PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer.

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.

S100A9 Derived from Chemoembolization-Induced Hypoxia Governs Mitochondrial Function in Hepatocellular Carcinoma Progression.

Transarterial chemoembolization (TACE) is the major treatment for advanced hepatocellular carcinoma (HCC), but it may cause hypoxic environment, leading to rapid progression after treatment. Here, using high-throughput sequencing on different models, S100 calcium binding protein A9 (S100A9) is identified as a key oncogene involved in post-TACE progression. Depletion or pharmacologic inhibition of S100A9 significantly dampens the growth and metastatic ability of HCC. Mechanistically, TACE induces S100A9 via hypoxia-inducible factor 1α (HIF1A)-mediated pathway. S100A9 acts as a scaffold recruiting ubiquitin specific peptidase 10 and phosphoglycerate mutase family member 5 (PGAM5) to form a tripolymer, causing the deubiquitination and stabilization of PGAM5, leading to mitochondrial fission and reactive oxygen species production, thereby promoting the growth and metastasis of HCC. Higher S100A9 level in HCC tissue or in serum predicts a worse outcome for HCC patients. Collectively, this study identifies S100A9 as a key driver for post-TACE HCC progression. Targeting S100A9 may be a promising therapeutic strategy for HCC patients.

Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma.

BACKGROUND: Elafin is a serine protease inhibitor critical for host defence. We previously reported that Elafin was associated with the recurrence of early-stage hepatocellular carcinoma (HCC) after surgery. However, the exact role of Elafin in HCC remains obscure. METHODS: HCC tissue microarrays were used to investigate the correlation between Elafin expression and the prognosis of HCC patients. In vitro migration, invasion and wound healing assays and in vivo lung metastasis models were used to determine the role of Elafin in HCC metastasis. Mass spectrometry, co-immunoprecipitation, western blotting, and immunofluorescence staining assays were performed to uncover the mechanism of Elafin in HCC. Dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the transcriptional regulation of Elafin. RESULTS: Elafin expression was frequently increased in HCC tissues compared to normal tissues, and high Elafin expression in HCC tissues was correlated with aggressive tumour phenotypes and a poor prognosis in HCC patients. Elafin dramatically enhanced the metastasis of HCC cells both in vitro and in vivo by interacting with EGFR and activating EGFR/AKT signalling. Moreover, Elafin attenuated the suppressive effects of erlotinib on HCC metastasis. Besides, Elafin was transcriptionally regulated by Sp1 in HCC cells. Clinically, Elafin expression was positively correlated with Sp1, Vimentin, and EGFR signalling in both our HCC tissue microarrays and TCGA database analysis. CONCLUSIONS: Upregulation of Elafin by Sp1 enhanced HCC metastasis via EGFR/AKT pathway, and overexpression of Elafin attenuated the anti-metastatic effects of erlotinib, suggesting a valuable prognostic biomarker and therapeutic target for HCC.

Surgical Resection versus Re-Ablation for Intrahepatic Recurrent Hepatocellular Carcinoma after Initial Ablation Therapy.

BACKGROUND AND AIMS: Whether surgical resection or repeated ablation should be recommended for intrahepatic recurrent hepatocellular carcinoma (HCC) conforming to the Milan criteria after initial ablation remains unclear. In this study, we compared the outcomes of patients who underwent surgical resection with those who underwent re-ablation for recurrent HCC after initial curative-intent ablation. METHODS: The data of 28 and 98 patients who underwent surgical resection and re-ablation, respectively, for recurrent HCC after initial ablation between January 2003 and 2017 were analyzed using propensity score matching. RESULTS: Before matching, the 1-, 3-, and 5-year overall survival (OS) rates were 95.7, 83.0, and 74.4% for the ablation group, compared to 92.9, 89.1, and 70.9% for the resection group (p = 0.490). The corresponding disease-free survival (DFS) rates were 67.5, 40.1, and 25.6% for the ablation group and were 85.4, 59.9, and 53.3% for the resection group (p = 0.018). After matching, the 1-, 3-, and 5-year OS rates for the ablation and resection group were 95.2, 85.5 and 81.8% versus 96.0, 96.0, and 76.4%, respectively (p = 0.550). The 1-, 3-, and 5-year DFS rates were 58.0, 39.5, and 29.9% for the ablation group and were 95.8, 67.2, and 59.8% for the resection group (p = 0.004). Cox proportional hazards model identified surgical resection as the only significant prognostic factor for DFS but not for OS. CONCLUSION: For intrahepatic recurrent HCC patients after initial ablation, surgical resection could provide better DFS than re-ablation, while no difference in OS was observed between the 2 treatment groups.

