Mikiya Kitamoto

The assessment of proliferating cell nuclear antigen immunohistochemical staining in small hepatocellular carcinoma and its relationship to histologic characteristics and prognosis

Background. A precise prognostic factor for small hepatocellular carcinoma (HCC), the diagnosis of which recently has increased in incidence because of the development of diagnostic imaging techniques, is desirable. It has been reported that proliferating cell nuclear antigen (PCNA) would be related to proliferating cells, and thus the PCNA labeling index may provide useful information about the biologic behavior of small HCC.

Long-term Prognosis of Patients Undergoing Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Comparison of Cisplatin Lipiodol Suspension and Doxorubicin Hydrochloride Emulsion

PURPOSE To evaluate long-term prognosis of transcatheter arterial chemoembolization (TACE) with use of cisplatin (CDDP) lipiodol (LPD) suspension (CDDP/LPD) compared with that with use of doxorubicin hydrochloride (ADM) LPD emulsion (ADM/LPD) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS One hundred eight patients were treated with use of CDDP/LPD and 26 were treated with use of ADM/LPD. Survival rates and frequency of side effects and complications in the CDDP/LPD group were compared with those in the ADM/LPD group. RESULTS CDDP/LPD was given at a dose of 15-70 mg (mean dose, 41 mg), whereas ADM/LPD was given at a dose of 20-100 mg (mean dose, 57 mg) throughout the study period. The survival rates in the CDDP/LPD group were 81% at 1 year, 41% at 3 years, 19% at 5 years, and 13% at 7 years, whereas those in the ADM/LPD group were 67% at 1 year, 18% at 3 years, and 0% at 5 years. The CDDP/LPD group showed significantly better survival than the ADM/LPD group (P <.05). In the CDDP/LPD group, there was a significant prolongation of survival in patients with monofocal HCC (P <.05) and patients with HCC assessed as an almost complete LPD accumulation (P <.05). There were no significant differences in survival rates in the ADM/LPD group according to tumor size and number of tumors. Hepatic failure was observed in 8% of all procedures and was not different between the two therapeutic groups. Renal dysfunction was observed in 2% of all treatments involving CDDP/LPD, and it resolved spontaneously with appropriate medications. CONCLUSIONS TACE with use of low-dose CDDP was efficacious for unresectable HCC and had few complications. TACE with use of CDDP may contribute to prolongation of the life span of patients with HCC versus TACE with use of ADM.

The long-term outcome of patients with bleeding gastric varices after balloon-occluded retrograde transvenous obliteration

BackgroundThe purpose of our study was to evaluate the long-term outcome and complications of balloon-occluded retrograde transvenous obliteration (B-RTO) in patients with hemorrhage from gastric fundal varices.MethodsThirty-four consecutive patients with bleeding from gastric varices who were treated with B-RTO were enrolled in this study between December 1994 and September 2005 (urgent cases, n = 12; elective cases, n = 22). The long-term outcome, complications, and various liver functions were evaluated.ResultsComplete obliteration was achieved in 31 of 34 (91%) patients with an acute bleeding episode. In one of the remaining patients, there was a technical failure, and the other two had only partial obliteration. The two patients with partial obliteration did not obtain hemostasis. Thus, the rate of hemostasis was 94% (31/33). Gastric varices disappeared in all patients with complete obliteration during the treatment. The rate of gastric variceal eradication was 91%. Variceal rebleeding from esophageal varices occurred in three patients. The rate of rebleeding was 10% (3/31). Rebleeding from gastric varices was not observed after complete obliteration. None of the patients showed worsening of their Child-Pugh score. Although the 5-year cumulative worsening rate of esophageal varices was 52%, neither portal hypertensive gastropathy nor ectopic varices were observed. The patients with worsening esophageal varices were successfully treated with an endoscopic procedure. The 5-year survival rate was 68%.ConclusionsB-RTO is useful for treatment of bleeding gastric varices, achieving high eradication of gastric varices, a low rebleeding rate, and a fairly good prognosis with improved hepatic function.

