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Yong-Fa Zhang,1,2,* Liang-He Lu,3,4,* Chong Zhong,5,* Min-Shan Chen,3,4 Rong-Ping Guo,3,4 Lu Wang1,2 1Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Hepatobiliary Oncology of Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 4State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 5Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lu WangDepartment of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of ChinaTel/Fax +8620-64175590Email cms024mm@163.comRong-Ping GuoDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of ChinaTel/Fax +8620-87342266Email guorp@sysucc.org.cnPurpose: This study aimed to evaluate the prognostic value of the lymphocyte-C-reactive protein ratio (LCR) score, a novel inflammation-based score based on lymphocytes and C-reactive protein, in hepatocellular carcinoma (HCC) patients treated with curative intent.Patients and Methods: A total of 1158 HCC patients undergoing surgical resection or radiofrequency ablation with curative intent were recruited from 3 different centres and divided into a primary cohort (n=716) and a validation cohort (n=442). Univariate and multivariate analyses were performed to identify variables associated with overall survival (OS). The discriminatory accuracy of seven inflammation-based scores was compared by using the concordance index (C-index).Results: The LCR score differentiated HCC patients into two groups with distinct prognoses (1-, 3-, and 5-year OS rates and median OS: 92.9%, 81.9%, 73.3% and 99.2 months and 79.8%, 56.6%, 49.7% and 69.1 months; P< 0.001). Multivariate analysis showed that LCR score, AFP, ALBI score, tumour size, and TNM stage were independently associated with OS. When patients were stratified according to different disease states, the LCR score could still differentiate HCC patients into two groups with distinct prognoses (all P< 0.005). The LCR score demonstrated a markedly superior C-index of 0.621 compared with the other inflammation-based scores (0.503– 0.590). These findings were supported by the validation cohort.Conclusion: The preoperative LCR score is a novel, stable, and clinically feasible prognostic marker for patients with HCC, independent of liver function, tumour characteristics, and treatment allocation and is superior to other inflammation-based scores in terms of its prognostic ability.Keywords: hepatocellular carcinoma, resection, radiofrequency ablation, prognosis, LCR, inflammation-based score

Vessels that encapsulate tumor clusters (VETC) is a novel described vascular pattern different from microvascular invasion (MVI) for patients with hepatocellular carcinoma (HCC). The prognostic value of integrating VETC and MVI (VETC-MVI model) in HCC patients after resection remains unclear. From January 2013 to December 2016, 498 HCC patients who underwent curative resection were enrolled from five academic centers and stratified into different groups according to their VETC and MVI statuses. Overall survival (OS), disease-free survival (DFS), and early and late recurrence rates were evaluated. The patients were divided into four subgroups: VETC−/MVI− (n = 277, 55.6%), VETC−/MVI+ (n = 110, 22.1%), VETC+/MVI− (n = 53, 10.6%), and VETC+/MVI+ (n = 58, 11.6%). The patients in the VETC+/MVI− and VETC−/MVI+ groups had similar long-term outcomes (OS: p = 0.402; DFS: p = 0.990), VETC−/MVI− patients showed the best prognosis, and VETC+/MVI+ patients had the worst prognosis. Further analysis revealed that the VETC-MVI model showed a similar stratification ability for early recurrence but not for late recurrence. The area under the curve values for early recurrence was 0.70, 0.63 and 0.64 for the VETC-MVI model, VETC, and MVI, respectively (VETC-MVI model vs VETC: p

Yong-Fa Zhang,1,2,* Ming Shi,3,* Liang-He Lu,3 Lu Wang,1,2 Rong-Ping Guo3 1Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 3The Department of Hepatobiliary Oncology of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lu WangDepartment of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of ChinaTel/Fax +8620-64175590Email cms024mm@163.comRong-Ping GuoDepartment of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of ChinaTel/Fax +8620-87342266Email guorp@sysucc.org.cnPurpose: It remains unknown which staging system is best in predicting the survival of patients with intermediate stage hepatocellular carcinoma (HCC). We aimed to investigate the performance of nine currently used HCC staging systems.Patients and Methods: Between 2005 and 2014, a large cohort of 880 consecutive patients with intermediate stage HCC and sufficient data for utilization in all staging systems were enrolled. The prognostic performance of each staging system was compared. Independent prognostic variables were also identified.Results: Multivariate analysis revealed that alkaline phosphatase (ALP), aspartate aminotransferase (AST), etiology, alpha-fetoprotein (AFP), Child-Pugh stage, tumor size, and tumor number were independent prognostic factors for survival. In the entire cohort, the Hong Kong Liver Cancer (HKLC) staging system was associated with the highest Harrell’s c-index and lowest Akaike information criterion value in comparison with other systems. In subgroup analysis according to treatment strategy, the HKLC staging system remained the best prognostic model in patients undergoing hepatic resection (n=222) or transarterial chemoembolization (n=658). Additional prognostic factors of AST, ALP, etiology, and AFP improved the discriminatory ability of HKLC.Conclusion: The HKLC staging system is stable and consistently the best prognostic model in all patients with intermediate-stage HCC and in patients subjected to different treatment strategies. Selecting an optimal staging system is helpful in improving the design of future clinical trials in intermediate stage HCC.Keywords: hepatocellular carcinoma, intermediate-stage, staging system, prognosis, overall survival, hepatic resection, transarterial chemoembolization

The lymphocyte-C-reactive protein ratio (LCR) is a recently described inflammation-based score, and it remains unclear which is the optimal inflammation-based score among patients with hepatocellular carcinoma (HCC) who underwent transarterial chemoembolization (TACE). A large cohort of HCC patients (n=1625) who underwent TACE as the initial treatment were enrolled in the present study. Inflammation-based scores, including the Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), high-sensitivity modified Glasgow Prognostic Score (Hs-mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), and LCR, were all related to the survival of HCC patients, but only the LCR score was a significant and independent predictor in multivariate analysis (hazard ratio: 1.45; 95% confidence interval: 1.27-1.65; P

RNA-binding motif protein 25 (RBM25) is a poorly characterized RNA-binding protein that is involved in several biological processes and regulates the proliferation and metastasis of tumor cells. The regulatory role of RBM25 in hepatocellular carcinoma (HCC) is unknown. Here, RBM25 expression and outcomes in HCC patients were evaluated using The Cancer Genome Atlas database. RBM25 was overexpressed in HCC patients compared with the healthy group. The high expression of RBM25 in tumor tissues was significantly related to poor overall survival (P, Graphical abstract

To explore the protective mechanism of L-arginine against T-2 toxin-induced apoptosis in mouse Leydig cells, we investigated whether L-arginine can prevent T-2 toxin-induced apoptosis in mouse Leydig cells and explored the underlying mechanisms. Leydig cells were isolated and cultured with control, T-2 toxin (10 nM), L-arginine (0.25, 0.5, and 1.0 mM), and T-2 toxin (10 nM T-2 toxin) + L-arginine (0.25, 0.5, or 1.0 mM) for 24 h. Cells and supernatants were harvested to examine proliferation of the cells, the apoptosis rate, activity of caspase-3 and mitochondria, and the gene expression levels of Bcl-2, Bax, PARP, and caspase-3. Results showed that proliferation and mitochondrial activity of Leydig cells were inhibited by administration of T-2 toxin. Bcl-2 gene expression levels was decreased, while the gene expression levels of Bax and PARP were increased, which could trigger mitochondria-mediated apoptosis, activate downstream caspase-3, and then increased caspase-3 at both activity and gene expression levels. The expression of the Bcl-2 gene was upregulated and the expression of Bax, caspase-3, and PARP gene were downregulated when L-arginine was added to the cultured cells. The results of this study showed that L-arginine could block T-2 toxin-induced apoptosis in mouse Leydig cells by regulating specific intracellular death-related pathways.