Apatinib versus sorafenib in patients with advanced hepatocellular carcinoma: a preliminary study.

BACKGROUND: Apatinib, a selective inhibitor of vascular endothelial growth factor receptor 2 (VEGFR 2), has exhibited modest antitumor efficacy in hepatocellular carcinoma (HCC). We aimed to evaluate the effectiveness and tolerability of apatinib versus sorafenib in patients with advanced HCC. METHODS: All patients with advanced HCC who underwent sorafenib or apatinib between January 2016 to December 2017 were retrospectively reviewed. Seventy-two patients received apatinib (26 patients, 500 mg, daily) or sorafenib (46 patients, 400 mg, twice daily) until disease progression or intolerable toxicities. Primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rate (ORR) per modified response evaluation criteria in solid tumors (RECIST), disease control rate (DCR), and safety. RESULTS: The median follow-up was 13.2 (5.7-20.7) months. The 1-year OS for apatinib of 62.0% was comparable to that of sorafenib [64.2%, hazard ratio (HR), 1.15; 95% confidence interval (CI), 0.369-3.58]. The median PFS was 4.1 months in the apatinib group (95% CI, 3.2 to 7.4 months) and 3.6 months in the sorafenib group (95% CI, 2.7 to 5.9 months; HR, 1.03; 95% CI, 0.586 to 1.800; P=0.925). The apatinib group exhibited higher ORR (19.2% vs. 2.2%, P=0.012) but similar DCR (57.7% vs. 50%, P=0.530) compared with the sorafenib group. The most common any-grade adverse events in the apatinib and sorafenib groups were hand and foot syndrome (53.8% vs. 50%), hypertension (50% vs. 19.6%), diarrhea (34.6% vs. 28.3%), and elevated transaminase (57.7% vs. 63%). CONCLUSIONS: Compared with sorafenib, apatinib yielded comparable PFS and OS, and even better ORR, in patients with advanced HCC.

Dysregulated Sp1/miR-130b-3p/HOXA5 axis contributes to tumor angiogenesis and progression of hepatocellular carcinoma.

Angiogenesis, one of the hallmarks of cancer, is essential for both tumor growth and metastasis. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are largely unknown. Here, we report the role of HOXA5 in tumor angiogenesis of HCC. Methods: The expression of miR-130b-3p and HOXA5 was determined by qRT-PCR and immunohistochemistry, respectively. Capillary tube formation assay, chicken chorioallantoic membrane assay, and subcutaneous xenograft experiments were performed to investigate the role of miR-130-3p and HOXA5. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to evaluate the interaction between Sp1, miR-130b-3p and HOXA5. Results: miR-130b-3p was found up-regulated in HCC and correlated with a poor prognosis. miR-130b-3p promoted HCC angiogenesis both in vitro and in vivo. Mechanistically, HOXA5 was validated as a direct target of miR-130b-3p. Furthermore, we demonstrated that HOXA5 was down-regulated in HCC and its down-regulation was associated with larger tumor size, shorter overall survival, and higher recurrence probability. Moreover, HOXA5 was significantly associated with angiogenesis biomarkers such as CD31 and CD34. Functional studies revealed that the knockdown of HOXA5 also significantly promoted HCC angiogenesis both in vitro and in vivo. Knocking-down HOXA5 significantly provoked HCC cells to induce the capillary tube formation, migration and proliferation of endothelial cells. In xenograft animal models, we found that a decrease of HOXA5 effectively enhanced tumor growth and increased microvessel densities. We further demonstrated that miR-130b-3p could be directly transcriptionally regulated by Sp1. Conclusions: This study showed that a dysregulation in the Sp1/miR-130b-3p/HOXA5 axis contributed to HCC progression and angiogenesis, and that HOXA5 can be considered as a promising therapeutic target for treating HCC.

Transcatheter arterial chemoembolization alone or combined with ablation for recurrent intermediate-stage hepatocellular carcinoma: a propensity score matching study.

