Hyun Young Woo

Sequential Therapy With JX-594, A Targeted Oncolytic Poxvirus, Followed by Sorafenib in Hepatocellular Carcinoma: Preclinical and Clinical Demonstration of Combination Efficacy

JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.

Long‐term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus–related cirrhosis

The effect of viral suppression on long‐term disease outcome after decompensation in patients with hepatitis B virus (HBV)‐related cirrhosis has not been established. The aim of this study was to determine the long‐term effect of antiviral therapy (AVT) in patients with HBV‐related decompensated cirrhosis. This was a multicenter, prospective, inception cohort study of 707 patients who presented with first‐onset decompensated complications, including 284 untreated and 423 antiviral‐treated patients (58 previously treated, 253 with early treatment, and 112 with delayed treatment). The primary endpoint was 5‐year liver transplantation (LT)‐free survival. Secondary endpoints included virological response (VR) and serological response and improvement in liver function. Despite baseline high HBV activity and worse liver function, antiviral‐treated patients had significantly better transplant‐free survival than untreated patients (5‐year survival rates of 59.7% vs. 46.0%, respectively), with more apparent benefits from antivirals in Child‐Turcotte‐Pugh class B/C and high‐viremia groups. The rate of VR and hepatitis B e antigen seroconversion at 5 years in antiviral‐treated patients was 14.2% and 49.1%, respectively. A significant improvement in liver function was observed in treated versus untreated patients, with 33.9% of treated patients delisted for LT. Patients with early treatment had better clinical outcomes than those with delayed treatment. Survival was dependent on antiviral response, being significantly better in responders than in nonresponders or untreated cases. The initial benefit of AVT was negated over time in nonresponders. Antiviral treatment and maintained VR remained independently predictive of survival. The study results were corroborated by propensity score‐matching analysis. Conclusion: AVT significantly modifies the natural history of decompensated cirrhosis, improving liver function and increasing survival. The results underscore the importance of promptly administering potent antiviral drugs to patients under consideration for LT. (Hepatology 2015;61:1808–1820)

Current consensus and guidelines of contrast enhanced ultrasound for the characterization of focal liver lesions

The application of ultrasound contrast agents (UCAs) is considered essential when evaluating focal liver lesions (FLLs) using ultrasonography (US). Microbubble UCAs are easy to use and robust; their use poses no risk of nephrotoxicity and requires no ionizing radiation. The unique features of contrast enhanced US (CEUS) are not only noninvasiveness but also real-time assessing of liver perfusion throughout the vascular phases. The later feature has led to dramatic improvement in the diagnostic accuracy of US for detection and characterization of FLLs as well as the guidance to therapeutic procedures and evaluation of response to treatment. This article describes the current consensus and guidelines for the use of UCAs for the FLLs that are commonly encountered in US. After a brief description of the bases of different CEUS techniques, contrast-enhancement patterns of different types of benign and malignant FLLs and other clinical applications are described and discussed on the basis of our experience and the literature data.

The impact of hepatitis B viral load on recurrence after complete necrosis in patients with hepatocellular carcinoma who receive transarterial chemolipiodolization: implications for viral suppression to reduce the risk of cancer recurrence.

Hepatocellular carcinoma (HCC) has a high tendency for recurrence after radical treatment. Apart from tumor and liver function parameters, little is known about the role of hepatitis B virus (HBV) factors in the recurrence of HCC. The objective of this study was to identify the potential relation between viral load and HCC recurrence in patients undergoing transarterial chemolipiodolization.

Risk of HBV reactivation according to viral status and treatment intensity in patients with hepatocellular carcinoma.

BACKGROUND There are no convincing data supporting the routine use of pre-emptive therapy against HBV reactivation in various loco-regional therapies for hepatocellular carcinoma (HCC). This study investigated the incidence, severity and risk factors of HBV reactivation during loco-regional therapies. METHODS A total of 205 prospectively enrolled patients were classified in order of increasing intensity of loco-regional therapies: local ablation therapy (LAT; 43 patients), transarterial chemotherapy using adriamycin (TAC-ADR; 93 patients) or combined epirubicin-cisplatin (TAC-EC; 26 patients), and combined chemo-radiotherapy (TAC-EC+RT; 43 patients). RESULTS During the follow-up, 62 (30.2%) patients developed HBV reactivation. Multivariate analysis identified HBV DNA levels >10⁴ copies/ml (P=0.041) and treatment option (P=0.001) to be independent predictors of HBV reactivation. There was a significant trend for increasing risk of reactivation with increasing intensity of therapy, with hazard ratios of 1.0 for LAT, 2.45 for TAC-ADR, 4.19 for TAC-EC and 10.17 for TAC-EC+RT. The severity of reactivated disease was also increased with increasing treatment intensity (P-value for trend <0.05). Only one of the patients with low-level viraemia receiving LAT alone developed reactivation, whereas a substantial number of patients with high-level viraemia eventually developed reactivation. CONCLUSIONS High-level viraemia and high-level treatment intensity are the major risk factors for HBV reactivation during loco-regional therapy. Trends are evident for the increased risk and severity of reactivation with the aggressiveness of treatment. Pre-emptive antiviral therapy should be recommended for all patients with high-level viraemia irrespective of treatment option, or those undergoing any intensive therapy.