The role of surgery in breast cancer liver metastases (BCLM) remains elusive, and current application is limited. Our aim is to investigate whether hepatic resection (HR) of BCLM improves survival compared with non-hepatic resection (NHR) treatment.Three hundred and eighty-four patients with BCLM from 2008 to 2018 were divided into two groups. Propensity score matching (PSM) analysis was used to compare the clinical outcomes.After PSM the mean overall survival (OS) and the 1, 3, and 5-year OS rates in HR group were 61.8 months, 92.6%, 54.7% and 54.7%, respectively; while for NHR group these values were 38.6 months, 79.2%, 45.6% and 21.9%, respectively (p 0.007). Multivariate analysis indicated hormonal receptor status (p = 0.039) and hepatic resection (p = 0.032) were independent prognostic factors.Our study revealed that hepatectomy yields a survival benefit safely compared with medical treatments, especially for patients with positive hormonal receptors.

PURPOSE: The genomic alterations of intrahepatic cholangiocarcinoma (ICC) in the Chinese population have not been fully revealed. Molecular profiling may provide a reference for clinical management, especially targeted therapy. METHODS: A retrospective study was conducted in 122 ICC patients. All patients have been performed next-generation sequencing (NGS) assays that analyzed 417 cancer-associated genes. The genetic characteristics, clinical management and therapeutic responses were analyzed. RESULTS: The most commonly mutated genes were TP53 (34%), KRAS (25%) and ARID1A (17%). Targeted agents were used referring to molecular profiling, in combination with chemotherapy. Twenty-two patients with wild-type KRAS/NRAS/BRAF were treated with cetuximab. The disease control and response rates were 78% and 47%, respectively, which were higher than those achieved with chemotherapy alone (72% and 11%, P=0.16). Fifty-four patients underwent anti-VEGF treatment with bevacizumab. The disease control and response rates were 85% and 60%, respectively. Better therapeutic efficiency (P=0.001) and longer progression-free survival (PFS) were observed in the bevacizumab-treated group compared to chemotherapy alone group (15.4 and 6.7 months, respectively; P=0.04) . The PFS of ten patients who underwent hepatectomy after combined treatment with chemotherapy and bevacizumab was longer than that of 139 patients who underwent surgical treatment (28.9 vs 18.0 months, P=0.03). Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. CONCLUSIONS: This study provides an overview of genetic alterations in Chinese ICC patients and indicates the potential clinical implications for NGS-based personalized therapies.

Parecoxib plays an important role in inhibition of human cancer. However, the effect of parecoxib on esophageal squamous cell carcinoma (ESCC) is still not well known. The purpose of this study was to investigate the effect of parecoxib on ESCC and its underlying mechanism.RNA-sequence analysis was performed to identify functional alterations and mechanisms. Cell cycle, proliferation, invasion, and migration were assessed using flow cytometry, CCK-8 assay, colony formation, transwell, and wound healing assays. Extracellular matrix (ECM) degradation was detected by substrate gel zymography and 3D cell culture assay. Western blotting was used to detect parecoxib-dependent mechanisms involving cell cycle, proliferation, invasion, and migration. Tumor formation in vivo was detected by mouse assay.Functional experiments indicated that parecoxib induced ESCC cell cycle arrest in G2 phase, and inhibited cell proliferation, invasion, and migration in vitro. Western blotting revealed that parecoxib downregulated the phosphorylation levels of AKT and PDK1, as well as the expression of the mutant p53, cyclin B1, and CDK1, while upregulating p21waf1. Parecoxib inhibited matrix metalloproteinase-2 (MMP2) secretion and invadopodia formation, which were related to ECM degradation. Furthermore, we found that parecoxib suppressed ESCC growth in heterotopic tumor models.Parecoxib inhibits ESCC progression, including cell cycle, proliferation, invasion, and migration, via the PDK1-AKT signaling pathway.

Background As a class of the opioid receptors, the kappa opioid receptor (KOR) has been verified to be a potential biomarker and therapeutic target for human malignant tumors. However, a thorough understanding of whether KOR affects progression of esophageal squamous cell carcinoma (ESCC) is still lacking. This study focused on exploring the effect of knocking down KOR in ESCC and its underlying mechanism. Methods Bioinformatics analysis was used to compare the different expression level of OPRK1 (KOR gene) in tumor and adjacent normal tissues, and predict the relationship between KOR expression and overall survival. RNA-sequence analysis was performed to detect the altered functions and mechanisms after down regulating KOR. The in vitro and in vivo assays were used to detect the effects of down-regulated KOR on cell proliferation, migration and invasion. Substrate gel zymography and 3D cell culture assays were used to find the effect of KOR knockdown on the degradation of extracellular matrix (ECM), and immunefluorescence was performed to detect the altered cytoskeleton. Western blotting and immunohistochemistry were used to explore the underlying mechanism pathway. Results Bioinformatics analysis revealed that the expression of OPRK1 was lower in tumor tissue than that in adjacent normal tissues, and lowered expression of KOR was associated with poorer overall survival. The in vitro assays demonstrated that down-regulation of KOR enhanced ESCC proliferation, metastasis and invasion. Western blotting revealed that down-regulation of KOR could activate PDK1-AKT signaling pathway, which actively regulated the cancer progression. Down-regulation of KOR enhanced the formation of invadopodia, secretion of matrix metalloproteinase-2 (MMP2) and rearrangement of cytoskeleton, which were positively related with the invasion of ESCC. KOR knockdown enhanced the tumor invasion and elevated the AKT phosphorylation in nude mice. The AKT kinase inhibition could reverse the effect of down-regulation of KOR. Conclusion KOR might act as a tumor suppressor in ESCC and down-regulation of KOR could enhance the ESCC tumor phenotype. Graphical abstract

The objective of this study was to explore the protective mechanism of Vitamin E (VE) and selenium (Se) against T-2 toxin-induced oxidative damage of bovine Leydig cells. Leydig cells were isolated, cultured and divided into five treatment groups such as: control, T-2, Se + T-2, VE + T-2 and VE + Se + T-2. After treatment for 24 h, the cells and supernatants were harvested to examine the cell viability, the activities and mRNA expression of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT), the content of malondialdehyde (MDA) and DNA damage. Results showed that T-2 toxin exposure significantly reduced the cell viability, increased the MDA level, reduced GSH-Px, SOD and CAT activities and increased DNA damage (P 0.05). Meanwhile, T-2 toxin was attributed to the down-regulation of the mRNA expression of GSH-Px, SOD and CAT (P 0.05). However, VE and Se reduced T-2 toxin-induced oxidative damage and tended to maintain normal levels (P 0.05). Furthermore, VE and Se substantially up-regulated the activities and mRNA expressions of the GSH-Px, SOD and CAT. In conclusion, VE and Se, due to its anti-oxidative ability, could ameliorate T-2 toxin-induced cytotoxicities by regulating oxidative stress in bovine Leydig cells.