PURPOSE: The recurrence after curative hepatectomy is common. Limited data have investigated the effect of transcatheter arterial chemoembolization (TACE) combined with ablation in treating recurrent intermediate-stage hepatocellular carcinoma (HCC) after hepatectomy. We aim to compare the efficacy of TACE combined with ablation versus TACE alone in treating recurrent intermediate-stage HCC after hepatectomy. METHODS: A total of 183 patients with recurrent intermediate-stage HCC after hepatectomy were enrolled at Sun Yat-sen University Cancer Centre, including 111 patients who underwent TACE alone and 72 patients who underwent TACE combined with ablation (TACE-Ablation). Overall survival (OS) and progression-free survival (PFS) were compared by the log-rank test. Propensity score matching (PSM) was used to reduce the confounding bias. RESULTS: Before PSM, the 5-year OS rates were 43.3% vs. 27.9% (P = 0.001), and the 5-year PFS rates were 21.7% vs. 13.0% (P < 0.001) for TACE-Ablation and TACE-alone groups, respectively. After PSM, TACE-Ablation still resulted in better 5-year OS (41.6% vs. 30.2%, P = 0.028) and 5-year PFS rate (21.3% vs. 15.8%, P = 0.024) than that of TACE alone. Patients in TACE-Ablation group exhibited similar major complication rates to TACE-alone group but higher minor complication rates both before and after PSM. Cox regression analysis identified TACE-alone modality as an independently unfavourable predictor for OS and PFS (both P < 0.05). CONCLUSION: TACE combined with ablation is safe and superior to TACE alone in tumour control and prolonging overall survival in recurrent intermediate-stage HCC after hepatectomy.

Comparison of the prognostic value of inflammation-based scores in early recurrent hepatocellular carcinoma after hepatectomy.

BACKGROUND & AIMS: Inflammation-based prognostic scores, such as the Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), Prognostic Nutritional Index (PNI), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and systemic immune-inflammation index (SII), are correlated with the survival of hepatocellular carcinoma (HCC) patients, while remain unclear for recurrent HCC. This study aimed to compare the prognostic value of inflammation-based prognostic scores for post-recurrence survival (PRS) in patients with early recurrent HCC (ErHCC, within 2 years after hepatectomy). METHODS: A total of 580 patients with ErHCC were enrolled retrospectively. The association between the independent baseline and the time-dependent variables and PRS was evaluated by cox regression. The prediction accuracy of the inflammation-based prognostic scores was assessed by time-dependent receiver operating characteristic (ROC) and Harrell's concordance index (C-index) analyses. RESULTS: The GPS, mGPS, PI, PNI, NLR, PLR, LMR and SII were all related to the PRS of ErHCC patients, while only the SII (P < .001) remained an independent predictor for PRS in multivariate analysis (hazard ratio: 1.92, 95% confidence interval: 1.33-2.79). Both the C-index of the SII (0.65) and the areas under the ROC curves showed that the SII score was superior to the other inflammation-based prognostic scores for predicting the PRS of ErHCC patients. CONCLUSIONS: The SII is a useful prognostic indicator for PRS in patients with ErHCC after hepatectomy and is superior to the other inflammation-based prognostic scores in terms of prognostic ability.

KCNK levels are prognostic and diagnostic markers for hepatocellular carcinoma.

Two-pore-domain (KCNK, K2P) K+ channels are transmembrane protein complexes that control the flow of ions across biofilms, which underlie many essential cellular functions. Because KCNK family members are known to contribute to tumorigenesis in various types of cancer, we hypothesized that they might be differentially expressed in hepatocellular carcinoma (HCC) cells as compared to healthy tissue and serve as diagnostic or prognostic biomarkers. We tested this hypothesis through bioinformatic analyses of publicly available data for the expression of various KCNK subunits in HCC. We observed reduced expression of KCNK2, KCNK15, and KCNK17 in liver cancer, as well as overexpression of KCNK9, all of which correlated with a better prognosis for HCC patients per survival analyses. Moreover, ROC curves indicated that KCNK2, KCNK9, KCNK15, and KCNK17 levels could be used as a diagnostic biomarker for HCC. Finally, our western blot and qRT-PCR results were consistent with those obtained from bioinformatic analyses. Taken together, these results suggest that KCNK2, KCNK9, KCNK15, and KCNK17 could serve as potential diagnostic and prognostic biomarkers of HCC.

