Intermedin (adrenomedullin 2) promotes breast cancer metastasis via Src/c-Myc-mediated ribosome production and protein translation.

PURPOSE: Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-associated mortality in women worldwide. Intermedin (IMD, also known as Adrenomedullin 2, ADM2) is an endogenous peptide that belongs to the calcitonin gene-related peptide family and has been reported to play important roles in several types of cancers, including breast cancer. In this study, we sought to investigate how IMD affects the behavior of breast cancer cells, the underlying mechanism of these effects, and whether blockade of IMD has a therapeutic effect against breast cancer. METHODS: Transcriptome sequencing (RNA-Seq), cell biological experiments, Western blotting, immunoprecipitation, and animal tumor models were used. RESULTS: IMD expression was significantly increased in breast cancer samples, and the IMD level was positively correlated with lymph node metastasis and Ki67 expression. Cell biological experiments showed that IMD promoted the anchorage-independent growth, migration, and invasive ability of breast cancer cells. Inhibiting IMD activity with an anti-IMD monoclonal antibody blocked these tumor-promoting effects. In addition, blockade of IMD reduced in situ tumor growth and significantly decreased lung metastasis of 4T1 breast cancer in vivo. IMD induced Src kinase phosphorylation, which triggered the transcription of c-Myc, a major oncoprotein controlling the expression of genes that encode ribosomal components. Our data suggest that IMD is involved in breast cancer cell invasion and metastasis, potentially through increasing ribosome biogenesis and protein translation via the Src/c-Myc signaling pathway. CONCLUSION: These results suggest that IMD may be a novel target for the treatment of breast cancer.

Impact of Bile Duct Tumor Thrombus on the Long-Term Surgical Outcomes of Hepatocellular Carcinoma Patients: A Propensity Score Matching Analysis.

BACKGROUND: Hepatectomy with tumor thrombectomy is the preferred treatment option for hepatocellular carcinoma (HCC) patients with bile duct tumor thrombus (BDTT); however, the impact of BDTT on their prognosis is unclear. OBJECTIVE: We aimed to investigate the long-term surgical outcomes of HCC patients with BDTT. METHODS: The data of HCC patients with and without BDTT who underwent hepatectomy were retrospectively reviewed and the long-term outcomes were compared. For propensity score matching (PSM) analysis, patients were matched in a 1:1 ratio. Subgroup analysis was conducted according to the American Joint Committee on Cancer (AJCC) staging system. RESULTS: Before PSM, HCC patients with BDTT had more advanced tumor stages and adverse clinicopathological features. Recurrence-free survival (RFS) and overall survival (OS) were significantly higher in the non-BDTT group before PSM (RFS, p < 0.001; OS, p < 0.001), while after PSM, the BDTT group had significantly poorer RFS (p = 0.025). There was no difference in OS between the groups (p = 0.588). Subgroup analysis showed that RFS and OS in AJCC stage I-II patients were significantly poorer in the BDTT group; no differences were found in the AJCC stage III group before or after PSM. When the presence of BDTT was recommended to increase the AJCC staging system by one stage in AJCC stage I-II patients, the predictive ability for RFS and OS was higher. CONCLUSIONS: BDTT was associated with significantly poorer long-term surgical outcomes in AJCC stage I-II patients. A modified AJCC staging system including BDTT status in stage I-II might have a better prognostic ability.

Postoperative adjuvant transarterial chemoembolization improves outcomes of hepatocellular carcinoma associated with bile duct tumor thrombus: a propensity score matching analysis.

BACKGROUND: Surgical resection is the primary treatment for hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT). This study was conducted to investigate the efficacy of postoperative adjuvant TACE (PA-TACE) in patients with HCC and BDTT. METHODS: Data from patients who underwent surgery for HCC with BDTT at two medical centers were retrospectively analyzed. The survival outcomes of patients who were treated by hepatic resection followed by PA-TACE were compared with those of patients who underwent surgery alone. Propensity score matching (PSM) analysis was performed with a 1:1 ratio. RESULTS: Of the 308 consecutively enrolled HCC patients with BDTT who underwent surgical resection, 134 underwent PA-TACE whereas 174 underwent surgery alone. From the initial cohort, PSM matched 106 pairs of patients. The OS and DFS rates were significantly better for the PA-TACE group than the surgery alone group (for OS: before PSM, P = 0.026; after PSM, P = 0.039; for DFS: before PSM, P = 0.010; after PSM, P = 0.013). CONCLUSION: PA-TACE was associated with better survival outcomes than surgery alone for patients with HCC and BDTT. Prospective clinical trials are warranted to validate the beneficial effect of PA-TACE on HCC patients associated with BDTT.