The testosterone levels decreased by T-2 toxin in mouse Leydig cells were reported previously. It is not known, however, whether l -arginine improves the situation and what's the mechanism. Leydig cells were isolated and cultured with control, 10 nM T-2 toxin, 0.25, 0.5 or 1.0 mM l -arginine, and 10 nM T-2 toxin supplemented with 0.25, 0.5 or 1.0 mM l -arginine for 24 h. Cells and supernatants were collected to detect the mRNA expression and activities of P450scc (cholesterol side-chain cleavage enzyme), 3β-HSD-1 (3β-hydroxysteroid dehydrogenase/isomerase-1) and StAR (steroidogenic acute regulatory protein). Results revealed that l -arginine increased the testosterone levels declined by T-2 toxin and up-regulated the activities and mRNA expression of P450scc, 3β-HSD-1 and StAR down-regulated by T-2 toxin in Leydig cells. Therefore, we concluded that l -arginine ameliorated the testosterone levels decreased by T-2 Toxin via regulating the mRNA expression and activities of P450scc, 3β-HSD-1 and StAR in mouse Leydig cells.

l-arginine is beneficial for reproductive health; however, whether l-arginine may confer protection against T-2 toxin-induced reproductive impairment is not known. To address this, we used a mice model treated with T-2 toxin to investigate protective effects of l-arginine. Experimentally, we pre-treated mice with designed diet of l-arginine supplementation prior to the T-2 toxin-injected intraperitoneally exposure and then assessed semen quality, fertility and serum testosterone concentration. The results showed that l-arginine improved semen quality (e.g., live spermatozoa, abnormal spermatozoa, and acrosomal integrity of spermatozoa), testicular and cauda epididymal sperm counts, efficiency of sperm production and serum testosterone concentration in mice treated with T-2 toxin. In addition, l-arginine could increase pregnancy rate and decrease fetal resorption rate in females mated with T-2 toxin exposed males. Collectively, these findings suggest that dietary l-arginine supplementation may protect male reproductive impairments in mice treated with T-2 toxin through improving semen quality and serum testosterone levels.

To observe the clinical curative effect on attention deficit hyperactivity disorder (ADHD) and explore the relevant mechanism of acupuncture in treatment.A total of 100 ADHD children were randomized into an observation group (50 cases, 2 cases dropped off) and a control group (50 cases, 1 case dropped off). In the control group, the routine psychological intervention was used. In the observation group, on the base of the treatment as the control group, acupuncture was applied to Taichong (LR 3), Neiguan (PC 6), Shenmen (HT 7), Sanyinjiao (SP 6), Baihui (GV 20), Sishencong (EX-HN 1), etc., once daily, for 3 months. The Cambridge neuropsychological tests automated battery (CANTAB) was adopted to evaluate attention and response inhibition in two groups before and after treatment. Digi-Lite color transcranial Doppler was used to measure cerebral arterial blood velocity. The therapeutic effect was compared between the two groups.Regarding evaluation of attention, the mean delay time in the observation group after treatment was shorter than that before treatment and that in the control group separately (Acupuncture combined with psychological intervention may improve attention and response inhibition in ADHD children, which is possibly related to the regulation of cerebral blood flow.

To explore the protective mechanism of L-arginine against T-2 toxin-induced apoptosis in mouse Leydig cells, we investigated whether L-arginine can prevent T-2 toxin-induced apoptosis in mouse Leydig cells and explored the underlying mechanisms. Leydig cells were isolated and cultured with control, T-2 toxin (10 nM), L-arginine (0.25, 0.5, and 1.0 mM), and T-2 toxin (10 nM T-2 toxin) + L-arginine (0.25, 0.5, or 1.0 mM) for 24 h. Cells and supernatants were harvested to examine proliferation of the cells, the apoptosis rate, activity of caspase-3 and mitochondria, and the gene expression levels of Bcl-2, Bax, PARP, and caspase-3. Results showed that proliferation and mitochondrial activity of Leydig cells were inhibited by administration of T-2 toxin. Bcl-2 gene expression levels was decreased, while the gene expression levels of Bax and PARP were increased, which could trigger mitochondria-mediated apoptosis, activate downstream caspase-3, and then increased caspase-3 at both activity and gene expression levels. The expression of the Bcl-2 gene was upregulated and the expression of Bax, caspase-3, and PARP gene were downregulated when L-arginine was added to the cultured cells. The results of this study showed that L-arginine could block T-2 toxin-induced apoptosis in mouse Leydig cells by regulating specific intracellular death-related pathways.

OBJECTIVE: To study the association between maternal Th1/Th2 immune level at different pregnancy stages and cow's milk protein allergy (CMPA) in infants. METHODS: The healthy women with a singleton pregnancy, as well as their offspring, who attended Yidu Central Hospital of Weifang and Qingzhou Traditional Chinese Medicine Hospital from July 2016 to December 2018 were enrolled. The maternal levels of interleukin-2 (IL-2), interferon gamma (IFN-γ), interleukin-4 (IL-4), and interleukin-10 (IL-10) at the second and third trimesters of pregnancy were measured. A CMPA questionnaire survey was conducted within one year after birth. Food avoidance and cow's milk oral challenge tests were performed in infants suspected of CMPA. The 48 infants who met the diagnostic criteria for CMPA were included in the observation group, and the remaining 977 normal infants were included in the control group. A univariate analysis was performed on the infants with CMPA. A Poisson regression analysis was used to determine the association between maternal Th1/Th2 immune factors at different pregnancy stages and CMPA. RESULTS: The detection rate of CMPA was 4.68%. The clinical manifestations included the symptoms of the digestive system, skin, and respiratory system and other symptoms. The univariate analysis showed that compared with the control group, the observation group had significantly higher incidence rates of maternal food allergy and maternal history of allergic diseases (P < 0.05) and a significantly lower breastfeeding rate (P < 0.05). The observation group had significantly lower maternal levels of IL-2 (second and third trimesters) and IFN-γ (third trimester) than the control group (P < 0.05). Maternal low IFN-γ at the third trimester and maternal low IL-2 at the second and third trimesters were significantly associated with CMPA in infants (P < 0.05). After correction of the factors of breastfeeding, maternal food allergy, and maternal history of allergic diseases, it was found that maternal low IL-2 and IFN-γ at the third trimester were still significantly associated with CMPA in infants (P < 0.05). CONCLUSIONS: The maternal decrease in Th1 level at the third trimester of pregnancy may lead to the change in fetal immunity and thus increase the risk of CMPA in offspring.