Significance of telomerase activity in the diagnosis of small differentiated hepatocellular carcinoma

Precise diagnosis of well‐differentiated hepatocellular carcinoma (HCC) is sometimes difficult to establish. Telomerase activity was examined by telomeric‐repeat‐amplification protocol (TRAP) in 37 HCC nodules smaller than 3 cm in diameter, including 24 fine‐needle‐aspiration biopsy specimens, 22 non‐tumor chronic‐liver‐disease tissues (9 chronic hepatitis and 13 liver cirrhosis) and 3 normal liver tissues. Telomerase activity was assayed by serially diluted samples and quantitated by using an internal telomerase assay standard (ITAS). Telomerase activity was detected in all HCC and in 11 of 22 non‐tumor chronic‐liver‐disease tissues. Normal liver samples had undetectable telomerase activity. Cut‐off level of telomerase activity for its practical usage in HCC diagnosis was tentatively set for 0.6 μg liver protein/assay at 10‐cell equivalent activity of a gastric‐cancer cell line, MKN‐1. This level was twice the highest activity in non‐tumor chronic liver disease therefore, telomerase activity in all non‐tumor liver samples was below this level. The telomerase‐positive incidence exceeding this cut‐off level was 73% (11/15) in well‐differentiated HCC, 94% (16/17) in moderately differentiated HCC and 100% (5/5) in poorly differentiated HCC. Well‐differentiated HCC showed low positivity by other diagnostic markers. 21% by AFP, 0% by PIVKA‐II and 13% by angiography. The detection of telomerase activity may thus be a useful additional tool for precise and early diagnosis of small differentiated HCC, even when diagnosis is inconclusive by conventional techniques. Int. J. Cancer 74:141‐147, 1997.

Combination of transcatheter arterial chemoembolization using cisplatin-lipiodol suspension and percutaneous ethanol injection for treatment of advanced small hepatocellular carcinoma

BACKGROUND We evaluated the long-term efficacy of the combination of transcatheter arterial chemoembolization (TACE) using cisplatin-lipiodol suspension and percutaneous ethanol injection (PEI) for treatment of advanced small hepatocellular carcinoma (HCC). PATIENTS AND METHODS Sixty-nine patients with HCC less than 3 cm in diameter and at most three lesions were enrolled in this study. HCC nodules were confirmed to be hypervascular by angiography. Thirty-two patients were treated with a combination of TACE and PEI (TACE/PEI group) and 37 patients with TACE alone (TACE group). RESULTS The 5-year survival rates were 50% for the TACE/PEI group and 22% for the TACE group. The TACE/PEI group had a slightly but not significantly better survival than the TACE group. The 5-year survival rates of patients with solitary HCC were 61% for the TACE/PEI group and 24% for the TACE group. Although the two therapeutic groups both had high rates of recurrence, the rates in the TACE/PEI group were significantly lower than those in the TACE group (P <0.05). Severe complications such as intraperitoneal bleeding and segmental hepatic infarction were observed at low incidence, and recovered with supportive treatment. CONCLUSIONS The combination of TACE and PEI appears to prolong survival, compared with TACE alone. This combination therapy can thus be a valuable form of treatment for unresectable advanced small HCC.

Complications of radiofrequency ablation for hepatocellular carcinoma in a multicenter study: An analysis of 16 346 treated nodules in 13 283 patients

Aim:  We surveyed multiple centers to identify types and frequency of complications and mortality rate associated with radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC).

Immuno-histochemical detection of human telomerase reverse transcriptase in human liver tissues

Although telomerase activity in hepatocellular carcinoma (HCC) increases in accordance with degree of histological undifferentiation, it is unknown whether the level of telomerase activity in HCC reflects of the degree of activity in individual cells or the frequency of telomerase-positive HCC cells. Non-cancerous liver tissues exhibit low but significant levels of telomerase activity, but the nature of telomerase-positive cells in these tissues is unclear. In this study, we performed immunohistochemical staining using specific antibody against telomerase reverse transcriptase (hTERT) protein in 15 HCC samples and 13 adjacent non-cancerous liver tissues. There were hTERT-positive hepatocytes, though very low frequency, in non-cancerous liver tissues. The frequencies in hTERT positive hepatocytes were very well correlated with clinicopathological parameters and telomerase activity levels: the average frequencies of chronic hepatitis was 0.2%, liver cirrhosis 0.2%, well-differentiated HCC 3.0%, moderately differentiated HCC 28%, and poorly differentiated HCC 95%. The intensity of staining varied among cells within a given specimen, and correlation with degree of histological undifferentiation was less obvious. Portions of migrating lymphocytes and biliary epithelial cells were also hTERT-positive. These findings indicate that the up-regulation of telomerase activity with degree of undifferentiation of HCC is mainly due to the increase in frequency of hTERT positive HCC cells.

