Kiyotaka Kurose

Virtual Sonographic Radiofrequency Ablation of Hepatocellular Carcinoma Visualized on CT but Not on Conventional Sonography

OBJECTIVE Some nodules cannot be visualized clearly on conventional sonography but can be visualized on CT. In the present study, we evaluated the usefulness of real-time percutaneous ablation therapy under virtual sonographic guidance for these nodules. SUBJECTS AND METHODS In vitro experiments were performed with gelatin gel to evaluate the accuracy of virtual sonography. We also studied 50 patients with 58 hepatocellular carcinoma nodules, of whom 18 patients (21 nodules) underwent radiofrequency ablation by virtual sonography. This was the initial treatment for seven of these patients and an additional treatment for 11 patients. Thirty-two patients (37 nodules) received radiofrequency ablation without virtual imaging. The patients receiving standard radiofrequency ablation were retrospectively selected as the historical control group under the same conditions as the study group. RESULTS The in vitro gelatin gel study revealed that all punctures had been performed accurately. In both the initial-treatment group and the additional-treatment group, the mean number of treatments with virtual sonography was significantly lower than that without virtual sonography (p = 0.003 for both groups). The rates of local recurrence and complications did not differ significantly between the two groups. CONCLUSION In the treatment of nodules not depicted on sonography, radiofrequency ablation assisted by virtual sonography is an efficacious alternative.

Placebo-controlled trial of vaccination with hepatitis B virus surface antigen in hepatitis B virus transgenic mice

BACKGROUND/AIMS Treatment of hepatitis B virus carriers by vaccine containing hepatitis B surface antigen with Pre-S protein and HBsAg/ anti-HBs complex has been reported and these studies have constituted a new and promising concept for the treatment of HBV-carriers. The present communication, a placebo-controlled trial of vaccination in HBV-transgenic mice, was designed to examine the impact of vaccination using a high dose of HBsAg for a duration of 12 months to achieve further insights about the dose, duration and effectiveness of vaccine therapy. Another aim of this study was to analyse the mechanism underlying the antiviral and immunomodulatory potentiality of vaccine therapy in HBV-transgenic mice. METHODS HBV-transgenic mice positive for HBV DNA, hepatitis B surface antigen and hepatitis B e antigen in sera received either HBV-vaccine containing HBsAg in complete Freunds adjuvant (CFA), intraperitoneally, once a month for 12 consecutive months (vaccine recipients), or only CFA, intraperitoneally once in a month for 12 consecutive months (placebo recipients). Thirty-two vaccine-recipient and 16 placebo-recipient HBV-transgenic mice were injected, checked and followed on a monthly basis for the entire duration of 12 months. RESULTS Of the 32 transgenic mice from the vaccine-recipient group, 25 became completely negative for HBsAg and 30 for HBeAg. Five mice developed anti-HBs in sera after the observation period of 12 months. Semiquantitative estimation of HBV DNA by polymerase chain reaction showed that vaccination resulted in a decrease of HBV DNA in sera. Placebo-recipient transgenic mice did not show any significant change in the titres of HBV markers after receiving 12 monthly injections of CFA. Interleukin-2 could be detected in sera from vaccine-recipient transgenic mice, but not in placebo-recipient transgenic mice. CONCLUSIONS Vaccination with a high dose of HBsAg in adjuvant over a long period had a significant antiviral as well as immunomodulatory potential in HBV-transgenic mice. This inspires optimism that vaccine alone or in combination with antiviral agents can be used successfully for the treatment of human HBV-carriers.

Recent clinical features of Wilson’s disease with hepatic presentation

BackgroundWe carried out this study to evaluate recent clinical features of Wilson’s disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC).MethodsSixteen patients with hepatic manifestations were diagnosed with WD in the period 1976–2003. We divided this period into two periods, “past” and “recent”. The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital.ResultsFour patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects.ConclusionsRecently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.

Production of antibody to hepatitis B surface antigen (anti-HBs) by murine hepatitis B virus carriers : neonatal tolerance versus antigen presentation by dendritic cells

The inability of hepatitis B virus (HBV) transgenic mice, which express abundant hepatitis B surface antigen (HBsAg) in sera from the neonatal period onwards, to produce antibody to HBsAg (anti‐HBs) is considered to be due to defective function of lymphocytes. The defective function is thought to result from neonatal tolerance because antigenic challenge during the neonatal period is considered to be a tolerogenic event rather than an immunogenic one. However, a series of mixed culture experiments in vitro showed that lymphocytes taken from transgenic mice that had been injected with HBsAg in complete Freund’s adjuvant (CFA) constitutively produced anti‐HBs when cultured with dendritic cells from age‐, sex‐ and major histocompatibility complex (MHC)‐matched normal mice, but not when cultured with dendritic cells from transgenic mice. The expression of major histocompatibility complex (MHC) class II and B 7.2 (CD86) antigens on dendritic cells was significantly lower in transgenic mice compared with the same from the normal mice (P<0·05). Treatment of transgenic mice with interferon‐γ (IFN‐γ) resulted in up‐regulation of MHC class II on dendritic cells, and lymphocytes from HBsAg‐injected transgenic mice produced anti‐HBs in vitro when cultured with dendritic cells from IFN‐γ‐treated transgenic mice, but not when cultured with the dendritic cells from untreated transgenic mice. These experiments have shown that defective function of antigen‐presenting cells (APC), not immunogenic tolerance, is responsible for the inability of murine HBV‐carriers to produce anti‐HBs. Production of anti‐HBs by lymphocytes from HBsAg‐injected transgenic mice in the presence of dendritic cells that express higher levels of MHC class II and CD86 antigens has inspired optimism that a more effective vaccine therapy can be developed for chronic HBV‐carriers, injecting vaccine containing HBsAg with modulator(s) of APC function of dendritic cells.