BACKGROUND & AIMS The lymphocyte-C-reactive protein ratio (LCR) is a novel inflammatory-based score, based solely on the lymphocyte and C-reactive protein. We aimed to clarify the prognostic value of the LCR score in intrahepatic cholangiocarcinoma (ICC) patients after resection. METHODS We compared the prognostic accuracy of the LCR score with other inflammatory-based scores in this large, multicentre cohort study. The independent variables associated with overall survival (OS) were explored in both the primary (n = 228) and validation cohorts (n = 135). Harrell's concordance index (C-index) was used to compare the predictive ability of all the assessed inflammatory-based scores. RESULTS The LCR score was differentiated two groups of ICC patients with distinct prognoses (1-, 3-, and 5-year OS rates: 94.4%, 66.3%, and 59.3%; and 66.6%, 45.6%, and 32.7%, respectively) (P

Background and aims The optimal treatment strategy for recurrent hepatocellular carcinoma (HCC) remains unclear. Therefore, we aimed to compare the outcomes of repeat hepatic resection (RHR) and radiofrequency ablation (RFA) for recurrent HCC. Method From December 2004 to December 2015, 138 patients who underwent RHR and 194 patients who underwent RFA were enrolled. Propensity score matching (PSM) was performed to establish 1:1 RHR‐RFA group matching. Clinical outcomes were compared before and after matching. Results Before matching, the 1‐, 3‐, and 5‐year postrecurrence survival (PRS) rates were 91.8%, 82.0%, and 72.9% for the RHR group (n = 138) and 94.4%, 75.4%, and 61.7% for the RFA group (n = 194), respectively (P = .380). After matching, the PRS rates at 1, 3, and 5 years were 90.5%, 81.5%, and 71.8% for the RHR group (n = 120) and 91.0%, 61.0%, and 41.7% for the RFA group (n = 120), respectively (P = .002). In the subgroup analysis, the PRS rates for the RHR group were better than those for the RFA group for patients who relapsed within 2 years (P = .004) or patients with primary tumor burden beyond the Milan criteria (P = .004). Multivariate analysis showed that treatment allocation was identified as an independent prognostic factor for PRS. Conclusion Compared with RFA, RHR provided a survival advantage for recurrent HCC, especially for patients who relapsed within 2 years and those with primary tumor burden beyond the Milan criteria., Compared with RFA, repeat hepatic resection provided a survival advantage for recurrent HCC, especially for patients relapsed within 2 years and patients with primary tumor burden beyond Milan criteria.

The clinical significance of the sodium-potassium ATPase regulator FXYD domain-containing ion transport regulator 3 (FXYD3) has been demonstrated in a number of types of cancer. However, the role of this protein in human hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, 217 HCC tissue samples were analyzed to evaluate the expression and prognostic significance of FXYD3 in HCC. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA expression of FXYD3 in 80 primary HCC specimens and paired non-cancerous liver tissue samples, while western blotting was used to analyze the protein expression level of FXYD3 in another 24 pairs. These analyses demonstrated that the expression level of FXYD3 was significantly increasedb at the mRNA and protein levels in HCC tumor tissues compared with adjacent non-cancerous tissues. Immunohistochemical analysis of 137 paraffin-embedded HCC tissue samples indicated that the expression of FXYD3 was associated with HCC clinicopathological characteristics. Kaplan-Meier analysis demonstrated that patients with high FXYD3 protein expression (n=60) experienced significantly poorer overall survival time compared with patients with low FXYD3 protein expression (n=77) (P

The study aimed to investigate the prognostic role of the preoperative carbohydrate antigen 19-9 (CA19-9) level in alpha-fetoprotein (AFP)-negative (AFP 25 ng/ml) hepatocellular carcinoma (HCC) patients.From December 2004 to December 2013, 750 patients diagnosed with AFP-negative HCC following curative resection were enrolled. Both univariate and multivariate analyses were performed to clarify the prognostic factors for overall survival (OS) and disease-free survival (DFS).The optimal cutoff point for preoperative CA19-9 was 32.6 U/ml, and the value of the area under the curve was 0.640. The 1-, 3-, and 5-year OS rates were 88.4, 72.2, and 57.0%, respectively, for the CA19-9 32.6 U/ml group and 97.0, 83.3, and 79.9%, respectively, for the CA19-9 ≤ 32.6 U/ml group (P 0.001). The 1-, 3-, and 5-year DFS rates were 71.8, 47.7, and 34.8%, respectively, for the CA19-9 32.6 U/ml group and 80.8, 63.6, and 55.5%, respectively, for the CA19-9 ≤ 32.6 U/ml group (P 0.001). The multivariate analysis showed that CA19-9 32.6 U/ml was one of the most significant unfavorable predictors of OS and DFS (P 0.001 for both).Preoperative CA19-9 32.6 U/ml is a predictor of dismal prognosis and can be employed as a prognostic marker for patient selection in AFP-negative HCC management.

To explore the toxic effect of T-2 toxin on mouse Leydig cells and its underlying molecular mechanisms, we isolated Leydig cells from mature mice, set-up Leydig cells culture, treated cells with T-2 toxin, evaluated cell proliferation, detected the caspase-3 activity, mitochondrial activity and apoptosis rate, and measured the mRNA levels of Bcl-2, Bax, PARP and caspase-3. T-2 toxin inhibited cell proliferation at concentrations higher than 10−9 M or time more than 12 h, T-2 toxin also decreased Bcl-2 expression at the mRNA levels and mitochondrial activity at concentrations higher than 10−9 M. While, T-2 toxin increased the mRNA expressions of Bax and PARP at concentrations higher than 10−8 M and 10−9 M, respectively, triggered mitochondria-mediated apoptosis, activated downstream caspase-3, and then increased caspase-3 at the activity and mRNA levels at concentrations higher than 10−9 M. These data showed that T-2 toxin appears to activate specific intracellular death-related pathways leading to...