Microwave ablation versus resection for hepatocellular carcinoma within the Milan criteria: a propensity-score analysis.

BACKGROUND: Whether the efficient heat-generating mechanism of microwave ablation (MWA) is comparable with resection (RES) in treating hepatocellular carcinoma (HCC) remains unclear. METHODS: This retrospective cohort study comprised 126 and 1183 patients with HCC meeting the Milan criteria who received MWA or RES between 2002 and 2017. We compared 5-year overall survival (OS) and recurrence-free survival (RFS) using both propensity-score matching (PSM) and inverse-probability-of-treatment-weighting (IPW) analysis and investigated the prognostic factors with multivariate Cox analysis. RESULTS: After PSM (1:2), although MWA (n = 116) offered decreased 5-year RFS (30.6% versus 57.5%, p < 0.001) compared with RES (n = 212), both treatments provided similar 5-year OS (82.2% versus 80.5%, p = 0.360) because most patients with intrahepatic recurrence remained eligible for repeat treatments; similar results were found in the IPW analysis. Additionally, the comparable efficacy of MWA and RES was consistent across all subgroups: those with solitary HCC ⩽ 3.0 cm or >3.0 cm, or multifocal HCCs within the Milan criteria, patients with liver function of albumin-bilirubin grade 1 or 2, and older (⩾60 years) or younger (<60 years) patients. Multivariate Cox analysis confirmed that no difference was seen between MWA and RES in OS (hazard ratio = 0.85; p = 0.581) in the overall population; similar results were obtained in the propensity-score-matched and IPW cohorts. CONCLUSIONS: Compared with RES, MWA offered worse RFS for HCC within the Milan criteria; however, both treatments provided equivalent long-term OS because most patients with intrahepatic recurrence remained eligible for repeat treatments.

Resection vs Ablation for Multifocal Hepatocellular Carcinomas meeting the Barcelona-Clinic Liver Cancer A Classification: A Propensity Score Matching Study.

With development of surgical technology, we aimed to investigate whether resection could challenge the standard treatment, ablation, in treating multifocal hepatocellular carcinomas meeting the Barcelona-Clinic Liver Cancer A stage. From January 2005 to January 2017, the oncological outcomes of patients undergoing resection (n = 72) or ablation (n = 63) were retrospectively analysed using propensity score matching. At baseline, patients in the ablation group had more tri-focal lesions (30.2% vs. 6.9%, P = 0.001) and smaller tumours (2.00 cm vs. 2.50 cm, P = 0.002) than resection group. After matching, the baseline was well-balanced between treatments (n = 46 pairs); resection provided comparable 5-year overall survival (77.0% vs. 83.6, P = 0.790) and superior 5-year recurrence-free survival (40.4% vs. 16.9%, P = 0.022) to ablation. The multivariate Cox model confirmed that ablation was not associated with worse overall survival (HR = 0.89; 95% CI, 0.33 - 2.42, P = 0.819), but identified ablation as an unfavourable predictor of recurrence-free survival (HR = 2.13; 95% CI, 1.27 - 3.57, P <0.001). For subgroup patients with multifocal tumours located in different segments, both treatments offered similar 5-year overall survival (74.3% vs. 95.5%, P = 0.190) and 5-year recurrence-free survival (42.9 vs. 25.9%, P = 0.170). Additionally, ablation resulted in less major complications than resection (3.2% vs 13.9%, P = 0.035). Compared with ablation, resection achieved comparable overall survival and even superior recurrence-free survival for patients with multifocal hepatocellular carcinomas meeting the BCLC A stage.

Lipiodol deposition in portal vein tumour thrombus predicts treatment outcome in HCC patients after transarterial chemoembolisation.

