ability, and the difference was statistically significant (p < 0.05). The invasion and migration ability of MHCC97H + subpopulation cells with increased expression of miR-130b was significantly decreased, and the difference was notably significant (p < 0.05). When the expression of miR-130b in MHCC97H + subpopulation cells was inhibited, the expressions of Notch-Dll1 and SOX2, Nanog and E2F3 proteins in transplanted tumor tissues were significantly higher than those in other groups (p < 0.05). When miR-130b in MHCC97L- subpopulation cells was up-regulated, the expressions of Notch-Dll1 and Bcl-2, CCND1, Nanog and MET proteins in transplanted tumor tissues were significantly increased than those in other groups (p < 0.05). The prediction results of bioinformatics data suggest that the target gene of miR-130b may be Notch-Dll1 gene. The experiment of luciferase reporter gene confirmed that miR-130b gene can be inhibited and contains fluorescent reporter gene with complementary binding site, lost activity.Conclusion: The miR-130b gene can inhibit the protein expression of Notch-Dll1, and it can promote the invasion and metastasis of liver cancer cells.

Combination of 5-fluorouracil and 2-morphilino-8-phenyl-4H-chromen-4-one may inhibit liver cancer stem cell activity.

This work aims to evaluate the impact of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) combined 5-fluorouracil (5-FU) for the activity of CD90+ liver cancer cells derived from the human liver cancer cell line MHCC97H. MHCC97H sphere-forming cells (MSFCs) were amplified in serum-free medium and CD90+ cells were isolated from bulk MSFCs using flow cytometry. The phenotype of these CD90+ cells which show liver cancer stem cells (LCSCs) behavior was validated in vitro and in a xenograft model in nude mice. MSFCs, CD90+ liver cancer cells (CD90+ LCCs), and parental MHCC97H cells were treated with no drug, LY294002 alone, 5-FU alone, or both drugs together and then compared in terms of stem cell-related gene expression, proliferation, and invasion. Stem cell phenotype increased with increasing proportion of CD90+ cells, in ascending order: parental MHCC97H cells, MSFCs, and CD90+ liver cancer cells. LY294002 reduced the expression of CD90, Nanog, SALL4, and SHP2 in a concentration-dependent manner in CD90+ LCCs and MSFCs, but not in parental cells. LY294002 blocked AKT phosphorylation via the PI3K/AKT signaling pathway and inhibited CD90+ LCCs proliferation and tumorigenicity in vitro and in vivo. CD90+ liver cancer cells can express liver cancer stem cell phenotype. LY294002 inhibits the proliferation and invasion of MHCC97H-derived CD90+ LCCs and sensitized CD90+ LCCs-derived tumors to 5-FU in the current study which may provide insight into the association between the LY294002 combined 5-FU and liver cancer stem cell (LCSCs).

Postoperative hepatitis B virus reactivation and surgery-induced immunosuppression in patients with hepatitis B-related hepatocellular carcinoma.

BACKGROUND: Hepatectomy in hepatocellular carcinoma (HCC) patients lead to postoperative hepatitis B virus (HBV) reactivation (PHR) as well as immunosuppression. METHODS: This prospective study involved 135 HBV-related HCC patients and 42 control hepatic hemangioma patients. RESULTS: Among HCC patients, 26 (19.3%) suffered PHR. Risk factors for PHR were HBV-cAg S1 positivity [hazard ratio (HR) = 404.82, P = 0.004], high preoperative total bilirubin level (HR = 186.38, P = 0.036), small preoperative proportions of CD3-CD16 + CD56 + cells (HR = 0.01, P = 0.014) and CD19 + B cells (HR = 0.02, P = 0.016), blood transfusion (HR = 157.03, P = 0.006) and high liver cirrhosis S score (HR = 270.45, P = 0.004). On postoperative day (POD) 3, PHR patients showed much greater immunosuppression than non-PHR patients based on proportions of T cells (CD3+, CD3 + CD4+, CD3 + CD8+), B cells (CD19+) and on levels of IgG, IgA antibodies, complement proteins C3, and C4. By POD 7, PHR patients had partially recovered but not as quickly as non-PHR patients: PHR patients still showed deficits in T cells (CD3+, CD3 + CD4+), CD3-CD16 + CD56+ cells and in levels of IgM, C3, C4, and C-reactive protein. CONCLUSION: PHR may be associated with resection-induced immunosuppression in patients with HBV-related HCC.

Systematic review comparing the safety and efficacy of conventional and drug-eluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma.