Expression of telomerase component genes in hepatocellular carcinomas.

The aim of the study was to clarify the role of telomerase component genes in hepatocarcinogenesis and to examine both the relationship between the expression of telomerase component genes and histological differentiation in hepatocellular carcinoma (HCC) and the relationship between expression levels of telomerase component genes and telomerase activity in HCCs. Telomerase is a ribonucleoprotein enzyme composed of a template RNA and several proteins. Recently, three such telomerase component genes have been identified: human telomerase reverse transcriptase (hTERT); human telomerase RNA component (hTERC); and telomerase-associated protein 1 (TEP1). The expression of these components was evaluated in 34 HCCs and 24 non-cancerous liver tissues by reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of hTERT mRNA was detected in most HCCs, but not in the non-cancerous tissues (P<0.01). Expression of hTERC was detected in both HCCs and non-cancerous tissues, but the expression level in HCCs was higher than that in non-cancerous tissues (P<0.01) and tended to increase as histological differentiation became less marked. The expression level of hTERT mRNA correlated with relative telomerase activity (P<0.01). These results suggest that telomerase reactivation during hepatocarcinogenesis might be regulated by only hTERT and an increase in telomerase activity level in tumour progression might be regulated by both hTERT and hTERC.

Impact of aging on the development of hepatocellular carcinoma in patients with hepatitis C virus infection in Japan

Background: It is difficult to study the long-term outcome of hepatitis C virus (HCV) infection because chronic infection is often asymptomatic and duration of the disease is prolonged. The clinical outcome of HCV infection remains unclear in patients of advanced age. Methods: Among 575 patients consecutively diagnosed with hepatocellular carcinoma (HCC) from 1988 to 1999 at Hiroshima University, we examined 430 with HCV. We studied the differences between males and females in the following characteristics: age at first diagnosis of HCC, Child grade, various tumour factors, history of blood transfusion, duration to development of HCC, and history of alcohol intake. Results: The incidence of HCC patients with HCV increased in elderly persons, including female patients. Background liver function was significantly better for female patients ( P r < r 0.001). In both genders, the duration between blood transfusion and diagnosis of HCC was significantly shorter when the patients received blood transfusion at an older age ( P r < r 0.001). In habitual drinkers, the average age at first diagnosis of HCC was significantly younger ( P r < r 0.001), and duration to development of HCC significantly shorter ( P r < r 0.05). The percentage of atomic bomb survivors among HCV-positive HCC patients was significantly higher than that among HCV-negative HCC patients ( P r < r 0.05). Conclusions: Patients with HCV might exhibit slow disease progression and develop HCC finally with aging regardless of gender. Patients of advanced age with HCV, even female patients, should therefore be closely followed.BACKGROUND It is difficult to study the long-term outcome of hepatitis C virus (HCV) infection because chronic infection is often asymptomatic and duration of the disease is prolonged. The clinical outcome of HCV infection remains unclear in patients of advanced age. METHODS Among 575 patients consecutively diagnosed with hepatocellular carcinoma (HCC) from 1988 to 1999 at Hiroshima University, we examined 430 with HCV. We studied the differences between males and females in the following characteristics: age at first diagnosis of HCC, Child grade, various tumour factors, history of blood transfusion, duration to development of HCC, and history of alcohol intake. RESULTS The incidence of HCC patients with HCV increased in elderly persons, including female patients. Background liver function was significantly better for female patients (P < 0.001). In both genders, the duration between blood transfusion and diagnosis of HCC was significantly shorter when the patients received blood transfusion at an older age (P < 0.001). In habitual drinkers, the average age at first diagnosis of HCC was significantly younger (P < 0.001), and duration to development of HCC significantly shorter (P < 0.05). The percentage of atomic bomb survivors among HCV-positive HCC patients was significantly higher than that among HCV-negative HCC patients (P < 0.05). CONCLUSIONS Patients with HCV might exhibit slow disease progression and develop HCC finally with aging regardless of gender. Patients of advanced age with HCV, even female patients, should therefore be closely followed.

Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: A randomized, double-blind, placebo-controlled trial

Liver cirrhosis represents the end stage of any chronic liver disease, and it is associated with hepatic edema such as ascites. Many patients with ascites do not respond to diuretic therapy or require administration of diuretics at high doses that can cause adverse events. This 7‐day, multicenter, double‐blind trial of tolvaptan was designed to determine the optimal dose of tolvaptan for producing the intended pharmacological effect in hepatic edema.