OBJECTIVE: To study lipiodol deposition in portal vein tumour thrombus (PVTT) in predicting the treatment outcome of hepatocellular carcinoma (HCC) patients after transarterial chemoembolisation (TACE). METHODS: We retrospectively reviewed data from 379 HCC patients with PVTT who underwent TACE as the initial treatment at Sun Yat-Sen University Cancer Center from January 2008 to December 2015. Patients were grouped by positive and negative lipiodol deposition based on the extent of lipiodol deposition in PVTT. The overall survival (OS) and progression-free survival (PFS) were compared between negative and positive lipiodol deposition groups; furthermore, the value of the combinatorial evaluation of tumour responses and lipiodol deposition in PVTT in predicting prognosis was analysed in subgroup patients with stable disease (SD) after TACE. RESULTS: Of the 379 patients, 264 (69.7%) had negative and 115 (30.3%) had positive lipiodol deposition in PVTT after TACE. Multivariate analysis identified positive lipiodol deposition in PVTT as an independent prognostic factor for favourable OS (p = 0.001). The median OS and PFS of negative and positive lipiodol deposition groups were 4.70 vs. 8.97 months (p = 0.001) and 3.1 months vs. 5.8 months (p < 0.001). In subgroup patients, the median OS and PFS of negative and positive lipiodol deposition groups were 4.7 months vs. 10.5 months (p < 0.001) and 3.5 months vs. 7.0 months (p < 0.001), respectively. CONCLUSIONS: The patients with positive lipiodol deposition in PVTT had a longer OS than those with negative lipiodol deposition. Furthermore, the positive lipiodol deposition in PVTT can further differentiate HCC patients with favourable prognosis from SD patients. KEY POINTS: • Lipiodol deposition in PVTT is a prognostic indicator for HCC patients after TACE treatment. • Positive lipiodol deposition in PVTT is associated with a better prognosis.

Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis.

Spleen tyrosine kinase (SYK) plays a critical role in immune cell signaling pathways and has been reported as a biomarker for human hepatocellular carcinoma (HCC). We sought to investigate the mechanism by which SYK promotes liver fibrosis and to evaluate SYK as a therapeutic target for liver fibrosis. We evaluated the cellular localization of SYK and the association between SYK expression and liver fibrogenesis in normal, hepatitis B virus (HBV)-infected, hepatitis C virus (HCV)-infected and non-alcoholic steatohepatitis (NASH) liver tissue (n=36, 127, 22 and 30, respectively). A polymerase chain reaction (PCR) array was used to detect the changes in transcription factor (TF) expression in hepatic stellate cells (HSCs) with SYK knockdown. The effects of SYK antagonism on liver fibrogenesis were studied in LX-2 cells, TWNT-4 cells, primary human HSCs, and three progressive fibrosis/cirrhosis animal models, including a CCL4 mouse model, and diethylnitrosamine (DEN) and bile duct ligation (BDL) rat models. We found that SYK protein in HSCs and hepatocytes correlated positively with liver fibrosis stage in human liver tissue. HBV or HCV infection significantly increased SYK and cytokine expression in hepatocytes. Increasing cytokine production further induced SYK expression and fibrosis-related gene transcription in HSCs. Up-regulated SYK in HSCs promoted HSC activation by increasing the expression of specific TFs related to activation of HSCs. SYK antagonism effectively suppressed liver fibrosis via inhibition of HSC activation, and decreased obstructive jaundice and reduced HCC development in animal models. Conclusion: SYK promotes liver fibrosis via activation of HSCs and is an attractive potential therapeutic target for liver fibrosis and prevention of HCC development. (Hepatology 2018).

Optimized construction of MUC1-VNTRn DNA vaccine and its anti-pancreatic cancer efficacy.