Recurrence hazard rate in patients with hepatocellular carcinoma and bile duct tumor thrombus: a multicenter observational study.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) bile duct tumor thrombus (BDTT) have a high rate of postoperative recurrence. We aimed to describe the patterns and kinetics of recurrence in BDTT patients and provide management options accordingly. METHODS: This retrospective study included 311 HCC patients with BDTT who underwent surgery from 2009 to 2017 at five centers in China. The hazard rate of recurrence was calculated using the hazard function. RESULTS: The hazard rate of intrahepatic recurrence was higher than that of extrahepatic recurrence (0.0588 vs. 0.0301), and both showed a decreasing trend, and the intrahepatic recurrence and extrahepatic recurrence risk decreased to a lower level after 40 and 20 months, respectively. Patients who underwent anatomic resection had a consistently lower hazard rate of recurrence than patients who underwent nonanatomic resection, whereas patients who received postoperative adjuvant transarterial chemoembolization (TACE) mainly had a lower hazard rate of recurrence in the first year than patients who did not. CONCLUSION: The follow-up of BDTT patients should be at least 40 months because of its high rate of recurrence, in parallel with the need for vigilance for extrahepatic recurrence within 20 months. Anatomic hepatectomy and adjuvant TACE are recommended to improve BDTT patient outcomes.

Should associating liver partition and portal vein ligation for staged hepatectomy be applied to hepatitis B virus-related hepatocellular carcinoma patients with cirrhosis? A multi-center study.

BACKGROUND: It is unclear whether associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can be performed in hepatitis B virus-related hepatocellular carcinoma (HCC) patients with cirrhosis. We explored the efficacy of ALPPS in HCC patients. METHODS: Data of 54 patients who underwent ALPPS between August 2014 and July 2020 at three centers were collected. Adverse factors affecting their prognosis were analyzed and subsequently compared with 184 patients who underwent transcatheter arterial chemoembolization (TACE). RESULTS: Overall survival rates of the ALPPS group at 1, 3, and 5 years were 70.6%, 38.4%, and 31.7%, respectively; corresponding disease-free survival rates were 50.5%, 22.4%, and 19.2%, respectively. The ALPPS group had a significantly greater long-term survival rate than the TACE group (before propensity score matching, P < 0.001; after propensity score matching, P = 0.002). Multivariate analysis demonstrated that multifocal lesions (P = 0.018) and macroscopic vascular invasion (P = 0.001) were prognostic factors for HCC patients who underwent ALPPS. After the propensity score matching, the multifocal lesions (P = 0.031), macroscopic vascular invasion (P = 0.003), and treatment type (ALPPS/TACE) (P = 0.026) were the factors adversely affecting the prognosis of HCC patients. CONCLUSION: ALPPS was feasible in hepatitis B virus-related HCC patients with cirrhosis and resulted in better survival than TACE.

Long-Term Outcomes of Anatomic Versus Nonanatomic Resection in Hepatocellular Carcinoma Patients with Bile Duct Tumor Thrombus: A Propensity Score Matching Analysis.

BACKGROUND: Anatomic resection (AR) of the liver is generally recommended in hepatocellular carcinoma (HCC) patients. However, the benefits of AR and nonanatomic resection (NAR) in HCC patients with bile duct tumor thrombus (BDTT) are unknown. This study aimed to compare long-term outcomes of AR and NAR in HCC patients with BDTT after curative resection. PATIENTS AND METHODS: A total of 175 consecutive HCC patients with BDTT after curative resection between April 2009 and December 2017 were included. One-to-one propensity score matching (PSM) was performed to minimize the influence of potential confounders. Recurrence-free survival (RFS) and overall survival (OS) were compared between the cohorts. RESULTS: After PSM, 120 patients were analyzed. The AR group had better RFS than the NAR group (P = 0.010). Even though there was no statistically significant difference in OS (P = 0.140, power = 0.33), the 3- and 5-year OS rates in the AR group (52.4% and 44.2%, respectively) were obviously higher than those in the NAR group (35.4% and 30.4%, respectively). When patients were further stratified according to tumor size, better RFS and OS were observed in patients with small (≤ 5 cm) tumors after AR (P < 0.001 and P = 0.004, respectively). Multivariate analysis identified AR (P = 0.024) as an independent favorable prognostic factor for RFS in HCC patients with BDTT. CONCLUSIONS: AR is recommended for HCC patients with BDTT, especially in patients with small (≤ 5 cm) tumors.

Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence.

BACKGROUND: Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this "sunitinib resistance" remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence. METHODS: 4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated ß-galactosidase (SA-ß-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of "pre-metastatic niche" which promotes MBC to metastasize to the lungs. RESULTS: We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a "pre-metastatic niche"-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis. CONCLUSION: Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib "correctly" playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.

Intermedin Enlarges the Vascular Lumen by Inducing the Quiescent Endothelial Cell Proliferation.

OBJECTIVE: Intermedin plays an important role in vascular remodeling and significantly improves blood perfusion, but the precise mechanism remains unclear. Herein, we aimed to define whether vascular lumen enlargement is responsible for the intermedin-increased blood perfusion and explore the underlying cellular and molecular mechanisms. APPROACH AND RESULTS: To study the role of intermedin, we generated the IMD-KO (Adm2-/-) mice using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) system. Intermedin significantly promoted vascular lumen enlargement in vitro (fibrin beads assay) and in vivo (murine retinas), which contributed to the improved blood perfusion in both physiological (retinal) and pathological (tumor) angiogenic models. We designed experiments to calculate the endothelial cell (EC) size and found that the lumen enlargement is because of EC proliferation but not because of a change in cell shape. ECs that construct vessel walls are considered quiescent cells because they are in a state of contact inhibition and show reduced responsiveness to VEGF (vascular endothelial growth factor). Using immunoprecipitation, Western blot assay, and fluorescent microscopy, we found that intermedin induced the formation of a signaling complex containing CRLR (calcitonin receptor-like receptor)/ß-arr1 (ß-arrestin1)/Src in ECs and promoted it internalizing into cytoplasm in a clathrin-dependent manner to activate downstream ERK1/2 (extracellular signal-regulated kinase 1/2). Importantly, this effect was not abrogated by cell-cell contacts of ECs. Through this mechanism, intermedin could reactivate the quiescent ECs to proliferate, resulting in continuous lumen expanding and a more effective blood perfusion. CONCLUSIONS: Our findings suggest a novel mechanism that may explain how quiescent ECs overcome the contact inhibition and regain the ability to proliferate for continuous vascular lumen enlargement.

Upregulation of Long Noncoding RNA (lncRNA) X-Inactive Specific Transcript (XIST) is Associated with Cisplatin Resistance in Non-Small Cell Lung Cancer (NSCLC) by Downregulating MicroRNA-144-3p.

BACKGROUND Patients with advanced non-small cell lung cancer (NSCLC) treated with cisplatin, also termed cis-diamminedichloroplatinum (CDDP) or diamminedichloroplatinum (DDP), may develop chemoresistance. This study aimed to investigate the role of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) and multidrug resistance-1 (MDR1) in tumor tissue samples and the chemoresistant human NSCLC cell lines, H460/DDP and A549/DDP, and in a murine A549/DDP tumor xenograft. MATERIAL AND METHODS Tissue samples were from patients with NSCLC who responded cisplatin (DDP-sensitive) (n=24), patients with NSCLC unresponsive to cisplatin (DDP-resistant) (n=30), and normal lung tissue (n=25). In H460/DDP and A549/DDP cells, expression of XIST, microRNA (miR)-144-3p, MDR1, and multidrug resistance-associated protein 1 (MRP1) were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The MTT assay measured cell survival and proliferation, a transwell assay evaluated cell migration, and flow cytometry measured apoptosis. Luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays examined the relationship between XIST and miR-144-3p. Tumor xenografts from A549/DDP cells were studied in BALB/c nude mice. RESULTS In tissue from patients with DDP-resistant NSCLC and the mouse A549/DDP tumor xenograft, lncRNA-XIST expression was upregulated and miR-144-3p expression was inhibited. In A549/DDP and H460/DDP cells, down-regulation of lncRNA-XIST and upregulation of miR-144-3p reduced cell survival, proliferation, migration, induced apoptosis and suppressed MDR1 and MRP1 expression. CONCLUSIONS Upregulation of lncRNA-XIST was associated with cisplatin resistance in NSCLC by downregulating miRNA-144-3p in H460/DDP and A549/DDP cells, a murine A549/DDP tumor xenograft, and human tumor tissues from patients with cisplatin-resistant NSCLC.