AIM: Conventional transarterial chemoembolization (cTACE) is widely used for treating patients with inoperable hepatocellular carcinoma (HCC). A variation on the technique based on drug-eluting beads (DEB-TACE) has recently entered the clinic, but trials of its safety and efficacy have given conflicting results. This systematic review aimed to gain a current, comprehensive picture of how DEB-TACE compares with cTACE. METHODS: MEDLINE, EMBASE, the Cochrane Library, the Chinese National Knowledge Infrastructure database and clinical trial registries were searched through June 2014. Risk ratios (RR), hazard ratios (HR) and 95% confidence intervals (CI) were calculated. RESULTS: The analysis included four randomized controlled trials, one uncontrolled prospective study and one prospective case-control study, altogether involving 652 patients. Overall survival benefit was similar between cTACE and DEB-TACE patients (HR = 1.07, 95% CI = 0.82-1.40, P = 0.875). However, DEB-TACE was associated with a significantly higher objective tumor response rate (RR = 1.14, 95% CI = 1.01-1.29, P = 0.03) and a slightly lower incidence of adverse events. CONCLUSION: Though the available evidence suggests that although DEB-TACE is associated with better tumor response and potentially fewer adverse events, it does not provide greater survival benefit than cTACE. These results need to be validated in high-quality trials with large sample size.

Investigation of the causal relationship between breast cancer and thyroid cancer: a set of two-sample bidirectional Mendelian randomization study.

PURPOSE: A potential association between breast (BC) and thyroid cancer (TC) has been observed. We investigated if the relationship between BC and TC is causal using bidirectional Mendelian randomization (MR) in Asian and European populations. METHODS: BC-linked single nucleotide polymorphisms (SNPs) were acquired from a genome-wide association study (GWAS) conducted by the Breast Cancer Association Consortium and Biobank Japan. The most recent TC GWAS data were obtained from the FinnGen Project and National Biobank of Korea. We assessed the potential causal relationship between BC and TC using various MR methods, including inverse-variance-weighting (IVW). Sensitivity, heterogeneity, and pleiotropic tests were performed to assess reliability. RESULTS: We found a bidirectional causal association between BC and TC within Europeans (IVW, TC on BC: odds ratio [OR] 1.090, 95% confidence interval [CI]: 1.012-1.173, P = 0.023; BC on TC: OR 1.265, 95% CI: 1.158-1.381, P < 0.001). A one-way causal relationship between BC susceptibility and TC risk was found in Asians (IVW BC on TC: OR 2.274, 95% CI: 2.089-2.475, P < 0.001). Subsequently, we identified a noteworthy bidirectional causal relationship between estrogen receptor (ER)-positive BC and TC (IVW, TC on ER-positive BC: OR 1.104, 95% CI: 1.001-1.212, P = 0.038; ER-positive BC on TC: OR 1.223, 95%CI: 1.072-1.395, P = 0.003), but not ER-negative BC and TC in Europeans. CONCLUSION: We revealed a reciprocal causal association between ER-positive BC and TC. These findings establish a theoretical framework for the simultaneous surveillance and treatment of BC and TC.

Prognostic factors and an innovative nomogram model for patients with hepatocellular carcinoma treated with postoperative adjuvant transarterial chemoembolization.

PURPOSE: The purpose of this study was to estimate the clinical efficacy and identify the best beneficiaries of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 749 HCC patients who underwent surgical resection (380 underwent PA-TACE, 369 had resection only) with a high risk of recurrence were reviewed retrospectively. Patients receiving PA-TACE were randomly split into development and validation cohorts. Univariate and multivariate analyses were performed in the development cohort. A novel model for PA-TACE-insensitivity prediction was built based on univariate and multivariate analysis and was multi-dimensionally validated in the validation set and all samples. RESULTS: After propensity score matching (PSM), in the early-recurrence group, no significant improvement in RFS was achieved with PA-TACE compared to radical hepatic resection alone. PA-TACE insensitive patients were considered as the PA-TACE non-benefit population and were associated with six clinicopathological factors: AFP, node number, tumor capsule, Ki-67 index, MVI, and complications in the development cohort. These factors were incorporated into a nomogram model, which reliably predicted PA-TACE insensitivity, with concordance indices of 0.874 and 0.897 for the development and validation cohort, respectively. In the overall sample, PA-TACE did not significantly improve patients' RFS and OS in the high-score group, while the low-score group had statistical significance. Recurrence pattern diversity was also found to be a factor leading to PA-TACE insensitivity. CONCLUSION: We constructed a new PA-TACE-insensitivity prediction model with potential clinical value. The good predictive performance and availability would allow this model to effectively screen PA-TACE beneficiaries.KEY MESSAGESThe independent influencing factors of PA-TACE insensitivity in patients who received PA-TACE were analyzed to construct a predictive model and its clinical application performance was verified with multi-dimensional methods.PA-TACE treatment should be avoided for patients with high scores according to this model, while it should be cautiously recommended for patients with low scores after multiple considerations.Compared with other related models, this model has obvious advantages in versatility and effectiveness. It can effectively screen the best benefit population of PA-TACE and provide a reliable reference for the selection of precise treatment plans for patients after radical resection of hepatocellular carcinoma.