Interferon therapy for patients more than 60 years of age with chronic hepatitis C

Abstract Nineteen patients aged > 60 years with chronic hepatitis C (CHC) received interferon (IFN) therapy and a complete response (CR) was achieved by five of them (26%). The incidence of CH with severe fibrosis in this elderly group was significantly higher than in another 52 patients with CHC who were < 60 years of age (the younger group; P < 0.05). There was no significant difference in the hepatitis C virus (HCV) genotype distribution between the elderly group and the younger group. However, the HCV‐RNA titre was significantly higher in the elderly group than in the younger group (P < 0.05). There was no significant difference in the efficacy rate of IFN in the elderly and younger groups after standardization of the background factors. In the elderly group, the HCV‐RNA titre was significantly lower in the patients achieving CR than in those with no response (P < 0.05). These data suggest that elderly patients with a low HCV‐RNA titre can still respond well to IFN therapy.

Response to interferon in chronic hepatitis C due to mixed genotype infection

We examined the response to interferon (IFN) in patients with chronic hepatitis C (CHC) due to two different genotypes of hepatitis C virus (HCV) infection. Among 64 CHC patients studied, one (2%) had HCV‐RNA genotype I, 36 (56%) had genotype II, 19 (30%) had genotype III, 2 (3%) had genotype IV and 6 (9%) had both genotypes II and III. There was no significant difference in age, sex, history of blood transfusion and liver histology among patients with genotypes II, III and II + III. The HCV‐RNA titre of genotype II patients was significantly higher than that of genotype III patients (P < 0.05). However, there was no significant difference in the HCV‐RNA titre between genotype II + III and the other groups. The complete response rate achieved with IFN therapy was significantly higher in genotype III patients (74%) than in genotype II patients (17%; P < 0.01). Of the six patients with genotype II + III, a complete response to IFN was only achieved by two patients (33%), both of whom had a low HCV‐RNA titre (≦ 104,5 copies/mL) and HCV serotype 2. The remaining four patients had HCV serotype 1 and three of the patients had a high HCV‐RNA titre (≧ 105 copies/mL). The HCV genotype III was lost in two patients after IFN therapy. These data suggest that HCV‐RNA titre and HCV serotype are important factors for predicting the efficacy of IFN therapy in patients with mixed genotype infection and show direct evidence of higher susceptibility towards CHC of patients with genotype III than genotype II.

Carcinoma with shared pathologic characteristics of both hepatocellular carcinoma and cholangiocarcinoma.

BACKGROUND α-Fetoprotein (AFP) is a useful marker of hepatocellular carcinoma (HCC), and protein induced by vitamin K absence or antagonist II (PIVKA-II) and fucosylated AFP (AFP-L3) are specific tumor markers. OBJECTIVE The aim of this article was to report a case of intrahepatic cholangiocarcinoma (CC) with high levels of expression of AFP, AFP-L3, and PIVKA-II. METHODS A 70-year-old man weighing 66 kg with a diagnosis of intrahepatic CC presented with a liver tumor 4.0 cm in diameter and elevated concentrations of carbohydrate antigen 19-9 (575 U/mL), PIVKA-II (379 mAU/mL), and AFP (497 ng/mL; AFP-L3, 88.1%). On extended medial hepatic segmentectomy, microscopy showed that the tumor was a CC without HCC. The patient subsequently underwent immunohistochemical assessments using cytokeratin-19, epithelial membrane antigen (EMA), hepatocyte paraffin-1 (HP-1), PIVKA-II, and AFP. RESULTS In all specimens, desmoplasia was observed. However, results of immunohistochemistry showed positive results for cytokeratin-19 and EMA; HP-1 results were negative. Results of PIVKA-II and AFP testing in the tumor were positive. CONCLUSIONS The case presented here showed characteristics of CC and HCC, whereas the histologic expression of the tumor suggested CC. Based on the literature search, this is the first known report of a case of a CC expressing AFP and PIVKA-II confirmed on immunohistochemical staining. This case is interesting with regard to the ability of the progenitor cells to differentiate HCC and CC.

Laparoscopic Findings in Senescent Patients with Primary Biliary Cirrhosis

Abstract: Fifty ‐two patients with primary biliary cirrhosis (PBC), 10 of whom were 65 years or older at the time of diagnosis, were investigated by laparo‐scopy. Laparoscopic findings in these 10 patients were evaluated and compared with those in younger patients. The 10 cases were composed of nine females and one male, and two had been diagnosed as having symptomatic PBC with skin itching, while the remaining eight had asymptomatic PBC. Two, seven and one case were in Scheuers stage I, II and III, respectively, and eight had chronic non‐suppurative destructive cholangitis (CNSDC) on liver biopsy specimens. The majority of senescent PBC patients had typical findings of the early stage of PBC on the liver surface; mild undulations in nine and reddish patches in eight. The laparoscopic findings in senescent PBC were relatively mild.