[Impact of Non-middle Hepatic Vein Reconstruction on the Result of Low Graft-to-recipient Weight Ratio Living Donor Liver Transplantation].

OBJECTIVE: To analyze of the minimum graft-to-recipient weight ratio (GRWR) required for living donor liver transplantation (LDLT) without middle hepatic vein branch (MHVT) reconstruction. METHODS: We retrospectively collected the clinical data and outcomes of 303 LDLT patients over 16 years from 2001 to 2017. The minimum GRWR of non-middle hepatic vein reconstruction was analyzed by propensity score (PSM). RESULTS: With PSM analysis, no significant differences were observed in postoperative complications, SFSS, inpatient time, liver function, and coagulation function, but significant differences in 1-year, 3-year and 5-year survival between MHVT reconstruction and non-reconstruction group. The patients with MHVT reconstruction had better short-term and long-term survival than those without reconstruction. CONCLUSION: For LDLT patients without HMVT reconstruction, GRWR should be greater than 0.86%; for patients with HMVT reconstruction, GRWR is acceptable between 0.5% and 0.6%.

Outcomes following laparoscopic versus open major hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a propensity score-matched analysis.

BACKGROUND: Laparoscopic major hepatectomy (LMH) for hepatocellular carcinoma (HCC) in patients with cirrhosis remains controversial due to limited reports in the literature. This study analyzed the perioperative and oncological outcomes of LMH for HCC with cirrhosis compared with open major hepatectomy (OMH). METHODS: A retrospective analysis of patients with cirrhosis who underwent major hepatectomy for HCC between January 2015 and January 2017 was performed. Patients were divided into the LMH group and the OMH group. Short-term and oncological outcomes were compared before and after 1:1 propensity score matching (PSM). RESULTS: A total of 103 HCC patients who received major liver resection were enrolled. There were 36 (35.0%) patients in the LMH group and 67 (65.0%) patients in the OMH group. After 1:1 PSM, well-matched 32 patients in each group were evaluated. Significant differences were observed in operative time (median, 255 vs. 200 min, p < 0.001) and Pringle time (median, 50 vs. 30 min, p < 0.001) between two groups. The blood loss and transfusion requirement were comparable in two groups. The rate of overall postoperative complications did not differ between two groups, while the incidence of ascites in the LMH group was significantly less than OMH group (9.4 vs. 31.3%, p = 0.030). The oncological outcomes between the two groups were comparable with regard to 2-year overall survival (85.7 vs. 86.7%, p = 0.694) and disease-free survival (72.9 vs. 81.5%, p = 0.990), respectively. CONCLUSIONS: LMH for HCC patients with liver cirrhosis showed comparable results in terms of postoperative morbidity and oncological outcomes compared with traditional open procedure. LMH may serve as a safe and feasible alternative for selected HCC patients with cirrhosis.

Pure laparoscopic right hepatectomy of living donor is feasible and safe: a preliminary comparative study in China.

BACKGROUND: The adoption of laparoscopic techniques for living donor major hepatectomy has been controversial issue. The aim of this study is to present the preliminary experience of laparoscopic right hepatectomy in China. METHODS: All the donors receiving right hepatectomy for adult-to-adult living donor liver transplantation (LDLT) were divided into three groups: pure laparoscopic right hepatectomy (PLRH) group, hand-assisted right hepatectomy (HARH) group and open right hepatectomy (ORH) group. We compared the perioperative data and surgical outcomes of donors and recipients among three groups. RESULTS: From November 2001 to May 2017, 295 donors have received right hepatectomy for LDLT in our center. Among them, 7 donors received PLRH, 26 donors received HARH and 262 donors received ORH. The operation time of PLRH group (509.3 ± 98.9 min) was longer than that of the HARH group (451.6 ± 89.7 min) and the ORH group (418.4 ± 81.1 min, p = 0.003). The blood loss was the least in the PLRH group (378.6 ± 177.1 mL), compared with that in the HARH group (617.3 ± 240.4 mL) and that in the ORH group (798.6 ± 483.7 mL, p = 0.0013). The postoperative hospital stay was shorter in the PLRH group (7, 7-10 days) than that in the HATH group (8.5, 7.5-12 days) and ORH group (11, 9-14 days; p = 0.001). Only one donor had pleural effusion (Grade I) and another one experienced pulmonary infection (Grade II). One recipient (14.3%) in the PLRH group occurred hepatic venous stenosis. CONCLUSIONS: Laparoscopic approaches for right hepatectomy contribute to less blood loss, better cosmetic satisfaction, less severe complications, and faster rehabilitation. PLRH is a safe and feasible procedure, which must be performed in highly specialized centers with expertise of both LDLT and laparoscopic hepatectomy, and requires a hybrid-to-pure stepwise development.