Specific gut microbiome signature predicts hepatitis B virus-related hepatocellular carcinoma patients with microvascular invasion.

BACKGROUND: We aimed to assess differences in intestinal microflora between patients with operable hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) with microvascular invasion (MVI) and those without MVI. Additionally, we investigated the potential of the microbiome as a non-invasive biomarker for patients with MVI. METHODS: We analyzed the preoperative gut microbiomes (GMs) of two groups, the MVI (n = 46) and non-MVI (n = 56) groups, using 16S ribosomal RNA gene sequencing data. At the operational taxonomic unit level, we employed random forest models to predict MVI risk and validated the results in independent validation cohorts [MVI group (n = 17) and non-MVI group (n = 15)]. RESULTS: ß diversity analysis, utilizing weighted UniFrac distances, revealed a significant difference between the MVI and non-MVI groups, as indicated by non-metric multidimensional scaling and principal coordinate analysis. We also observed a significant correlation between the characteristic intestinal microbial communities at the genus level and their main functions. Nine optimal microbial markers were identified, with an area under the curve of 79.76% between 46 MVI and 56 non-MVI samples and 79.80% in the independent verification group. CONCLUSION: This pioneering analysis of the GM in patients with operable HBV-HCC with and without MVI opens new avenues for treating HBV-HCC with MVI. We successfully established a diagnostic model and independently verified microbial markers for patients with MVI. As preoperative targeted biomarkers, GM holds potential as a non-invasive tool for patients with HBV-HCC with MVI.

Gut microbiome dysbiosis in patients with hepatitis B virus-related hepatocellular carcinoma after extended hepatectomy liver failure.

Background: Hepatitis B virus-related hepatocellular carcinoma (B-HCC) negatively affects the gut microbiome. This study aimed to investigate the gut microbiome profiles and functions post-hepatectomy liver failure (PHLF) after extended hepatectomy (e-PHLF) to obtain valuable insights, identify potential diagnostic biomarkers, and assist in the treatment of this disease. Methods: B-HCC patients who underwent extended hepatectomy were consecutively recruited and divided into Group A (n=15) and Group B (n=15) based on the presence and absence of e-PHLF, respectively. The relationships between gut microbiota and extended hepatectomy liver failure were explored using 16S ribosomal RNA (16S rRNA) gene sequencing data. Results: Following extended hepatectomy, the α-diversity of Group A was significantly higher than that of Group B (Shannon P=0.034 or Simpson P=0.031), and the ß-diversity differed significantly between Groups A and B (P=0.004, R=0.100). At the genus level, 10 bacterial genera (Bacteroides, Pantoea, Methylobacterium-Methylorubrum, Inquilinus, Mycobacterium, Allisonella, Helicobacter, GCA-900066575, IS-44, and Faecalibacterium) were significantly enriched in Group A, whereas five genera (Papillibacter, Scardovia, Turicibacter, Catabacter, and Senegalimassilia) were significantly enriched in Group B. The highly abundant genera Bacteroides, Pantoea, Faecalibacterium, and Turicibacter participated in multiple amino acid metabolism pathways, organic acid metabolism pathways, pyrimidine metabolism pathways, palmitate biosynthesis, and stearate biosynthesis. Redundancy analysis showed that four environmental factors (total bilirubin, international normalized ratio, prealbumin, and albumin) were significantly correlated with intestinal microorganisms. The formation of interaction networks between different gut microbiomes revealed important correlations between the gut microbiome, and there was a significant correlation between the highly abundant gut microbiome and main functions. Conclusions: The gut microbiota characteristics in B-HCC patients after extended hepatectomy liver failure might allow for the use of non-invasive biomarkers for disease diagnosis and treatment.

Integrated omics analysis: the relationship between significantly increased Klebsiella post-hepatectomy and decreased hub-metabolite 3-methyl-2-oxobutanoic acid is associated with induced liver failure.

