Ren-jie Yang

Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models

AbstractAim:Oncolytic adenovirus, also called conditionally replicating adenovirus (CRAD), can selectively propagate in tumor cells and cause cell lysis. The released viral progeny can infect neighboring cancer cells, initiating a cascade that can lead to the ultimate destruction of the tumor. Suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) offers a potential treatment strategy for cancer and is undergoing preclinical trials for a variety of tumors. We hypothesized that HSV-TK gene therapy combined with oncolytic adenoviral therapy would have an enhanced effect compared with the individual effects of the therapies and is a potential novel therapeutic strategy to treat liver cancer.Methods:To address our hypothesis, a novel CRAD was created, which consisted of a telomerase-dependent oncolytic adenovirus engineered to express E1A and HSV-TK genes (Ad-ETK). The combined effect of Ad-ETK and GCV was assessed both in vitro and in vivo in nude mice bearing HepG2 cell-derived tumors. Expression of the therapeutic genes by the transduced tumor cells was analyzed by RT-PCR and Western blotting.Results:We confirmed that Ad-ETK had antitumorigenic effects on human hepatocellular carcinoma (HCC) both in vitro and in vivo, and the TK/GCV system enhanced oncolytic adenoviral therapy. We confirmed that both E1A and HSV-TK genes were expressed in vivo.Conclusion:The Ad-ETK construct should provide a relatively safe and selective approach to killing cancer cells and should be investigated as an adjuvant therapy for hepatocellular carcinoma.

Impact of Serum Vascular Endothelial Growth Factor on Prognosis in Patients with Unresectable Hepatocellular Carcinoma after Transarterial Chemoembolization

ObjectiveTo investigate the expression level of serum vascular endothelial growth factor (VEGF) in patients with unresectable hepatocellular carcinoma (HCC) and its relationship with the clinicopathological characteristics, and to assess the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization (TACE) treatments.MethodsSerum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) in 60 random patients who underwent TACE or transarterial infusion (TAI) for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients’ clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients’ survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis.ResultsThe median serum VEGF level in the HCC patients was 285 pg/ml (range 14–1,207 pg/ml), significantly higher than that of healthy controls (P=0.021). The serum VEGF levels were significantly correlated with platelet counts (r=0.396, P=0.002) but not other clinicopathological features. Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml (P=0.002). By multivariate analysis, the serum VEGF level was a significant prognostic factor.ConclusionHigh serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.

A comparative study between Embosphere® and conventional transcatheter arterial chemoembolization for treatment of unresectable liver metastasis from GIST

OBJECTIVE Transcatheter arterial chemoembolization (TACE) is a standard treatment for hepatocellular carcinoma (HCC) and/or some unresectable liver metastasis tumors. Hypervascular liver metastatic lesions such as metastasis from gastrointestinal stromal tumor (GIST) are an indication for transcatheter arterial embolization (TAE). The purpose of this study was to evaluate the efficacy and safety of Embosphere(®)-TAE (Embo-TAE) in comparison with conventional TACE (cTACE) for the treatment of liver metastasis from GIST. METHODS A total of 45 patients who underwent TACE between Aug 2008 and Feb 2013 were enrolled. Patients with GIST who underwent TAE with Embosphere(®) (n=19) were compared with controls who received cTACE (n=26). The primary end points were treatment response and treatment-related adverse events. The secondary end points were progression-free survival (PFS) and overall survival (OS). RESULTS The treatment response of Embo-TAE group was significantly higher than that of the cTACE group (P<0.001). The PFS was significantly better in the Embosphere(®)-group than in the cTACE group (56.6 and 42.1 weeks, respectively; P=0.003). However, there was no statistically significant difference in liver toxicity between the two groups (P>0.05). The median OS in the Embo-TAE group was longer than that in the cTACE group (74.0 weeks, 95% CI: 68.2-79.8 vs. 61.7 weeks, 95% CI: 56.2-67.2 weeks) (unadjusted P=0.045). The use of Embo-TAE significantly reduced the risk of death in patients with GIST with liver metastases according to the Cox proportional hazards regression model [hazard ratio (HR): 0.149; 95% CI: 0.064-0.475]. CONCLUSIONS TAE with Embosphere(®) showed better treatment response and delayed tumor progression compared with cTACE. There was no significant difference in treatment-related hepatic toxicities. Embo-TAE thus appears to be a feasible and promising approach in the treatment of liver metastasis from GIST.

