Wenzhe Fan

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Predictors of Survival and Metastasis for Recurrent Hepatocellular Carcinoma after Transarterial Chemoembolization

Purpose To evaluate whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) predict survival and metastasis in patients after transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma (RHCC). Materials and Methods Clinical and laboratory data from 132 RHCC patients treated with TACE from January 2003 to December 2012 were retrospectively reviewed. Prognostic factors were assessed by multivariate analysis, and the predictive values of NLR and PLR for overall survival (OS) and extrahepatic metastases were compared. Results Pretreatment mean NLR and PLR were 3.1 and 137, respectively. The 0.5-, 1-, and 2-year OS rates were 93.7%, 67.1%, and 10.1% in the low NLR group and 81.1%, 18.9%, and 3.8% in the high NLR group, respectively (P = 0.017). The corresponding OS rates in the low and high PLR groups were 92.5%, 58.1%, and 9.7% and 84.6%, 23.1%, and 2.6%, respectively (P = 0.030). The discriminatory performance predicting 1-year survival probability was significantly poorer for NLR (area under the curve [AUC] = 0.685, 95% confidence interval [CI] 0.598–0.763) than for PLR (AUC = 0.792, 95% CI 0.712–0.857; P = 0.0295), but was good for both ratios for predicting post-TACE extrahepatic metastasis. Multivariate analysis indicated that high PLR (hazard ratio [HR] = 0.373, 95% CI = 0.216-0.644, P < 0.001, vascular invasion (HR = 0.507, 95% CI = 0.310–0.832, P = 0.007), and multiple tumors (HR= 0.553, 95% CI = 0.333–0.919, P = 0.022) were independent prognostic factors for OS. Conclusions High NLR and PLR were both associated with poor prognosis and metastasis in RHCC patients treated with TACE, but high PLR was a better predictor of 1-year OS. High PLR, vascular invasion, and multiple tumors were independent, unfavorable prognostic factors.

OPN and αvβ3 expression are predictors of disease severity and worse prognosis in hepatocellular carcinoma.

Expressions of OPN and αvβ3 are associated with a poor prognosis in many malignancies. However, their relationship in hepatocellular carcinoma remains unclear. We systematically collected hepatocellular carcinoma tissue samples from 305 patients over 3 years, and analyzed the status of OPN and αvβ3 in hepatocellular carcinoma and correlate expression with patient disease status and survival outcome. Our study results indicated that OPN and αvβ3 are expressed at significantly higher rates in hepatocellular carcinoma compared with adjacent non-tumorous tissue (69.5% vs 18.4%, p<0.01 and 77.4% vs 21.6%, p<0.01, respectively). Both OPN and αvβ3 expression levels are associated with poor prognostic factors, including tumor size, capsular invasion, tumor thrombus of the portal vein, metastasis of the lymph node and clinical staging. Patients expressing OPN and αvβ3 had significantly shorter survival compared with patients negative for protein expression (p<0.01). Multivariate analysis also showed that both OPN and αvβ3 expression are independent prognostic factors for poorer survival in hepatocellular carcinoma. By this study, we conclude that OPN and αvβ3 are negative prognostic predictors in patients with hepatocellular carcinoma. The expressions of both OPN and αvβ3 are associated with worse survival outcome.

