Yoshiki Suginoshita

Gray-scale second harmonic imaging of the liver with galactose-based microbubbles

RATIONALE AND OBJECTIVES The authors evaluate the efficacy of SHU 508A, a galactose-based contrast agent used in gray-scale second harmonic imaging in vitro and in vivo experiments. METHODS A Toshiba prototype harmonic imaging system (2.5/5.0 MHz) was used with SHU 508A in a phantom experiment and to image the liver in five healthy rabbits and one rabbit that had VX-2 tumors in the liver. RESULTS In the second harmonic imaging, most of the fundamental components of the backscattered echo were eliminated, and good images with high contrast were obtained in the phantom experiment. Liver parenchyma was enhanced clearly in all rabbits at 0.3 mL/kg, an effect that lasted for 90 seconds. The tumor, which was mostly necrotic, was depicted clearly as a negative enhanced area surrounded by enhanced healthy liver. CONCLUSIONS Gray-scale second harmonic imaging is a promising new method for visualization of perfusion of organs.

Gray scale second harmonic imaging of the liver: A preliminary animal study

Gray scale second harmonic imaging (2.5 MHz/5.0 MHz) was evaluated in preliminary animal studies with a new ultrasound contrast agent (FS069). FS069 was administered intravenously in 10 rabbits (6 with normal liver, and 4 with implanted VX-2 tumors) and two woodchucks with hepatocellular carcinomas. The vasculature (including tumor vessels) and liver parenchyma were clearly enhanced at a low dosage (optimal dose was from 0.1 to 0.2 mL/kg) in all cases. Enhancement was reproducible and generally dose-dependent. Tumors were enhanced well during the early phase and tumor enhancement disappeared earlier than that of surrounding normal liver. Arterial phase and portal phase were easily distinguished and patterns of enhancement were diagnostic of the tumors. Gray scale second harmonic imaging is useful in the detection of hepatic tumors and in diagnosis of their hemodynamics.

Liver targeting of human interferon-β with pullulan based on metal coordination

Abstract Although interferon (IFN)-β is widely used for the elimination of hepatitis C virus in patients with chronic liver disease, its clinical efficacy is unsatisfactory. Targeting IFN-β to the liver might enhance its efficacy without increasing its side effects. The objective of the present study was to target IFN-β to the liver to enhance its biological activity and reduce its side effects. A chelating residue, diethylenetriaminepentaacetic acid (DTPA), was introduced to pullulan, a water-soluble polysaccharide with a high affinity to the liver (DTPA-pullulan) and natural human IFN-β was coordinately conjugated with the DTPA-pullulan by mixing in an aqueous solution containing zinc ions (Zn 2+ ). Intravenous injection of the IFN-β-DTPA-pullulan conjugate with Zn 2+ coordination into mice enhanced induction of an antiviral enzyme, 2′,5′-oligoadenylate synthetase (2-5AS), specifically in the liver to a significantly greater extent than free natural IFN-β. The enhanced 2-5AS level in the liver depended on the molar mixing ratio of IFN-β, DTPA residue of the DTPA-pullulan, and Zn 2+ . Moreover, the duration of the liver 2-5AS induction by the IFN-β-DTPA-pullulan conjugate was longer than that by free natural IFN-β. Thus, human IFN-β-DTPA-pullulan conjugate appears to be applicable for clinical use, which is promising for treatment of patients with chronic hepatitis C.

Influence of spontaneous portosystemic collateral pathways on portal hemodynamics in living-related liver transplantation in children: Doppler ultrasonographic study

We investigated the influence of spontaneous portosystemic collateral pathways on the portal hemodynamics and examined the necessity for ligating these vessels in pediatric liver transplantation from living donors. We assessed portal blood flow before, during, and after surgery in 82 pediatric recipients (mean age, 4.2 years), using Doppler ultrasonography. When blood flow in the reconstructed portal vein was decreased (< 10 ml/min/kg body weight) and portosystemic collaterals persisted during surgery, those vessels were ligated and Doppler flowmetry was examined again. Spontaneous portosystemic collaterals were detected at one or more sites in 67 patients before transplantation. These collaterals had been ligated in 17 patients before intraoperative flowmetry. Among the remaining 50 patients, initial Doppler studies revealed a decrease in portal blood flow in 22 patients. Nine patients had hepatofugal splenic venous flow and 6 had no significant flow signals from the intrahepatic portal vein. Ligation of collaterals resulted in a remarkable increase in portal blood flow in 20 patients, all of whom are alive. The remaining 2 patients died of graft failure due in part to portal hypoperfusion. On the other hand, the collaterals were not ligated in 24 patients because adequate portal blood flow was confirmed by intraoperative flowmetry. Postoperatively, flow signals from the unligated collateral vessels gradually diminished, but they still persisted in 3 patients at 12 months after transplantation. Hepatofugal blood flow through the portosystemic collateral pathways may persist after implantation of a normal graft. If the patent collaterals significantly reduce the effective portal blood flow, these vessels should be ligated in order to avoid graft failure.

Impaired IFN-α Production and the Risk of Cancer Development

Type I interferons (IFNs) play a pivotal role not only in antiviral immunity but also in the surveillance of cancer development. In order to quantify the critical function of type I IFNs in the suppression of human cancer development, IFN-alpha production in response to Sendai virus stimulation has been compared between healthy control subjects and hepatitis C virus (HCV)-infected patients, the latter being an ideal population for longterm monitoring of cancer development. Data for IFN-alpha production were obtained retrospectively over a 17-year period by examining medical records in a study population of 2315 individuals, of which 112 healthy controls and 20 HCV-infected patients were selected. Sixty percent of the HCV-infected patients had impaired or declining IFN-alpha production, in comparison to 17% in the healthy control group. Mean IFN-alpha levels were lower in patients who developed hepatocellular carcinoma than in the HCV-infected patients who remained cancer free. Our findings suggest that impairment of IFN-alpha production may be linked to an increased cancer risk and that dysfunction of the IFN system is associated with some types of cancer. Therefore, periodic assessment and quantification of IFN-alpha production can be a potential test for the early detection of cancer in humans.

Ultrasonographic arterial portography with second harmonic imaging: Evaluation of hepatic parenchymal enhancement with portal venous flow

Ultrasonographic arterial portography was evaluated with second harmonic and conventional gray scale imaging after the administration of 0.001 to 0.1 ml/kg of FS069 (Optison) in 10 dogs (four dogs with ligation of the portal vein branch) and two woodchucks with hepatocellular carcinomas. Harmonic imaging was required to obtain good liver parenchymal enhancement for ultrasonographic arterial portography to be useful. The tumors were visible as regions of greater enhancement after intravenous injection and as hypoechoic regions after superior mesenteric artery injection. The segments with portal vein ligation were not detected after intravenous injection but were clearly seen after superior mesenteric artery injection. Doppler signal measurement verified a significant difference between the portal vein and hepatic vein after superior mesenteric artery injection and in the femoral artery after intravenous versus superior mesenteric artery injection, demonstrating that minimal levels of FS069 pass through the liver.