To explore the toxic mechanism of T-2 toxin on Leydig cells of mice, we would investigate the toxicity and oxidative stress induced by T-2 toxin in the cells. Leydig cells were isolated and cultured with control or T-2 toxin (10

The liver function reserve in Child-Pugh (C-P) grade A hepatocellular carcinoma (HCC) patients varies widely, and the value of platelet-albumin-bilirubin (PALBI) grade in predicting posthepatectomy liver failure (PHLF) grade B/C and overall survival (OS) remains unknown.From Dec 2004 to Dec 2013, 2038 C-P grade A HCC patients after resection were enrolled. Univariate and multivariate analyses were performed to clarify the risk factors for PHLF grade B/C and OS.The PALBI grade had higher area under the curve values than albumin-bilirubin (ALBI) and C-P grade in predicting PHLF grade B/C (0.693, 0.683, 0.529 in the entire cohort; 0.677, 0.646, 0.516 in patients who underwent major resection). PALBI grade differentiated C-P grade A patients into three groups with distinct prognoses (P 0.001), whereas ALBI grade differentiated C-P grade A patients into two groups (P 0.001). Furthermore, PALBI grade identified three groups with clearly different prognoses in ALBI grade 1 patients (P = 0.032). Multivariate analyses showed that PALBI grade was one of the independent and significant prognostic factors of PHLF grade B/C and OS.PALBI grade offers a simple, objective and discriminatory method for risk stratification of PHLF grade B/C and OS in C-P grade A HCC patients following resection.

Background: The benefits of anatomical resection (AR) and non-anatomical resection (NAR) on hepatocellular carcinoma (HCC) patients with microscope vascular invasion (MVI) remain unknown. We aimed to investigate the prognostic outcomes of AR and NAR for HCC patients with MVI. Study Design: A total of 362 consecutive HCC patients diagnosed with MVI after hepatic resection between February 2005 and December 2013 were included in this study. The patient outcomes were compared, and a 1:2 propensity score matching (PSM) analysis was applied to eliminate selection bias. Results: Before PSM, compared to the NAR group, the AR group contained more patients that exceeded the Milan criteria, with larger, unilobar tumors and higher AST levels. After PSM, 100 patients were classified into the propensity-matched AR group (PS-AR), while 170 were classified into the propensity-matched NAR group (PS-NAR). Baseline data, including liver function and tumor burden measurements, were similar in the matched groups. The respective 1-, 3- and 5-year overall survival (OS) rates were 78.9%, 56.9%, and 51.5% in the PS-AR group and 76.2%, 53.0%, and 42.4% in the PS-NAR group (P = 0.301). The 1-, 3- and 5-year disease-free survival (DFS) rates were 51.1%, 44.7% and 42.0% in the PS-AR group and 44.9%, 34.3% and 26.4% in the PS-NAR group, respectively (P = 0.039). Multivariate analysis identified AR (P=0.025) as an independent favorable prognostic factor for DFS in HCC patients with MVI. Conclusions: Anatomical resection was superior to non-anatomical resection for improving DFS in hepatocellular carcinoma patients with microscope vascular invasion.

Background: The subgroups of patients with intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) who would truly benefit from hepatic resection (HR) are unknown. An objective point score was established to guide the selection of these patients for HR. Methods: In all, 255 consecutive patients with intermediate-stage HCC treated with HR were evaluated retrospectively and included in this study (the training cohort). The variables on overall survival (OS, log-rank test) were investigated and a point score (the NSP score) was developed by using a Cox-regression model and validated in an independent external cohort from another institution (n=169). Results: The NSP score differentiated two groups of patients (⩽1, >1 point) with distinct prognoses (median OS, 61.3 vs 19.3 months; P

Yong-Fa Zhang,1–3,* Wei Wei,1–3,* Jia-Hong Wang,1–3,* Li Xu,1–3 Pei-En Jian,1–3 Cheng-Zuo Xiao,4 Xiao-Ping Zhong,1–3 Ming Shi,1–3 Rong-Ping Guo1–3 1Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 2State Key Laboratory of Oncology in South China, 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, 4Department of General Surgery, Shenzhen Shajing Affiliated Hospital of Guangzhou Medical University, Shenzhen, People’s Republic of China *These authors contributed equally tothis work Objective: To compare the treatment outcomes of sorafenib plus transarterial chemoembolization (TACE) vs TACE alone in patients with hepatocellular carcinoma (HCC) and hepatic vein tumor thrombus (HVTT).Methods: Twenty patients who were initially diagnosed with HCC and HVTT and received TACE combined with sorafenib during February 2009 to October 2013 were included in the study. To minimize selection bias, these patients were compared with 60 case-matched controls selected from a pool of 81 patients (in a 1:3 ratio) who received TACE alone during the same period. The primary end point was overall survival (OS). The secondary end points were time to progression, disease control rate, and adverse events.Results: After a median follow-up period of 12.5months (range, 1.03–44.23months), the OS of the combined group was found to be significantly higher compared with the monotherapy group (14.9 vs 6.1months, P=0.010). The time to progression was found to be significantly longer in the combined group (4.9 vs 2.4months, P=0.016). Univariate and multivariate analyses revealed that the treatment allocation was an independent predictor of OS.Conclusion: Sorafenib plus TACE was well tolerated and was more effective in treating patients with advanced HCC and HVTT. Future trials with prospective larger samples are required to validate these results. Keywords: hepatocellular carcinoma, hepatic vein tumor thrombus, prognosis, adverse events

// Yong-Fa Zhang 1,2,3,* , Yong Le 1,2,3,* Wei Wei 1,2,3,* , Ru-Hai Zou 1,3,4,* , Jia-Hong Wang 1,2,3 , Han-Yue OuYang 1,2,3 , Cheng-Zuo Xiao 5 , Xiao-Ping Zhong 1,2,3 , Ming Shi 1,2,3 and Rong-Ping Guo 1,2,3 1 Department of Hepatobiliary Oncology of Sun Yat-sen University Cancer Center, Guangzhou, P.R. China 2 State Key Laboratory of Oncology in South China, Guangzhou, P.R. China 3 Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China 4 Department of Ultrasonography of Sun Yat-sen University Cancer Center, Guangzhou, P.R. China 5 Department of General surgery, Shenzhen Shajing Affiliated Hospital of Guangzhou Medical University, Shenzhen, P.R. China * These authors have contributed equally to this work Correspondence to: Rong-Ping Guo, email: // Ming Shi, email: // Keywords : hepatocellular carcinoma, portal vein tumor thrombus, hepatic resection, en bloc resection, peeling off resection Received : October 22, 2015 Accepted : March 29, 2016 Published : April 07, 2016 Abstract Objectives: The optimal surgical resection method for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) that maximizes both safety and long-term outcome has not yet been determined. The aim of this study was to compare the clinical outcomes following peeling off versus en bloc resection for PVTT. Methods: From 2005 to 2012, 252 patients with HCC and type I/II PVTT who underwent hepatic resection were divided into two groups according to whether they received en bloc resection ( n = 113) or peeling off resection ( n = 139). The clinical outcomes were compared before and after propensity score matching. Results: The propensity model matched 113 patients with en bloc resection for further analyses. After matching, overall survival (OS) and disease-free survival (DFS) rates were significantly increased in the en bloc group compared with the peeling off group ( p = 0.011 and p = 0.015). A multivariate analysis indicated that en bloc resection independently improved both OS and DFS (HR = 1.471, 95% CI: 1.071-2.018, p = 0.017 and HR = 1.415, 95% CI: 1.068-1.874, P =0.016). The adverse events were not significantly different between the two groups. However, the peeling off group showed a significantly increased recurrence rate of vascular invasion compared with the en bloc group (23.9% vs . 9.7%, p = 0.005). Similar results were also demonstrated prior to the matched analysis. Conclusions: An en bloc resection is safe and confers a survival advantage compared with a peeling off resection in HCC patients with PVTT; thus, en bloc resection should be recommended as a standard treatment for these patients when possible.