Decreased WWOX expression promotes angiogenesis in osteosarcoma

WWOX (WW domain-containing oxidoreductase) is known to be an important tumor suppressor in cancer. In this study, we used samples from 201 osteosarcoma patients to investigate the effects of WWOX on angiogenesis and invasion. WWOX levels were negatively correlated with RUNX2 and VEGF levels, but were not correlated with OPN levels. Among the clinicopathological characteristics examined, WWOX was associated only with response to neoadjuvant chemotherapy, and its expression in osteosarcoma tissues was a predictor of disease-free survival. WWOX promoted apoptosis and inhibited invasion and expression of bcl-2, OPN, RUNX2, and VEGF in osteosarcoma cells in vitro. In MG-63 cells, bcl-2 increased VEGF expression, while RUNX2 increased VEGF and OPN expression. Administration of DNA methylation inhibitors increased WWOX expression in MG-63 cells and methylation of WWOX gene promoter CpG island in the osteosarcoma of patients was associated with suppression of WWOX expression. Overexpression of WWOX in osteosarcoma cells inhibited tube formation in co-cultured HUVEC cells, and high WWOX expression was associated with decreased microvessel density (MVD). These results suggest that reduced WWOX expression in osteosarcoma inhibits apoptosis, promotes invasion and increases MVD.WWOX (WW domain-containing oxidoreductase) is known to be an important tumor suppressor in cancer. In this study, we used samples from 201 osteosarcoma patients to investigate the effects of WWOX on angiogenesis and invasion. WWOX levels were negatively correlated with RUNX2 and VEGF levels, but were not correlated with OPN levels. Among the clinicopathological characteristics examined, WWOX was associated only with response to neoadjuvant chemotherapy, and its expression in osteosarcoma tissues was a predictor of disease-free survival. WWOX promoted apoptosis and inhibited invasion and expression of bcl-2, OPN, RUNX2, and VEGF in osteosarcoma cells in vitro. In MG-63 cells, bcl-2 increased VEGF expression, while RUNX2 increased VEGF and OPN expression. Administration of DNA methylation inhibitors increased WWOX expression in MG-63 cells and methylation of WWOX gene promoter CpG island in the osteosarcoma of patients was associated with suppression of WWOX expression. Overexpression of WWOX in osteosarcoma cells inhibited tube formation in co-cultured HUVEC cells, and high WWOX expression was associated with decreased microvessel density (MVD). These results suggest that reduced WWOX expression in osteosarcoma inhibits apoptosis, promotes invasion and increases MVD.

Comparison of intraluminal radiofrequency ablation and stents vs. stents alone in the management of malignant biliary obstruction.

Abstract Purpose: To retrospectively evaluate the added benefit of adding intraluminal radiofrequency ablation (RFA) to biliary metal stent placement for patients with malignant biliary obstruction (MBO). Methods: From November 2013 to December 2015, 89 patients with MBO who had undergone percutaneous intraluminal RFA and stent placement (RFA-stent group, n = 50) or stent placement only (stent group, n = 39) were included. Outcomes were compared according to the type of tumour: cholangiocarcinoma or non-cholangiocarcinoma. Results: Primary and secondary stent patency (PSP, SSP) were significantly higher for the RFA-stent group than the stent group (PSP: 7.0 months vs. 5.0 months, p = 0.006; SSP: 10.0 months vs. 5.6 months, p < 0.001), with overall survival being comparable (5.0 months vs. 4.7 months, p = 0.068). In subgroup analysis, RFA-stent showed significant PSP benefits compared to stent alone in patients with cholangiocarcinoma (7.4 months vs. 4.3 months; p = 0.009), but with comparable outcomes in patients with non-cholangiocarcinoma (6.3 months vs. 5.2 months; p = 0.266). The SSP was improved in both subgroups (cholangiocarcinoma, 12.6 months vs. 5.0 months, p < 0.001; non-cholangiocarcinoma, 10.3 months vs. 5.5 months, p = 0.013). Technical success and clinical success were not significantly different between the two groups. The rate of complication was higher for the RFA-stent group, but tolerable when compared to the stent group. Conclusions: Although survival was comparable between the groups, RFA-stent confers therapeutic benefits to patients with MBO in terms of stent patency compared to stent placement alone, especially in those with cholangiocarcinoma.

Percutaneous computed tomography-guided cryoablation for recurrent retroperitoneal soft tissue sarcoma: a study of safety and efficacy