Background: This study sought to evaluate the association between intestinal Klebsiella and post-hepatectomy liver failure (PHLF) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (B-HCC), and identify the inner relationship. Methods: Patients with B-HCC were divided into Groups A and B based on the presence or absence of PHLF. 16S ribosomal ribonucleic acid surveys were used to identify gut microbiome alterations. PICRUST2 was used to examine the metagenomic data in PHLF patients. Fecal and serum samples were processed by chromatography-mass spectrometry based non-targeted metabonomics, then comprehensively analyzed to obtain hub metabolites. A Spearman correlation analysis was then conducted to find any associations between fecal differential metabolites and the relative abundance of differential microbes. Results: Hepatectomies were significantly associated with a gut microbial imbalance in B-HCC patients, and a significant elevation of Klebsiella abundance was observed in PHLF patients. Klebsiella appears to act on 13 amino acid-related pathways, especially significantly observed in branched-chain amino acid (BCAA) metabolic pathways. Additionally, Klebsiella was found to be highly correlated with 3-methyl-2-oxobutanoic acid shared by feces and serum in the BCAA metabolic pathway. Conclusions: Hepatectomy can lead to an imbalance of intestinal microflora in B-HCC patients. Due to its potential connections with 3-methyl-2-oxobutanoic acid in the BCAA pathway, significantly increased Klebsiella has the potential to be an evaluation indicator of PHLF in B-HCC patients. Moreover, 3-methyl-2-oxobutanoic acid has research value in PHLF-targeted treatments.

Operable hepatitis B virus-related hepatocellular carcinoma: gut microbiota profile of patients at different ages.

Background: Age was important prognostic factors for operable hepatocellular carcinoma patients. The aim of the present study was to assess the difference in gut microbiota in patients with operable hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) at different ages ; to investigate the features of the microbiota and its function associated with different ages; to provide a preliminary look at effects of the gut microbiota dimension on prognostic. Methods: From September 2020 to May 2021, patients with HBV-HCC were able to undergo liver resection and were recruited consecutively and divided into the younger age group (age <45 years) (Y.AG) (n=20), middle age group (age from 45 to 65 years) (M.AG) (n=13) 45-65 years, and older age group (age >65 years) (O.AG) (n=20). The relationships between gut microbiota and different ages were explored using 16S rRNA gene sequencing data. PICRUST2 was used to examine the metagenomic data in PHLF patients. Fisher's exact and Mann-Whitney U-test were used for the data analysis. Results: Pairwise comparison between the three groups showed that the α-diversity of Y.AG was significantly higher than that of O.AG (ACE Index, P=0.017; chao1 Index, P=0.031; observed_species Index, P=0.011; and goods_coverage Index, P=0.041). The ß-diversity in the 3 groups differed significantly (stress =0.100), while the composition (ß-diversity) differed significantly between the Y.AG and the M.AG (stress =0.090), the M.AG and the O.AG (stress =0.095), and the Y.AG and the O.AG (stress =0.099). At the genus level, 7 bacterial genera were significantly enriched in the O.AG compared with the Y.AG, of which Streptococcus, Blautia, Erysipelotrichaceae_UCG-003, and Fusicatenibacter represented the major variances in O.AG microbiomes. Eleven genera were significantly increased in the O.AG, of which Prevotella, Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Ruminiclostridium, and Phascolarctobacterium represented the major variances in the O.AG. The Y.AG and the O.AG were predicted by PICRUSt2 analysis, which found 72 pathways related to differential gut microbiome at the genus level. Redundancy analysis showed that 7 environmental factors were significantly correlated with intestinal microorganisms, especially in the Y.AG compared with the O.AG. Conclusions: Analysis of gut microbiota characteristics in patients of different ages could ultimately contribute to the development of novel avenues for the treatment of HCC at different ages.

Preoperative Ratio of Neutrophils to Lymphocytes Predicts Postresection Survival in Selected Patients With Early or Intermediate Stage Hepatocellular Carcinoma.