Although many staging classifications have been proposed for hepatocellular carcinoma (HCC), determining a patient's prognosis in clinical practice is a challenge due to the molecular diversity of HCC. We investigated the relationship between MEP1A, a candidate oncogene, and clinical outcomes of HCC patients; furthermore, we explored the role of MEP1A in HCC. In this report, it was demonstrated by quantitative real-time polymerase chain reaction that MEP1A messenger RNA levels were significantly elevated in HCC tumor tissues compared with matched adjacent nonneoplastic tissues and nonmalignant liver disease tissues. Immunohistochemical analyses of tissue samples from two independent groups of 394 HCC patients showed that positive expression of MEP1A in tumor cells was an independent and significant risk factor affecting survival after curative resection in both cohort 1 (hazard ratio = 2.05, 95% confidence interval 1.427-2.946; P < 0.001) and cohort 2 (hazard ratio = 1.89, 95% confidence interval 1.260-2.833; P = 0.002). Analysis of Barcelona Clinic Liver Cancer stage 0-A subgroup further showed that patients with positive MEP1A expression in tumor cells had poorer surgical prognoses than those with negative MEP1A expression in tumor cells (cohort 1 P = 0.001, cohort 2 P < 0.001). Both in vitro and in vivo assays showed that MEP1A promoted HCC cell proliferation, migration, and invasion. Further analyses found that MEP1A played an important role in regulating cytoskeletal events and induced epithelial-mesenchymal transition in HCC cells. Conclusion: MEP1A is a novel prognostic predictor in HCC and plays an important role in the development and progression of HCC. (Hepatology 2016;63:1227-1239)

Background The optimal therapeutic strategy in UICC stage T3 hepatocellular carcinoma (HCC) patients that maximizes both safety and long-term outcome has not yet been determined. Our aim was to compare clinical outcomes following hepatic resection (HR) versus transarterial chemoembolization (TACE) for stage T3 HCC. Methods From 2005 to 2013, 1179 patients with T3 HCC who underwent HR or TACE were divided into two groups, HR group (n = 280) or TACE group (n = 899). The clinical outcomes were compared before and after propensity score matching. Results The propensity model matched 244 patients in each group for further analyses. After matching, medium overall survival (OS), 1, 3, and 5-year OS rates in TACE group were 11.8 (95%CI, 9.9–13.7) months, 49.6, 16.5, and 8.4%, respectively; which in HR group were 17.8 (95% CI, 14.8–20.8) months, 63.1, 33.3, and 26.4%, respectively; (log rank = 19.908, P

Hepatocellular carcinoma (HCC) is among the most fatal types of cancer worldwide due to its high rates of recurrence and metastasis. The molecular processes involved in HCC progression require further investigation to identify biomarkers for use in diagnosis and treatment. In the present study, the significance and prognostic value of matrix metallopeptidase 12 (MMP12) expression in human HCC was investigated. MMP12 mRNA expression was investigated using reverse transcription-quantitative polymerase chain reaction analysis of 42 pairs of tumor and non-tumor liver tissues obtained from patients with HCC following surgical treatment. Immunohistochemical staining was used to detect MMP12 and forkhead box P3 (FOXP3) expression in 158 paraffin-embedded HCC tissues. The prognostic value of MMP12 expression was determined using Kaplan-Meier analysis and the Cox proportional hazards model. MMP12 mRNA levels were significantly higher in liver tumor tissues compared with matched non-tumor liver tissues. MMP12 expression and FOXP3+ regulatory T cell (Treg) infiltration was positively correlated (r=0.302; P

With the common urea split application (CU) as the control, a field experiment was conducted to examine the effects of loss-controlled urea by split application (LCUS) and loss-controlled urea by basal application (LCUB) on ammonia volatilization (NH通过田间试验,以普通尿素分次施用处理(CU)为对照,研究了控失尿素分次施用(LCUS)和一次施用(LCUB)对水稻田土壤氨挥发特征、水稻氮素营养状况、稻谷产量及氮肥利用效率的影响. 结果表明: 普通尿素分次施用、控失尿素分次施用和控失尿素一次施用条件下,生育期氨挥发总量占总施氮量的比例分别为15.8%、13.4%和19.7%. 与普通尿素分次施用处理相比,控失尿素分次施用处理可降低土壤氨挥发损失量4.4 kg N·hm

To explore the protective mechanism of l-arginine against T-2 toxin-induced oxidative damage in mouse Leydig cells, Leydig cells were isolated and cultured with control, T-2 toxin (10 nM), l-arginine (0.25, 0.5, and 1.0 mM), and T-2 toxin (10 nM T-2 toxin) with l-arginine (0.25, 0.5, or 1.0 mM) for 24 hours. Cells and supernatants were harvested to examine cell viability, activities, and messenger RNA (mRNA) expression of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), malondialdehyde (MDA) content, and DNA damage. Results showed that T-2 toxin significantly reduced cell viability, improved MDA content and DNA damage, and decreased activities and mRNA expression of GSH-Px, SOD, and CAT. However, l-arginine reduced T-2 toxin-induced oxidative damage and tended to maintain normal levels. Furthermore, l-arginine upregulated mRNA expressions of GSH-Px, SOD, and CAT. Collectively, l-arginine, due to its antioxidative ability, could ameliorate T-2 toxin-induced cytotoxicities in mouse Leydig cells by regulating oxidative stress.