Considering mucin 1-variable number tandem repeat (MUC1-VNTRn) as a novel target for pancreatic cancer immunotherapy, the present study aimed to screen and identify the pVAX1-MUC1-VNTRn DNA vaccine with the strongest immunogenicity. Following construction of a pVAX1-MUC1-VNTRn plasmid, immature dendritic cells (DCs) were subjected to transfection, and mature DCs were then co-cultured with autologous T-cells. The numbers of cytotoxic T lymphocytes (CTLs) secreting interferon (IFN)-γ were determined using an enzyme-linked immunospot assay, and CytoTox® was also used to examine the MUC1-VNTRn-specific Lethal effect of CTLs on Capan2 cells. Additional in vivo experiments in mice were performed to confirm the antitumor effect of the DNA vaccine candidate. The present study successfully constructed the pVAX1-MUC1-VNTRn plasmid, which expresses the target protein in eukaryotic cells. Additionally, upon uptake of the pVAX1-MUC1-VNTRn plasmid, the immature DCs differentiated into mature DCs. The levels of the DC surface molecules cluster of differentiation (CD) 80, CD86, human leukocyte antigen-antigen D related, interleukin (IL)-12, IL-17 and IFN-γ were significantly higher, while the levels of IL-10 and IL-14 were lower, in mature DCs of the stimulated groups compared with the immature DCs of the non-stimulated groups (all P<0.01). In addition, the MUC1-VNTR6 and MUC1-VNTR9 groups, in which DCs were capable of activating autologous T-cells, showed increased IFN-γ-producing T-cells compared with the other groups (strong MUC1-VNTR1, weak VNTR1, VNTR3, VNTR4 and MUC1-cDNA groups; all P<0.001). In addition, the Lethal effect of CTLs on Capan2 cells in these two groups was stronger compared with the other groups (all P<0.001). Furthermore, the induced protective and therapeutic immune responses in mouse experiments showed that the pVAX1-MUC1-VNTR6DNA vaccine likely possessed the strongest immunogenicity, and its ability to inhibit panc02-MUC1 tumor growth was superior to other DNA vaccines (P<0.01). The present study provides compelling evidence that pVAX1-MUC1-VNTRn has the potential to express the target protein in eukaryotic cells, and thatpVAX1-MUC1-VNTR6 was characterized by the strongest Lethal effect in both in vivo and in vitro experiments.

Serum Insulin-Like Growth Factor Axis and the Risk of Pancreatic Cancer: Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the association between serum concentration of insulin-like growth factor (IGF) and the risk of pancreatic cancer (PaC). METHODS: We identified eligible studies in Medline and EMBASE databases (no reference trials from 2014 to 2016) in addition to the reference lists of original studies and review articles on this topic. A summary of relative risks with 95% confidence intervals (CI) was calculated using a random-effects model. The heterogeneity between studies was assessed using Cochran Q and I² statistics. RESULTS: Ten studies (seven nested case-control studies and three retrospective case-control studies) were selected as they met our inclusion criteria in this meta-analysis. All these studies were published between 1997 and 2013. The current data suggested that serum concentrations of IGF-I, IGF-II and insulin-like growth factor binding protein-3 (IGFBP-3)in addition to the IGF-I/IGFBP-3 ratio were not associated with an increased risk of PaC (Summary relative risks (SRRs) = 0.92, 95% CI: 0.67-1.16 for IGF-I; SRRs = 0.84, 95% CI: 0.54-1.15 for IGF-II; SRRs = 0.93, 95% CI: 0.69-1.17 for IGFBP-3; SRRs = 0.97, 95% CI: 0.71-1.23 for IGF-I/IGFBP-3 ratio). There was no publication bias in the present meta-analysis. CONCLUSION: Serum concentrations of IGF-I, IGF-II, IGFBP-1 and IGFBP-3 as well as the IGF-I/IGFBP-3 ratio were not associated with increased risk of PaC.

Sorafenib therapy following resection prolongs disease-free survival in patients with advanced hepatocellular carcinoma at a high risk of recurrence.

Sorafenib is the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC); however, its therapeutic value in patients with HCC following resection remains controversial. The current retrospective study was undertaken to assess the effects of sorafenib treatment following surgical resection in patients with advanced HCC disease who were at a high risk for recurrence. Between July 2010 and July 2013, a consecutive cohort of 42 patients with advanced HCC and at a high risk of recurrence (i.e., those with portal vein tumor thrombosis, adjacent organ involvement or tumor rupture) who underwent resection were analyzed. The patients were categorized into the sorafenib group (n=14) or the best supportive care (BSC) group (n=28). Although the histological grade, Barcelona Clinic Liver Cancer Stage, tumor size, nodule number and proportion of patients with high serum α-fetoprotein levels were comparable between the sorafenib and BSC groups, those receiving sorafenib following resection had significantly longer disease-free survival (DFS) of 5.2 months [95% confidence interval (CI), 1.2-9.2 months] compared with the BSC group [1.8 months (95% CI, 0.6-3.0 months)]. No differences in overall survival were noted between the groups. Furthermore, no drug-related adverse events resulted in discontinuation of sorafenib therapy. Univariate log-rank analysis revealed that sorafenib treatment (P=0.002) and treatment prior to resection (P=0.012) were significantly associated with longer DFS; however, sorafenib therapy (P=0.027) and tumor size (P=0.028) were associated with longer DFS by multivariate analysis. Furthermore, sorafenib was well-tolerated and improved DFS in patients with advanced HCC who underwent hepatic resection. Thus, tumor resection followed by sorafenib therapy may represent an effective therapeutic strategy for patients with advanced HCC. This possibility should be confirmed in larger, multicenter studies.