This study aims to clarify the prognostic value of the preoperative neutrophil-to-lymphocyte ratio (NLR) for patients with hepatocellular carcinoma (HCC) after potentially curative hepatic resection (HR). The prognostic value of the NLR for HCC patients has not been definitely reviewed by large studies, especially for those with different Barcelona Clinic Liver Cancer (BCLC) stages.A consecutive sample of 963 HCC patients who underwent potentially curative HR was classified as having low or high NLR using a cut-off value of 2.81. Overall survival (OS) and tumor recurrence were compared for patients with low or high NLR across the total population, as well as in subgroups of patients in BCLC stages 0/A, B, or C. Clinicopathological parameters, including NLR, were evaluated to identify risk factors of OS and tumor recurrence after potentially curative hepatic resection. Multivariate analyses were performed using the Cox proportional hazards model or subdistribution hazard regression model.Multivariate analyses showed that NLR (>2.81), tumor number (>3), incomplete capsule, serum albumin (≤35 g/L), alanine transaminase activity (>40 U/L), and macrovascular invasion were risk factors for low OS, whereas NLR (>2.81), tumor size (>5 cm), alpha fetal protein concentration (>400 ng/L), and macrovascular invasion were risk factors for low tumor recurrence. NLR > 2.81 was significantly associated with poor OS and tumor recurrence in the total patient population (both P < 0.001), as well as in the subgroups of patients in BCLC stages 0/A or B (all P < 0.05). Moreover, those with high NLR were associated with low OS (P = 0.027), and also with slightly higher tumor recurrence than those with low NLR for the subgroups in BCLC stage B (P = 0.058). Neither association, however, was observed among patients with BCLC stage C disease.NLR may be an independent predictor of low OS and tumor recurrence after potentially curative HR in HCC patients in BCLC stages 0/A or B.

Comprehensive treatments for hepatocellular carcinoma with tumor thrombus in major portal vein.

AIM: To evaluate the efficacy of transcatheter arterial chemoembolisation (TACE) compared with surgical intervention and sorafenib for treatment of hepatocellular carcinoma (HCC) in patients with tumor thrombus extending to the main portal vein. METHODS: From 2009 to 2013, a total of 418 HCC patients with tumor thrombus extending to the main portal vein were enrolled in this study and divided into four groups. These groups underwent different treatments as follows: TACE (n = 307), surgical intervention (n = 54), sorafenib (n = 15) and palliative treatment (n = 42). Overall survival rates were determined by Kaplan-Meier method, and differences between the groups were identified through log-rank analysis. Cox's proportional hazard model was used to identify the risk factors for survival. RESULTS: The mean survival periods for patients in the TACE, surgical intervention, sorafenib and palliative treatment groups were 10.39, 4.13, 5.54 and 2.82 mo, respectively. For the TACE group, the 3-, 6-, 12- and 24-mo survival rates were 94.1%, 85.9%, 51.5% and 0.0%, respectively. The corresponding rates were 60.3%, 22.2%, 0.0% and 0.0% for the surgical intervention group and 50.9%, 29.5%, 0.0% and 0.0% for the sorafenib group. Evidently, the results in the TACE group were significantly higher than those in the other groups (P < 0.0001). Furthermore, no significant difference among survival rates was observed between TACE with/without sorafenib (10.22 mo vs 10.52 mo, P = 0.615). No significant difference in survival rates was also found among the surgical intervention, sorafenib and palliative treatment groups (P > 0.05). These values significantly increased after TACE with/without sorafenib compared with other treatments (P < 0.05). CONCLUSION: For HCC patients with tumor thrombus extending to the main portal vein, TACE can yield a higher survival rate than surgical intervention or sorafenib treatment.

Comparison of long-term survival of patients with solitary large hepatocellular carcinoma of BCLC stage A after liver resection or transarterial chemoembolization: a propensity score analysis.

BACKGROUND: The aim of this study was to compare the long-term outcome of patients with a solitary large (> 5 cm) hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage A who received liver resection (LR) or transarterial chemoembolization (TACE). METHODS: Our study examined 128 patients treated by LR and 90 treated by TACE. To reduce bias in patient selection, we conducted propensity score analysis in the present study and 54 pairs of patients after propensity score matching were generated, their long-term survival was compared using the Kaplan-Meier method. Independent predictors of survival were identified by multivariate analysis. RESULTS: Long-term survival was significantly better for the LR group by log-rank test (P < 0.001). In multivariate analysis, tumor size, serum ALT level and TACE independently predicted survival. Despite similar baseline characteristics after propensity score matching, LR group still had significantly better survival (1 year, 68.5 vs. 55.0%; 3 years, 47.6 vs. 21.2%; 5 years, 41.3 vs. 18.5%; P = 0.007) than TACE group. The LR and TACE groups had comparable 30- and 90-day post-treatment mortality. Multivariate analysis showed that serum ALT level, serum AFP level and TACE independently predicted survival by multivariate analysis after propensity score matching. CONCLUSION: Our propensity-score-matched study suggested that LR provided significantly better long-term survival than TACE for a solitary large HCC of the BCLC stage A, regardless of tumor size.