Introduction: EGF, latrophilin, and seven transmembrane domain containing 1 (ELTD1) constitutes an orphan G-protein-coupled receptor (GPCR) of the adhesion family. High expression of ELTD1 is correlated with favorable prognosis of hepatocellular carcinoma (HCC). After silencing ELTD1 expression, however, tumor invasiveness is drastically reduced. The underlying mechanism of this apparent contradictory phenomenon is unknown. Because adhesion GPCRs couple extracellular adhesion to intracellular signaling, as a member of this family, ELTD1 function may be related to its tumor microenvironment. We therefore investigated the interaction between ELTD1 and the HCC tumor microenvironment. Methods: ELTD1 expression was assessed by immunohistochemical analyses of tissue samples from two independent groups of 333 patients with HCC. Correlations between the ELTD1 expression and the clinicopathological values were examined. We also constructed ELTD1 overexpression and knockdown HCC cell lines and conducted a series of in vivo and in vitro ELTD1 functional assays. We further collected carcinoma associated fibroblast (CAF) culture supernatants to culture HCC cell lines and repeat the respective functional assays in comparison with the control group. Results: Clinicopathologic correlations and in vivo models indicated ELTD1 as a tumor suppressor gene, whereas in vitro experiments suggested that ELTD1 could promote malignancy in HCC cell lines. Immunohistochemical staining of the generated ELTD1 overexpression xenograft tumors demonstrated that the CAF markers vimentin and α-SMA were highly expressed compared to the control group. This suggests that ELTD1 expression is correlated to CAF distribution. In addition, culturing with CAF supernatants inhibited HCC cell proliferation and invasion rates, confirming the correlation between CAF and ELTD1. Conclusion: The results of this study indicated that ELTD1 regulation of HCC progression is CAF-dependent, suggesting that ELTD1 function is regulated by its tumor microenvironment. Further investigation is required to determine the underlying mechanisms.

To evaluate the outcomes of preoperative transarterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) with portal vein invasion. From February 2006 to July 2011, 320 patients initially diagnosed with resectable HCC and portal vein invasion were prospectively non-randomized into two arms. In the immediate resection arm (Arm 1, n = 205) patients received immediate surgical resection. 115 patients were included in the preoperative TACE arm (Arm 2), and eventually 85 patients underwent TACE followed by surgical resection. The 1-, 3- and 5-year overall survival rates were 48.3 %, 18.7 % and 13.9 % for Arm 1 and 61.2 %, 31.7 % and 25.3 % for Arm 2 (P = 0.001), respectively. In the subgroup analysis of types I and II portal vein tumour thrombus (PVTT), the preoperative TACE arm demonstrated significantly better survival rates than the immediate resection arm (P I = 0.001, P II = 0.036). However, no significant difference was found for patients with type III PVTT (P III = 0.684). No significant difference was found between the two arms in terms of complications and mortality. Preoperative TACE seems to confer a survival benefit for resectable HCC with PVTT, especially for types I and II PVTT, and preoperative TACE should therefore be recommended as a routine procedure. • Preoperative TACE improves the clinical outcomes for patients with PVTT • Preoperative TACE could significantly improve the rate of en bloc thrombectomy • Preoperative TACE does not increase the related adverse events

The present study aimed to identify the risk factors influencing the survival of patients with hepatocellular carcinoma (HCC) affected by portal vein tumor thrombus (PVTT), following hepatic resection, and to establish a prognostic model. Between March 2001 and May 2008, 234 cases of HCC with PVTT that underwent hepatic resection were randomly divided into experimental or validation groups. The association between the clinicopathological factors and disease-free survival (DFS) and overall survival (OS) was analyzed, and the significant factors involved were used to establish a prognostic model, which was then validated. Tumor rupture, number of tumors and macroscopic vascular invasion were observed to be independent risk factors of DFS and OS. In the prognostic model, the DFS and OS of low-, medium- and high-risk patients in the experimental group were observed to be significantly different, compared to those in the validation group. In conclusion, the present study established a prognostic model for patients with HCC affected by PVTT following hepatectomy, and demonstrated that the model may be used to guide the treatment of these patients and predict their prognosis.

Objective To compare the outcomes of hepatic resection and transcatheter arterial chemoembolization for resectable hepatocellular carcinoma with hepatic vein tumor thrombus. Methods From January 2006 to November 2013, 28 patients initially diagnosed with resectable hepatocellular carcinoma combined with hepatic vein tumor thrombus received hepatic resection. These patients were compared with 56 case-matched controls (1:2 ratio) selected from a pool of 91 patients who received transcatheter arterial chemoembolization as an initial treatment during the same period. Clinical characteristics, adverse events, overall survival and survival-related factors were analyzed. Results The 1-, 2- and 3-year overall survival rates were 66.5, 37.4 and 28.5% for the hepatic resection group and 32.3, 18.7 and 15.6% for the transcatheter arterial chemoembolization group (P = 0.015), respectively. No significant difference was found between the two groups in terms of complications and mortality. Multivariate analyses revealed combined portal vein tumor thrombosis (HR = 2.116; 95% CI: 1.26-3.57; P = 0.005) and treatment allocation (hepatic resection = 2.289; 95% CI, 1.30-4.02; P = 0.004) as risk factors for overall survival. Conclusions Hepatic resection provides a good prognosis for hepatocellular carcinoma patients with hepatic vein tumor thrombus compared with patients undergoing transcatheter arterial chemoembolization, and the most important factor related to survival was co-existence with portal vein invasion.

Sorafenib is recommended for the first-line treatment of advanced hepatocellular carcinoma (HCC). However, the median progression-free survival (PFS) of patients with HCC and major portal vein tumor thrombosis treated with sorafenib monotherapy is no more than 3 months. A prospective single-arm phase II study was conducted to determine whether adding hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin to sorafenib could improve on these results. Thirty five patients were treated with sorafenib 400 mg orally twice a day, oxaliplatin 85 mg/m2 HAI on day 1, leucovorin 400 mg/m2 HAI on days 1, and 5-fluorouracil 2800 mg/m2 on days 1 and 2, repeated every 21 days. The primary end point was the 3-month PFS rate. The 3-, 6-, and 12-month PFS rates were 82.9, 51.4, and 22.9%, respectively. The median PFS and overall survival was 6.7 and 13.2 months, respectively. The objective response rate was 40%, and the disease control rate was 77.1% by RECIST criteria. Five (14.3%) patients achieved conversion to complete resection after the study treatment, and one of them experienced a pathological complete response. Treatment-related deaths did not occur. Grade 3–4 toxicities consisted of increases in aspartate aminotransferase (31.4%), hand-foot syndrome (17.1%), thrombocytopenia (14.3%), and neutropenia (8.6%). The combination treatment met the pre-specified end point of a 3-month progression free survival rate exceeding 65% and was clinical tolerable. The merits of this approach need to be established with a phase III trial. Clinical trial number http://ClinicalTrials.gov (No. NCT02981498).