Marginal turbid band and light blue crest, signs observed in magnifying narrow-band imaging endoscopy, are indicative of gastric intestinal metaplasia

BackgroundGastric intestinal metaplasia (IM) usually appears in flat mucosa and shows few morphologic changes, making diagnosis using conventional endoscopy unreliable. Magnifying narrow-band imaging (NBI) endoscopy enables evaluation of detailed morphological features that correspond with the underlying histology. The aim of this study was to investigate and clarify the diagnostic efficacy of magnifying NBI endoscopic findings for the prediction and diagnosis of IM.MethodsForty-seven patients were prospectively enrolled, and magnifying NBI examinations were performed in the lesser curvature of the midbody and the greater curvature of the upper body. The marginal turbid band (MTB) was defined as an enclosing white turbid band on the epithelial surface/gyri; light blue crest (LBC), as a fine, blue-white line on the crest of the epithelial surface/gyri. Immediately after observation under magnifying endoscopy, biopsy specimens were obtained from the evaluated areas.ResultsThe degree of IM significantly increased with increasing MTB/LBC positivity (MTB-/LBC-, 0.00 ± 0.00; MTB+/LBC-, 0.44 ± 0.51; MTB+/LBC+, 0.94 ± 0.24; p < 0.001). Moderate-to-severe IM was more common in MTB+/LBC+ areas than in MTB+/LBC- areas (p < 0.001). For the diagnosis of IM, MTB had a sensitivity, specificity, and accuracy of 100%, 66.0%, and 81.7%, respectively, and the corresponding values for LBC were 72.1%, 96.0%, and 84.9%.ConclusionMTB and LBC observed in the gastric mucosa with magnifying NBI endoscopy are highly accurate indicators of the presence of IM. MTB likely represents a sign of early gastric IM, while LBC appears with progression to severe IM.

A comparative study of high-dose hepatic arterial infusion chemotherapy and transarterial chemoembolization using doxorubicin for intractable, advanced hepatocellular carcinoma.

Background/Aims Transarterial chemoembolization (TACE) has long been used as a palliative therapy for unresectable hepatocellular carcinoma (HCC). High-dose hepatic arterial infusion chemotherapy (HAIC) has showed favorable outcomes in patients with intractable, advanced HCC. The aim of this study was to compare the effectiveness and safety of high-dose HAIC and conventional TACE using doxorubicin for advanced HCC. Methods The high-dose HAIC group comprised 36 patients who were enrolled prospectively from six institutions. The enrollment criteria were good liver function, main portal vein invasion (including vascular shunt), infiltrative type, bilobar involvement, and/or refractory to prior conventional treatment (TACE, radiofrequency ablation, or percutaneous ethanol injection), and documented progressive disease. Patients received 5-fluorouracil (500 mg/m2 on days 1~3) and cisplatin (60 mg/m2 on day 2 every 4 weeks) via an implantable port system. In the TACE group, 31 patients with characteristics similar to those in the high-dose HAIC group were recruited retrospectively from a single center. Patients underwent a transarterial infusion of doxorubicin every 4~8 weeks. Results Overall, 6 patients (8.9%) achieved a partial response and 20 patients (29.8%) had stable disease. The objective response rate (complete response+partial response) was significantly better in the high-dose HAIC group than in the TACE group (16.7% vs. 0%, P=0.030). Overall survival was longer in the high-dose HAIC group than in the TACE group (median survival, 193 vs. 119 days; P=0.026). There were no serious adverse effects in the high-dose HAIC group, while hepatic complications occurred more often in the TACE group. Conclusions High-dose HAIC appears to improve the tumor response and survival outcome compared to conventional TACE using doxorubicin in patients with intractable, advanced HCC.

Role of long-term lamivudine treatment of hepatitis B virus recurrence after liver transplantation.