Safety and effectiveness of day-surgery laparoscopic cholecystectomy is still uncertain: meta-analysis of eight randomized controlled trials based on GRADE approach.

BACKGROUND: Currently, there is no consensus on whether laparoscopic cholecystectomy (LC) performed as day-surgery is safe and effective and can be considered as the standard for the management of symptomatic gallbladder disease. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the safety and effectiveness of this intervention based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. METHODS: We conducted a systematic search of several databases from their inception to November 10, 2016 for entries on the mortality, morbidity after discharge, readmission, postoperative morbidity, and patient satisfaction at 1 week of day-surgery LC. Pooled risk ratio (RR) with 95% confidence intervals (CI) was calculated using the fixed-effects model. Rare outcomes were presented as the Peto odds ratio (Peto OR). Meta-analysis was performed by using the RevMan 5.1 software, and the level of evidence was assessed by using the GRADE guideline and GRADEpro GDT software. RESULTS: Eight RCTs totaling 624 participants were included. The result showed no intergroup difference in short-term mortality. Compared to overnight-stay surgery, day-surgery did not show any clear evidence of reduced morbidity after discharge (Peto OR 0.89; 95% CI 0.39-2.02), lower readmission rate (Peto OR 0.68; 95% CI 0.23-2.05), or higher postoperative morbidity rates (RR 1.28; 95% CI 0.81-2.02). However, the results suggested that day-surgery may improve patient satisfaction at 1 week (RR 1.17; 95% CI 1.03-1.33). Evaluation by the GRADE approach revealed that the quality of evidence for each outcome was of low to very low quality due to the risk of bias, imprecision, and inconsistency. CONCLUSION: Our meta-analysis shows that the safety and effectiveness of day-surgery LC is still uncertain. Additional well-designed and adequately powered RCTs are required before the procedure can be recommended as the standard for clinical practice.

Cost-effectiveness analysis of transcatheter arterial chemoembolization with or without sorafenib for the treatment of unresectable hepatocellular carcinoma.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) and TACE in combination with sorafenib (TACE-sorafenib) have shown a significant survival benefit for the treatment of unresectable hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of TACE against TACE-sorafenib for unresectable HCC using a decision analytic model. METHODS: A Markov cohort model was developed to compare TACE and TACE-sorafenib. Transition probabilities and utilities were obtained from systematic literature reviews, and costs were obtained from West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was calculated. Sensitive analysis was performed by varying potentially modifiable parameters of the model. RESULTS: The base-case analysis showed that TACE cost $26 951 and yielded survival of 0.71 QALYs, and TACE-sorafenib cost $44 542 and yielded survival of 1.02 QALYs in the entire treatment. The ICER of TACE-sorafenib versus TACE was $56 745 per QALY gained, which was above threshold for cost-effectiveness in China. Sensitivity analysis revealed that the major driver of ICER was the cost post TACE-sorafenib therapy with stable state. CONCLUSION: TACE is a more cost-effective strategy than TACE-sorafenib for the treatment of unresectable HCC.

Microvascular invasion patterns affect survival in hepatocellular carcinoma patients after second hepatectomy.