Phase II Study of Hepatic Arterial Infusion Chemotherapy with Oxaliplatin and 5-Fluorouracil for Advanced Perihilar Cholangiocarcinoma

Purpose To evaluate the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin and 5-fluorouracil for advanced perihilar cholangiocarcinoma (PCC) in this prospective phase II study. Materials and Methods The protocol was approved by the local ethics committee, and all patients gave informed consent. Patients with nonresectable PCC were included in a prospective, open phase II study investigating HAI through interventionally implanted port catheters. HAI consisted of infusions of oxaliplatin 40 mg/m2 for 2 hours, followed by 5-fluorouracil 800 mg/m2 for 22 hours on days 1-3 every 3-4 weeks. A maximum of six cycles of HAI were applied for tumor control patients followed by maintenance with oral capecitabine until tumor progression. The primary end points were tumor response and progression-free survival (PFS). The secondary end points were local PFS, overall survival, and adverse events. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the risk factors for survival. Results Between 2012 and 2015, 37 patients were enrolled. The overall response rate was 67.6% (25 of 37), and the disease control rate was 89.2% (33 of 37). Median PFS, local PFS, and overall survival were 12.2, 25.0, and 20.5 months, respectively. All three survival lengths in patients with periductal infiltrating pattern were found to be significantly longer than those in patients with mass-forming pattern (P < .001, hazard ratio < 0.2). Macroscopic growth patterns (P = .018) and number of HAI cycles (P < .001) were independent risk factors of survival. The most frequent adverse events were grades 1 and 2 gastrointestinal side effects and sensory neuropathy in 31 (83.8%) and 28 (75.7%) patients, respectively. Conclusion HAI with oxaliplatin and 5-fluorouracil may be an encouraging treatment choice for advanced PCC due to its high tumor control, survival benefit, and low toxicity, especially in patients with periductal infiltrating pattern.

Hepatocellular carcinoma with blood supply from parasitized omental artery: Angiographic appearance and chemoembolization

ObjectiveTo analyze angiographic appearance of hepatocellular carcinoma (HCC) with blood supply from parasitized omental artery (POA), and evaluate the technical feasibility, safety and therapeutic efficacy of chemoembolization via the POAs.MethodsA total of 1,221 HCC patients who had undergone chemoembolization procedures were evaluated retrospectively. The evaluated indexes included the incidence rate of POAs, success rate of superselective catheterization, post-reaction after chemoembolization, and the cumulative survival rates.ResultsTotally 1,221 HCC patients had undergone 3,639 chemoembolization procedures, and 32 patients with POAs were enrolled, with 97 POAs found in 76 angiography procedures, giving an incidence rate of 2.09%. POA was observed mostly at the right lobe and left medial lobe except the segment II, and 62 POAs underwent superselective catheterization with microcatheter, giving a success rate of 63.9%. The angiographic appearance was: (1) hypertrophic POAs participating in tumor staining (n=28); (2) stiff and distorted POA (n=11), displaced due to tumor’s oppression (n=8); and (3) defective tumor staining close to either gastrocolic omentum distribution or liver capsule (n=7). In 19 patients, chemoembolization via POAs was performed successfully (A group), while the remaining 13 patients failed (B group). Except 1 acute edema pancreatitis case, no serious complication was recorded. The cumulative survival rates of 6-, 12-, 18- and 24-month were 78.9%, 47.4%, 31.6% and 21.1% respectively for A group; correspondingly, 61.5%, 30.8%, 15.4% and 7.7%% for B group, in which 2 patients died of ruptured HCC.ConclusionChemoembolization with microcatheter via POAs is a relatively safe, feasible and valuable method.

Chemoembolization alone vs combined chemoembolization and hepatic arterial infusion chemotherapy in inoperable hepatocellular carcinoma patients.

AIM To compare the efficacy and safety of chemoembolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy (HAIC), including oxaliplatin (OXA), 5-fluorouracil (5-FU) and folinic acid (CF), in inoperable hepatocellular carcinoma (HCC) without distant metastasis. METHODS Eighty-four inoperable HCC patients were enrolled. Thirty-nine patients underwent chemoembolization alone, and the other 45 patients underwent chemoembolization + HAIC (OXA/5-FU/CF) treatment non-randomly. The progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse reactions were compared between the two groups. RESULTS A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS (mPFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease, with or without vessel invasion, the chemoembolization + HAIC group showed better mPFS when compared to chemoembolization alone, but no significant difference was found in patients with BCLC stage C disease. The parameter of pain (grade III-IV) in the chemoembolization + HAIC group was increased statistically. CONCLUSION Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis.

Dual phase cone-beam computed tomography in detecting <3 cm hepatocellular carcinomas during transarterial chemoembolization

Objective: The objective of this study was to evaluate the sensitivity of dual phase cone-beam computed tomography (CBCT) in detecting small (<3 cm in diameter) hepatocellular carcinoma (HCC) tumors during transarterial chemoembolization (TACE). Materials and Methods: Twenty-two consecutive patients with unresectable small HCCs in whom TACE was performed were retrospectively evaluated. Contrast CT or contrast magnetic resonance imaging (MRI) was performed in all patients within 1 month prior to the procedure. Dual phase CBCT was performed prior to TACE and lipiodol-CBCT was performed after treatment. The sensitivity of dual phase CBCT in detecting small HCCs was compared to hepatic angiography, contrast enhanced CT and MRI. Results: Seventy HCC tumors with sizes of < 3 cm were detected in 22 patients. Dual phase CBCT depicted 67 small tumors either on arterial or venous phase and was significantly more sensitive compared to hepatic angiography, contrast CT, or MRI (95.7%, 65.7%, and 71.4%, respectively; P < 0.001). Conclusions: Dual phase CBCT is significantly more sensitive than hepatic angiography, contrast enhanced CT, and MRI in detecting smaller than 3 cm HCC tumors and can be a helpful modality in making accurate planning for treatment of HCC.