In this study, the long‐term (>3 years) efficacy of combination therapy for hepatitis B virus (HBV) recurrence and the associated factors were investigated. One hundred and sixty‐five consecutive HBsAg‐positive patients (92 with liver cirrhosis, 73 with hepatocellular carcinoma; HCC) who underwent liver transplantation were assessed with a median follow‐up time of 40 months. One hundred and twenty‐one patients (121/165, 73.3%) were treated with lamivudine before transplantation for a mean of 8.4 months (range 0.1–72 months). The post‐transplantation treatment protocol consisted of a high dose intravenous hepatitis B immunoglobulin (HBIg) followed by a low dose intramuscular HBIg and lamivudine combination therapy. Seven (4.2%, 7/165) recipients experienced HBV recurrence at a median time of 19 months (range 5–36 months) following transplantation. Six of seven cases of HBV recurrence were treated with lamivudine before transplantation for a median period of 15 months (range 0.6–30 months). Eighteen (24.6%, 18/73) patients had HCC recurrences after transplantation. Of the four patients with both HCC and HBV recurrence, three experienced HBV recurrence after recurrence of HCC. The clinical factor associated with HBV recurrence in the total cohort (n = 165) was the duration of antiviral treatment (over 6 months) before transplantation (P = 0.004). In the HCC group, HCC recurrence after transplantation (P = 0.002), tumor burden before transplantation (P = 0.005), and postoperative adjuvant chemotherapy (P = 0.002), were additional factors for HBV recurrence. Combination therapy of HBIg and antiviral drugs was effective over 3 years regardless of the pretransplantation viral load. However, the possible recurrence of HBV needs to be monitored cautiously in patients treated with long‐term (over 6 months) lamivudine. J. Med. Virol. 80:1891–1899, 2008.

Serum IP-10 Levels Correlate with the Severity of Liver Histopathology in Patients Infected with Genotype-1 HCV

Background/Aims Interferon-γ-inducible protein 10 (IP-10) plays important roles in the pathogenesis of hepatitis C virus (HCV) infection. We investigated the association between serum IP-10 levels and liver pathology in patients with chronic HCV infection. Methods The serum IP-10 concentration was assessed in 85 patients with chronic HCV infection using a solid phase sandwich enzyme-linked immunosorbent assay, and a liver biopsy specimen was obtained. The pathology was scored using the Knodell histologic activity index (HAI). Results Of the 85 patients, 58 had genotype 1 HCV infection, 21 had genotype non-1, and 6 were undetermined. The serum IP-10 levels did not differ between patients infected with genotype 1 and genotype non-1 (p=0.472). In patients with genotype 1 infection, the total HAI score and the stage of fibrosis were highly correlated with the serum IP-10 level (r=0.555, r=0.578, p<0.001). Furthermore, the serum IP-10 concentrations of patients with severe fibrosis (stages 3, 4) were higher than those of patients with mild fibrosis (stages 0 to 2; 214.4 vs. 72.3 pg/mL, p=0.002) among patients with genotype 1 infection. However, in patients without genotype 1 infection, the histopathology was not associated with the serum IP-10 level. A multivariate analysis showed that serum IP-10 was an independent predictor of fibrosis (stages 3, 4) in patients with genotype 1 infection (odds ratio, 1.034; 95% confidence interval, 1.006 to 1.064; p=0.018). Conclusions Serum IP-10 concentration was significantly correlated with the severity of liver histology in genotype 1 HCV infection.

Tumor doubling time after initial response to transarterial chemoembolization in patients with hepatocellular carcinoma

Abstract Objective. Following initial transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC), these tumors can frequently recur, making it important to determine the appropriate follow-up interval after initial response to TACE. We therefore assessed the time taken by new recurrent HCCs to double in volume after an initial response to TACE. Material and methods. This retrospective cohort study included 73 patients who achieved an initial response after TACE. After intrahepatic distant recurrence of HCC, dynamic CT scans were reviewed by two radiologists without clinical information, and the doubling time of new recurrent nodules was determined. The relationship between doubling time and clinical factors was also analyzed. Results. In 32 of the 73 patients, 40 intrahepatic distant recurrent (IDR) nodules were detected over a median period of 14 months (range 4–46 months). The 1-, 2- and 3-year cumulative IDR rates of patients were 27%, 45% and 65%, respectively. The doubling time of IDR HCC ranged from 20 to 104 days, with a median of 46 days. Over 90% of IDR HCCs had a doubling time of less than 3 months. The doubling time (median 108 days; range 51–129 days) of primary HCC in five patients for whom we had information regarding primary tumors was longer than that of recurrent nodules (median 28 days; range 24–90 days) in the same five patients (P = 0.022). Conclusions. The median doubling time of IDR HCCs after an initial response was 47 days (range 20–104 days). These findings indicate that the appropriate follow-up interval for dynamic CT in patients with an initial response after TACE is less than 3 months.