BACKGROUND: Microvascular invasion (MVI) is an important risk factor for survival of patients with hepatocellular carcinoma (HCC) after hepatectomy. However, its impact on patients with recurrent HCC who receive a second hepatectomy is unknown. METHODS: We enrolled 167 patients with HCC who underwent a second hepatectomy because of intrahepatic recurrences. We compared the patients' demographic, tumor, and pathologic characteristics with 766 cases of original hepatectomy. We analyzed the possible risk factors for survival after the first and second hepatectomies and the influence of different MVI patterns on patients' survival after the second hepatectomy. RESULTS: The median overall survival was comparable between the first and second hepatectomy groups, 34 (3-84) mo versus 27 (3-57) mo, P = 0.09. For patients who underwent a first hepatectomy, the presence of macro-VI or MVI, an early recurrence pattern, and a total tumor diameter >5 cm were independent risk factors. For survival after the second hepatectomy, MVI patterns that were positive-positive or negative-positive and a total recurrent tumor diameter >5 cm were significant risk factors for survival. CONCLUSIONS: A second hepatectomy provides satisfying survival for patients with intrahepatic recurrence of HCC after the initial operation. Different MVI patterns affect survival after the second hepatectomy. Because MVI represents the biological behavior of HCC, we place a high premium on the clinical value of MVI after each hepatectomy.

Combined hepatectomy and radiofrequency ablation versus TACE in improving survival of patients with unresectable BCLC stage B HCC.

BACKGROUND: Combined hepatectomy and radiofrequency ablation (RFA) provides an additional treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) who are conventionally deemed unresectable. This study aimed to analyze the outcome of this combination therapy by comparing it with transarterial chemoembolization (TACE). METHODS: We retrospectively reviewed 51 patients with unresectable BCLC stage B HCC who had received the combination therapy. We compared the survival of these patients with that of 102 patients in the TACE group (control). Prognostic factors associated with worse survival in the combination group were analyzed. RESULTS: No differences in tumor status and liver function were observed between the TACE group and combination group. The median survival time for the combination group and TACE group was 38 (6-54) and 17 (3-48) months, respectively (P<0.001). The combination group required longer hospitalization than the TACE group [8 (5-14) days vs 4 (2-9) days, P<0.001]. More than two ablations decreased the survival rate in the combination group. CONCLUSIONS: Combined hepatectomy and RFA yielded a better long-term outcome than TACE in patients with unresectable BCLC stage B HCC. Patients with a limited ablated size (≤2 cm), a limited number of ablations (≤2), and adequate surgical margin should be considered candidates for combination therapy.

Aberrant promoter methylation of SOCS-1 gene may contribute to the pathogenesis of hepatocellular carcinoma: a meta-analysis.

PURPOSE: We conducted this meta-analysis of published case-control studies aiming to evaluate the relationship between abnormal suppression of cytokine signaling-1 (SOCS-1) promoter methylation and the risk of hepatocellular carcinoma (HCC). METHODS: Relevant studies were retrieved from PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and China Biological Medicine (CBM) databases without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. We calculated odds ratio (OR) and its 95 % confidence interval (95% CI) to estimate the correlations. RESULTS: Sixteen case-control studies with a total of 941 HCC patients and 114 individuals with benign liver diseases met our inclusion criteria. Our results demonstrated that the frequency of SOCS-1 promoter methylation in cancer tissues was significantly higher than in adjacent non-tumorous tissues and benign tissues (cancer tissue vs adjacent tissue: OR=3.05, 95%CI 1.62-5.77, p=0.001; cancer tissue vs benign tissue: OR=11.55, 95%CI 5.93-22.49, p=0.000). Subgroup analyses by ethnicity, detecting method and sample size also suggested that abnormal SOCS-1 promoter methylation was correlated to the risk of HCC in the majority of these subgroups. CONCLUSION: Our findings provide empirical evidence that abnormal SOCS-1 promoter methylation may contribute to the pathogenesis of HCC. Thus, detection of SOCS-1 promoter methylation may be a valuable diagnostic biomarker for HCC.

Intermedin restricts vessel sprouting by inhibiting the loosening of endothelial junction.

Vessel sprouting from pre-existing vasculature is a key step for the formation of a functional vasculature. The low level of vascular endothelial growth factor (VEGF) induces normal and stable angiogenesis, whereas high level of VEGF causes irregular and over sprouted vasculature. Intermedin (IMD) is a novel member of calcitonin family, and was found to be able to restrict the excessive vessel sprouting. However, the underlying mechanism had not been elucidated. In this study, using in vitro and in vivo angiogenic models, we found that the loosening of endothelial junction could significantly increase the ability of low-dose VEGF to induce vessel sprouting. IMD inhibited the junction dissociation-induced vessel sprouting by re-establishing the complex of vascular endothelial cadherin on the cell-cell contact. Our findings suggested a novel mechanism through which IMD could restrict the excessive vessel sprouting by preventing the endothelial junction from dissociation, and provide new insight into the understanding of the regulation of sprouting angiogenesis.