Aims To evaluate the use of computed tomography image-guided percutaneous cryoablation for recurrent retroperitoneal soft tissue sarcomas (RPSs). Results Adverse events were limited to grades 1 and 2, included fever (n = 19), local pain (n = 11), emesis (n = 10), frostbite (n = 6), and nerve injury (n = 1). Fever was more frequent in the large tumor group (15.8%) than in small tumor group (1.9%) (P = 0.008). Median PFS and OS were 37.0 ± 7.7 months (range, 4–39 months) and 43.0 ± 5.9 months (range, 6–54 months), respectively. PFS and OS were significantly longer in the small tumor group than in the large tumor group (P = 0.011 and P = 0.015, respectively), but the response rate (82.7% vs. 72.8%, P = 0.240) did not differ significantly. On univariate analysis, tumor size, tumor invasion grade, and distant metastasis were significant prognostic factors for PFS and OS. On multivariate analysis, a tumor size ≥10 cm was an independent negative prognostic factor for PFS and OS after cryoablation (HR: 3.98, 95% CI: 1.27–12.50, P = 0.018 and HR: 4.33, 95% CI: 1.41–13.26, P = 0.010, respectively). Materials and Methods Data from 72 patients with recurrent RPSs who underwent percutaneous cryoablation were reviewed retrospectively. The prognostic factors for progression-free survival (PFS), overall survival (OS), and efficacy based on mRECIST criteria were analysis. Adverse events were compared according to tumor size (<10 and ≥10 cm). Conclusion Minimally invasive percutaneous cryoablation was safe and efficacious for recurrent RPSs.

Initial Experience: Alleviation of Pain with Percutaneous CT–Guided Cryoablation for Recurrent Retroperitoneal Soft-Tissue Sarcoma

PURPOSE To evaluate the pain-alleviating effect of computed tomography (CT)-guided percutaneous cryoablation for recurrent retroperitoneal soft-tissue sarcomas (RPSs). MATERIALS AND METHODS Data from 19 men and 20 women (median age, 50.3 y) with recurrent malignant RPS who underwent percutaneous cryoablation were reviewed retrospectively. A total of 50 tumors were treated by cryoablation, including a single tumor in 29 patients, 2 tumors in 9, and 3 tumors in 1. Adverse events and analgesic outcomes were compared as a function of tumor size (< 10 cm and ≥ 10 cm). Efficacy was assessed based on modified Response Evaluation Criteria In Solid Tumors and progression-free survival (PFS). RESULTS Grade 1/2 adverse events included fever (n = 17), emesis (n = 7), frostbite (n = 5), and local pain (n = 4). The median follow-up period and PFS were 18.5 months (range, 12-42 mo) and 13.4 months ± 6.2, respectively. At the end of follow-up, 13 patients had died and 26 were living. The mean severe local pain scores on pretreatment day 1 and posttreatment days 1, 5, 10, 15, 20, and 25 were 7.49, 7.40, 6.51, 5.81, 5.35, 5.04, and 5.44, respectively, and significant differences versus pretreatment (P < .001) were reported for posttreatment days 5-25. Immediate relief occurred more frequently in the small-tumor group (4 of 7; 57.1%; P = .018), whereas delayed relief occurred more frequently in the large-tumor group (17 of 22; 77.3%; P = .030). CONCLUSIONS Minimally invasive percutaneous cryoablation improves local pain and is a feasible treatment for recurrent RPSs.

Raltitrexed based Transcatheter Arterial Chemoembolization (TACE) forUnresectable Hepatocellular Carcinoma: A Single-center Randomized ControlledStudy

Background: We aimed to evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE), a combination of raltitrexed, oxaliplatin, and epirubicin, for unresectable hepatocellular carcinoma (HCC). Methods: We enrolled 163 patients in this single-center, randomized, controlled trial comparing TACE with epirubicin and oxaliplatin (control group; 83 patients) to TACE with raltitrexed, epirubicin, and oxaliplatin (raltitrexed group; 80 patients).The primary endpoint was overall survival(OS);secondary endpoints included progression-free survival(PFS),tumor response and adverse events. Results: The median progression-free survival (mPFS) and overall survival (mOS) were similar (mPFS: 4.3 vs. 4.6 months, P = 0.201; mOS: 9.6 vs. 9.8 months, P = 0.698, respectively). The disease control rates for the control and raltitrexed groups were 57.8% and 63.8%, respectively, and did not reach statistical significance (P = 0.439). Adverse events were also similar in both the groups (P > 0.05). Conclusion: Although the study did not meet its primary endpoint, the treatment induced a high response rate and promising PFS and OS rates in patients, suggests that the use of raltitrexed as an alternative for TACE may confer some benefit to patients with unresectable HCC.