Hepatocellular carcinoma (HCC) is among the most fatal types of cancer worldwide due to its high rates of recurrence and metastasis. The molecular processes involved in HCC progression require further investigation to identify biomarkers for use in diagnosis and treatment. In the present study, the significance and prognostic value of matrix metallopeptidase 12 (MMP12) expression in human HCC was investigated. MMP12 mRNA expression was investigated using reverse transcription-quantitative polymerase chain reaction analysis of 42 pairs of tumor and non-tumor liver tissues obtained from patients with HCC following surgical treatment. Immunohistochemical staining was used to detect MMP12 and forkhead box P3 (FOXP3) expression in 158 paraffin-embedded HCC tissues. The prognostic value of MMP12 expression was determined using Kaplan-Meier analysis and the Cox proportional hazards model. MMP12 mRNA levels were significantly higher in liver tumor tissues compared with matched non-tumor liver tissues. MMP12 expression and FOXP3+ regulatory T cell (Treg) infiltration was positively correlated (r=0.302; P

Our previous miRNA profiling study indicated that microRNA-34c-3p (miR-34c-3p) was overexpressed and associated with survival in HCC. This study is aimed to confirm its clinical significance and explore the function and underlying mechanism of miR-34c-3p in HCC. We first evaluated miR-34c-3p expression and its relationship with prognosis in HCC patients. We then established stable HCC cell lines with miR-34c-3p overexpression and knockdown by the lentiviral packaging systems and performed the functional assays in vitro and in vivo, respectively. We next identified the target of miR-34c-3p by using microRNA target databases and dual-luciferase assay. Finally, the correlation between the expression of miR-34c-3p and the target gene was analyzed by immunohistochemistry and qRT-PCR in HCC tissues and hepatoma xenografts. Overexpressed miR-34c-3p was confirmed in HCC tissues and significantly associated with poor survival of HCC patients. miR-34c-3p expression was also recognized as an independent risk factor for DFS and OS in multivariate analysis. Ectopic expression of miR-34c-3p significantly promotes the proliferation, colony formation, invasion and cell cycle regression of HCC cell lines. Knockdown of miR-34c-3p remarkably blocked hepatoma growth in the xenograft model. miRNA target databases and luciferase reporter assay showed that NCKAP1 was a direct target of miR-34c-3p in HCC cells and the high expression of NCKAP1 in HCC tissues is significantly correlated with low expression of miR-34c-3p and associated with a favorable prognosis of HCC patients. The current study demonstrates that miR-34c-3p functions as a tumor promoter by targeting NCKAP1 that is associated with prognosis in HCC. miR-34c-3p and NCKAP1 may be new potential molecular targets for HCC therapy.

Background & aims The discontinuation rules of transarterial chemoembolization (TACE) for patients who were assessed as progressive disease (PD) but stage progression-free (SP-free: still belongs to Barcelona Clinic Liver Cancer B) after TACE are unclear. We aimed to evaluate the impact of the PD-pattern on the survival of these patients retreated with TACE. Methods In total, 115 consecutive patients who were assessed as PD but SP-free after TACE and then underwent at least one subsequent TACE session were included. Sixty patients were assessed as PD with target lesion progression (TP), and 55 patients were assessed as PD with target lesion non-progression (TNP). Survival and treatment-related adverse events were compared between the two groups. Additional external validation was performed using a data set (n = 103) from another institution. Results Patients with TNP had significantly longer median post-progression survival (PPS) than those with TP (21.0 vs. 11.9 months, P = 0.004). After TACE retreatment, the incidence of liver dysfunction was significantly higher for patients with TP than for patients with TNP (45% vs. 20%, P = 0.031). In the multivariate analysis, the target lesion response was one of the most significant prognostic factors for PPS (HR = 2.01; 95% confidence interval: 1.23-3.27; P = 0.005). The findings were supported by an independent external cohort. Conclusions Compared to patients with TNP, patients with TP might exhibit no improvement in survival and even present damaged liver function after retreatment with TACE. Target lesion response is useful as a clinical decision for repeated TACE in these patients.

Background The optimal strategy for adjuvant therapy after curative resection for hepatocellular carcinoma (HCC) patients with solitary tumor and microvascular invasion (MVI) is controversial. This trial evaluated the efficacy and safety of adjuvant transcatheter arterial chemoembolization (TACE) after hepatectomy versus hepatectomy alone in HCC patients with a solitary tumor ≥ 5 cm and MVI. Methods In this randomized, open-labeled, phase III trial, HCC patients with a solitary tumor ≥ 5 cm and MVI were randomly assigned (1:1) to receive either 1–2 cycles of adjuvant TACE after hepatectomy (Hepatectomy-TACE) or hepatectomy alone (Hepatectomy Alone). The primary endpoint was disease-free survival (DFS); the secondary endpoints included overall survival (OS) and adverse events. Results Between June 1, 2009, and December 31, 2012, 250 patients were enrolled and randomly assigned to the Hepatectomy-TACE group (n = 125) or the Hepatectomy Alone group (n = 125). Clinicopathological characteristics were balanced between the two groups. The median follow-up time from randomization was 37.5 months [interquartile range 18.3–48.2 months]. The median DFS was significantly longer in the Hepatectomy-TACE group than in the Hepatectomy Alone group [17.45 months (95% confidence interval [CI] 11.99–29.14) vs. 9.27 months (95% CI 6.05–13.70), hazard ratio [HR] = 0.70 (95% CI 0.52–0.95), P = 0.020], respectively. The median OS was also significantly longer in the Hepatectomy-TACE group than in the Hepatectomy Alone group [44.29 months (95% CI 25.99–62.58) vs. 22.37 months (95% CI 10.84–33.91), HR = 0.68 (95% CI 0.48–0.97), P = 0.029]. Treatment-related adverse events were more frequently observed in the Hepatectomy-TACE group, although these were generally mild and manageable. The most common grade 3 or 4 adverse events in both groups were neutropenia and liver dysfunction. Conclusion Hepatectomy followed by adjuvant TACE is an appropriate option after radical resection in HCC patients with solitary tumor ≥ 5 cm and MVI, with acceptable toxicity.

Purpose To compare the stability of stable and unstable water-in-oil emulsions and the efficacy and safety of these emulsions in a single-center, prospective double-blind trial of transarterial chemoembolization for hepatocellular carcinoma (HCC). Materials and Methods A total of 812 patients with inoperable HCC were randomized (stable emulsion, n = 402; unstable emulsion, n = 410). The 2 emulsions were prepared by using the same protocol except that different solvents were used for chemotherapy agents, including epirubicin, lobaplatin, and mitomycin C. The solvent in the stable emulsion arm was contrast medium and distilled water, and the solvent in the unstable emulsion arm was distilled water. The primary endpoint was overall survival (OS), and secondary endpoints were time to progression (TTP), tumor response, adverse events (AEs), and plasma epirubicin concentrations. Results In vitro, stable emulsions did not occur until 1 day, and unstable emulsions, with a lower peak plasma concentration (P = .001) in vivo, exhibited rapid separation of the oil and aqueous phases after 10 minutes. Median OS times in the stable and unstable emulsion arms were 17.7 and 19.2 months, respectively (P = .81). No differences were found in TTP, tumor response, and AEs except for myelosuppression (anemia, 3.5% vs 7.6%; thrombocytopenia, 11.5% vs 17.7%), which was significantly more severe and frequent in the unstable emulsion arm (P = .013). Conclusions Chemoembolization is equally effective with the use of stable and unstable emulsions, but the use of a stable emulsion has the advantage of less myelosuppression and a favorable pharmacokinetic profile.