Effectiveness of ω-3 Polyunsaturated Fatty Acids Based Lipid Emulsions for Treatment of Patients after Hepatectomy: A Prospective Clinical Trial.

OBJECTIVE: The present study aimed to investigate the effectiveness of parenteral nutritional support with ω-3 PUFAs-based lipid emulsions in patients after liver resection. METHODS: A total of 119 patients were randomly assigned to the immunonutrition (IM) group (n = 59) and control group (n = 60). The IM group was continuously given Omegaven(®) 10% 100 mL/day rather than regular nutrition for five days postoperatively. Venous blood samples were obtained from all subjects before surgery and D1, D3 and D7 after surgery. RESULTS: No significant difference was found in baseline characteristics of the two groups. On D1 after surgery, no statistically significant differences were observed in the blood sample tests between the two groups. On D3 after surgery, the levels of white blood cell count (WBC), alanine aminotransferase (ALT), aspartate transaminase (AST) and total bilirubin (TBil) were dramatically decreased in the IM group (t = 3.065, p = 0.003; t = 2.149, p = 0.034; t = 5.313, p= 0.001; and t = 2.419, p = 0.017, respectively). Furthermore, on D7 after surgery, not only could a significant decrease be observed in the IM group concerning the levels of WBC, ALT and TBil (t = 3.025, p = 0.003; t = 2.094, p = 0.038; and t = 2.046, p = 0.043, respectively), but it was also seen in the level of Δprothrombintime (PT) (t = 2.450, p = 0.016). An increase in the level of prealbumin (Pre-Alb) in the IM group was observed on D7 after surgery (t = 2.237, p = 0.027). The frequency of total complications in the IM group were significantly lower than in the control group (χ² = 4.225, p = 0.040 and χ² = 3.174, p = 0.075). The trend favored the IM group in reducing the total infective complications rate (χ² = 3.174, p = 0.075). A significant decrease in the duration of the hospital stay after surgery was also observed in the IM group (t = 2.012, p = 0.047). CONCLUSION: ω-3 PUFAs-based lipid emulsions for treatment of patients after hepatectomy are safe and effective in controlling inflammation, protecting liver function, and consequently reducing the rate of total complications and the duration of the hospital stay.

Resection versus ablation in hepatitis B virus-related hepatocellular carcinoma patients with portal hypertension: A propensity score matching study.

BACKGROUND: With recent improvements in operative techniques, many studies have reported that resection is safe for hepatocellular carcinoma (HCC) patients with portal hypertension (PHT). However, no direct evidence exists to compare resection with ablation in patients with hepatitis B virus (HBV)-related PHT. METHODS: Of 259 HBV-related PHT patients who met the Milan criteria, 123 patients underwent resection and 136 underwent ablation as a primary treatment. Complications were graded with the Clavien-Dindo system, and oncologic outcomes were analyzed with a propensity score matching (PSM) method. RESULTS: Compared with the ablation group, the resection group showed larger tumors, greater white blood cell counts, greater platelet counts, lower γ-glutamyltransferase levels, and lower model of end stage liver disease scores (all P < .05). Although more frequent complications occurred in the resection group (P < .001), the difference was significant for the Grade I complications but not for Grade II-V complications. The recurrence-free survival (RFS) and overall survival (OS) rates were greater in the resection group than in the ablation group (P = .001 and P = .010, respectively). After one-to-one PSM, 77 resection patients and 77 ablation patients were selected for further analyses. The advantages of resection over ablation were still observed in RFS (P = .002) and OS (P = .012). Grade I-V complications were comparable between the 2 groups (all P > .100). CONCLUSION: Resection is safe and confers a survival advantage over ablation in HBV-related PHT patients. Resection may be recommended as an optimal treatment for these patients.