Percutaneous Intraductal Radiofrequency Ablation for Malignant Biliary Obstruction Caused by Recurrence and Metastasis after Primary Tumor Resection

Background: To assess the feasibility and safety of percutaneous intraductal radiofrequency ablation (RFA) for malignant biliary obstruction caused by recurrence and metastasis after primary tumor resection. Patients and Methods: Percutaneous intraductal biliary RFA and stent placement were performed in 19 consecutive patients with 24 RFA procedures. Procedure-related complications, stent patency, and survival after treatment were investigated. Results: During 30 days after each RFA procedure there was no 30-day mortality, hemorrhage, bile duct perforation, or pancreatitis. Of the 19 patients, 2 are still alive and 17 are dead with a median survival time of 6.0 (range 1.2-16) months and a median stent patency of 3.2 (range 1.2-14) months. 10 patients had their stent patent at the time of last follow-up or death. 3 patients with stent blockage at 50, 182, and 200 days post procedure underwent repeat ablation. 1 patient with stent blockage underwent 2 repeat RFA procedures at 192 days after the first ablation and at 86 days after the repeat ablation. Conclusion: Percutaneous intraductal RFA is a technically safe and feasible therapeutic option for palliative treatment of these selected patients.

A novel mechanism of the M1-M2 methionine adenosyltransferase switch-mediated hepatocellular carcinoma metastasis

Hepatocellular carcinoma (HCC) manifests as a highly metastatic cancer with extremely poor prognosis. However, mechanisms underlying metastasis of HCC are not fully understood. Here, we showed that switching gene expression from MAT1A to MAT2A (M1‐M2 switch) promoted cancer invasion and metastasis. Reversion of the M1‐M2 switch repressed, whereas enhancing the M1‐M2 switch promoted the ability of HCC cells to metastasize. Moreover, we provided clinical data showing that tipping the balance between MAT1A and MAT2A expression correlated with increased metastasis and inferior recurrence‐free survival in HCC patients. Molecular pathways analysis showed that downregulation of MAT1A, which augmented osteopontin (OPN) expression through decreasing methylation of the OPN promoter, and MAT2A upregulation, which induced integrin β3 (ITGB3) expression by binding to ITGB3 promoter, collaboratively triggered ERK signaling and thereby promoted metastasis. Thus, the simultaneous downregulation of MAT1A and upregulation of MAT2A are necessary and sufficient for HCC metastasis in the process of M1‐M2 switch. Our findings provide novel mechanistic insights into cancer metastasis. Inhibition and prevention of the M1‐M2 switch would offer a novel therapeutic option for treatment of HCC.

Large hepatocellular carcinomas: treatment with transarterial chemoembolization alone or in combination with percutaneous cryoablation

Abstract Purpose: To evaluate the safety and efficacy of transarterial chemoembolization (TACE) combined with cryoablation (TACE-cryoablation) in large (main tumor ≥5 cm in diameter) hepatocellular carcinomas (HCCs). Methods: From January 2010 to December 2015, 56 patients were treated with combination therapy via a single TACE session followed by one to three percutaneous cryoablation sessions twice a week (TACE-cryoablation group). A total of 54 patients were treated with TACE alone for two to six sessions once a month (TACE group). The decision between TACE and TACE cryoablation was based on patient choice. Outcomes of patients in two groups were compared according to the largest tumor diameter (subgroup): Group A (5 cm ≤ tumor <10 cm), Group B (10 cm ≤ tumor <15 cm), and Group C (tumor ≥15 cm). Results: The mean number of cryoablation sessions per patient was 2.3 (range: 1–6). Within Group B, TACE-cryoablation significantly improved survival compared with TACE alone (11.0 vs 6.0 months; p = .008). This was also seen in Group C (8.0 vs 5.0 months; p = .001). However, no significant difference was noted in Group A (17.0 vs 13.0 months; p = .674). The complications related to TACE were comparable between the two groups. Two adverse events of grade 3 − 4 related to cryoablation occurred in two patients (3.6%). The independent prognostic factors for survival included: TACE cryoablation, AFP level, main tumor size and extrahepatic metastasis. Conclusions: TACE-cryoablation may improve overall survival in patients with HCC who presented with a tumor diameter ≥10 cm, with minimal complications, when compared with TACE alone.