Byeong-Ho Park

The Targeted Oncolytic Poxvirus JX-594 Demonstrates Antitumoral, Antivascular, and Anti-HBV Activities in Patients With Hepatocellular Carcinoma

JX-594 is a targeted oncolytic poxvirus that is designed to eradicate cancer cells having cell-cycle defects, through replication, cell lysis, and spread within tumors; oncolysis-induced tumor vascular shutdown and immunostimulation are augmented by granulocyte monocyte-colony-stimulating factor (GM-CSF) transgene expression. We have previously shown, in animal models of hepatocellular carcinoma (HCC), that JX-594 is a promising anticancer agent. We tested JX-594 in three patients with advanced refractory hepatitis B virus (HBV)-associated HCC through intratumoral administration. JX-594 treatment was well-tolerated and resulted in antitumoral efficacy in all three patients, despite the presence of high levels of neutralizing antibodies. JX-594 replication, its release into the circulation, distant tumor targeting were demonstrated. JX-594 administration resulted in the induction of antivascular cytokines, and was associated with tumor vascular shutdown. We also showed, for the first time, that oncolytic virotherapy can suppress underlying HBV replication in HCC patients, and that tumor tissue could be the primary source of acute HBV replication and acute post-treatment HBV release. JX-594 treatment in HBV-associated HCC warrants further clinical testing; a Phase II trial is underway.

Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model

Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species.

Hepatic involvement in hypereosinophilia: sonographic findings.

Hypereosinophilic syndrome may cause eosinophil‐related tissue damage to various organs. The purpose of this paper is to describe sonographic findings in 13 patients with hypereosinophilia in whom the liver was involved. The diagnosis in these 13 patients was based on liver biopsy in seven patients with bone marrow biopsy in six patients. Eight patients had hypereosinophilic syndrome and five patients had clonorchiasis. All 13 patients had mild to marked hepatomegaly. Seven of 13 patients showed multiple round or oval hypoechoic (n = 6) or variably echogenic (n = 1) lesions measuring 1 to 2 cm with poorly defined margins in both lobes of the liver. Four patients had one or two hypoechoic lesions 3 to 4 cm in size, with geographic pattern and poorly defined margins. Two patients showed diffuse hepatomegaly with increased parenchymal echogenicity. The number of lesions and the extent of diffuse lesions seem to be proportional to the degree of eosinophilia. Hypereosinophilia may produce multiple small focal hepatic lesions or diffuse segmental or lobar echogenic lesions simulating primary or metastatic tumor of the liver.

Vascular administration of adenoviral vector soaked in absorbable gelatin sponge particles (GSP) prolongs the transgene expression in hepatocytes

Transcatheter hepatic arterial chemoembolization using emulsions composed of anticancer agents and gelatin sponges (GS) has been an efficient and safe palliative treatment for inoperable hepatocellular carcinoma (HCC). We employed catheter-mediated left hepatic arterial embolization (CHAE) to increase transduction efficiency of adenoviral vector in canine hepatocytes. The emulsion was prepared by mixing pieces of GSP and adenoviral vectors expressing recombinant β-galactosidase (Ad.LacZ) or human hepatocyte growth factor (Ad.hHGF). After the left hepatic artery was catheterized under angiography, CHAE with Ad.LacZ or Ad.hHGF was performed. Livers were removed and stained for LacZ activity on day 7. The expression pattern of LacZ staining was either scarce or patchy around the central hilum of the hepatic artery, or was homogeneously distributed in whole lobes, depending on whether large or small pieces of GSP were used. Hematological and serum biochemical changes during CHAE exhibited only a few effects. The chronological measurement of serum HGF concentration showed that the duration of transgene expression was greater after CHAE with Ad.hHGF. A similar pattern of transgene expression was observed in a rat model after hepatic arterial embolization with differential doses of Ad.hHGF soaked in GSP. These results suggest that hepatic arterial embolization by transcatheter mediated infusion with a mixture of adenovirus-GSP could be used for human HCC.

Suprapapillary versus Transpapillary Stent Placement for Malignant Biliary Obstruction: Which Is Better?

PURPOSE To compare the complications, stent patency, and patient survival with self-expandable metal stents (SEMSs) placed above or across the sphincter of Oddi in malignant biliary obstruction. MATERIALS AND METHODS From January 2008 to December 2012, 155 patients were treated with percutaneous transhepatic SEMS placement. Seventy-four patients underwent suprapapillary stent placement (group A), and 81 patients underwent transpapillary stent placement (group B). Complications rates, stent patency, and patient survival were evaluated and analyzed for potential predictors. RESULTS In group A, 68 covered and 28 uncovered SEMSs were placed, and, in group B, 78 covered and 19 uncovered SEMSs were placed. Thirty-six stent-related early complications were observed in a total of 154 patients (23.4%): pancreatitis (n = 23), cholangitis (n = 12), and cholecystitis (n = 1). The early complication rates for groups A and B were 14.9% (11 of 74) and 31.3% (25 of 80), respectively (P = .016). Pancreatitis occurred in three patients (4.1%) in group A and 20 patients (25.0%) in group B (P = .001). Stent location was a single independent predictor of pancreatitis (P < .001). Stent occlusions by tumor growth was more frequently observed in group A than in group B (P = .007), whereas stent occlusion by sludge incrustation was more frequently found in group B than in group A (P = .007). There was no significant difference in cumulative stent patency (P = .401) or patient survival (P = .792) between groups. CONCLUSIONS To decrease the incidence of pancreatitis, suprapapillary placement of SEMSs is recommended for malignant biliary obstruction, but not in the lower 2 cm of the common bile duct.