Yasuhiro Yumoto

Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma — a comparison of lipiodol-transcatheter arterial embolization with and without Adriamycin (first cooperative study)

SummaryA randomized, controlled clinical trial comparing the use of lipiodol-transcatheter arterial embolization (L-TAE) in the presence versus the absence of Adriamycin (ADR) for the treatment of hepatocellular carcinoma was conducted from August 1988 through September 1989. In all, 125 Japanese hospitals participated in this study and 289 patients were entered in the trial. The patients were randomly allocated into group A (L-TAE) or group B (L-TAE+ADR) by telephone registration. There was no significant difference in background factors between group A and group B. Additional treatment, including repeated TAE or hepatic resection, was given to 189 patients. Among the four endpoints analyzed, the rate of tumor reduction and lipiodol accumulation in the tumor did not significantly differ between the two groups. The 3-year survival values for groups A and B were 33.6% and 34.9%, respectively; the difference was not significant. The serum alpha-fetoprotein level, however, decreased to a significantly greater extent in the group that received ADR than in the group that did not (P<0.05). This result suggests that ADR has some favorable additional effect in L-TAE for the treatment of hepatocellular carcinoma.

Serum gamma-interferon-inducing factor (IL-18) and IL-10 levels in patients with acute hepatitis and fulminant hepatic failure.

Background and Aims: The aim was to determine the role of T‐helper (Th)1/Th2 cytokine responses in the clinical outcome of patients with acute liver injury.

Loss of heterozygosity and analysis of mutation of p53 in hepatocellular carcinoma.

Abstract Thirty‐six hepatocellular carcinoma (HCC) tissues obtained from 34 patients were classified according to histological diagnosis into six well‐differentiated HCC, 20 moderately differentiated HCC and 10 poorly differentiated HCC. High molecular weight DNA was prepared from each tumour and the corresponding non‐tumour tissue. Loss of heterozygosity (LOH) on chromosomes 4q, 5q, 10q, 11p, 16q, 17p, mutation of the p53 gene and polymorphism of intron 25 of the retinoblastoma (RB) gene were simultaneously analysed. The patients were composed of three cases of small HCC (the diameter of which was < 3 cm) and 31 cases of advanced HCC. Twenty‐nine of 34 (85.3%) patients analysed had been exposed to hepatitis B virus and/or hepatitis C virus. The frequencies of LOH on seven chromosomes were 57.9% in 17p13.3, 45.1% in 17p, 45.1% in 11p, 41.9% in 5q, 41.9% in 16q24, 29.0% in 4q, 25.8% in 10q in advanced HCC (four of well differentiated, 18 of moderately differentiated and nine of poorly differentiated carcinoma). In contrast, LOH was observed on 4q, 5q, 16q and 17p in 33% (1/3) of the small HCC (two of well differentiated and one of moderately differentiated carcinoma).

Decreased expression of B7 costimulatory molecules and major histocompatibility complex class-I in human hepatocellular carcinoma

Background and Aim:  We analyzed the expression of antigen‐processing and antigen‐presenting molecules in surgically resected fresh samples of human hepatocellular carcinoma (HCC) tissue to elucidate a mechanism of immune escape. We also examined the expression of interleukin (IL)‐10 protein, which might act to downregulate expression of antigen‐processing and antigen‐presenting molecules.

Preoperative estimation of remnant hepatic function using fusion images obtained by 99mTc-labelled galactosyl-human serum albumin liver scintigraphy and computed tomography

Assessment of hepatic functional reserve is important in hepatic resection. The aim of this study was to evaluate the role of hepatic asialoglycoprotein receptor (ASGP‐R) analysis in the preoperative estimation of remnant liver function in liver surgery.

Treatment of hepatocellular carcinoma by transcatheter hepatic arterial injection of radioactive iodized oil solution

SummaryAfter 12 days of culture, VX2 carcinoma cells were inoculated into the liver of 16 rabbits; 14 days later,131I-labeled iodized oil ([131I]-Lp) suspended in lipiodol was injected into the hepatic artery. Selective accumulation of the contrast material in the tumor for an extended time was evident on X-rays and hepatic scintiphotographs. The antitumor effect was remarkable. [131I]-Lp agents warrant further examination for their clinical usefulness. Internal radiation therapy by transcatheter hepatic arterial injection of [131I]-Lp (group A) was evaluated in 9 patients with hepatocellular carcinoma (HCC, tumor stage III or IV) associated with liver cirrhosis (LC) and compared with combination therapy of Lp-TAE (group B) in 18 patients with HCC (tumor stage III or IV) associated with LC. In group A, serum AFP levels dropped rapidly in eight of the nine patients who had an elevated intial level of more than 500 ng/ml. The average reduction in tumor size was 50% in eight cases as determined by computed tomography. Histological examination of one resected liver specimen at 3 months after the third injection of [131I]-Lp revealed microscopic features highly suggestive of a radiation effect in the [131I]-Lp-containing area. The 1-year survival value for patients with HCC was estimated at 49.0% using the Kaplan-Meier method. The survival of patients treated with internal radiation therapy tended to be better than that of those treated with Lp-TAE (P=0.119).

Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison between L-TAE with Farmorubicin and L-TAE with Adriamycin: preliminary results (second cooperative study)

A randomized controlled clinical trial was conducted to compare the use of Farmorubicin (FARM) and Adriamycin (ADR) in Lipiodol transcatheter arterial chemoembolization (L-TAE) as a treatment of hepatocellular carcinoma. In all, 192 hospitals participated, and 415 patients were enrolled in the study during the period from October 1989 through December 1990, and their data were collected. The patients were randomly allocated to group A (FARM) or group B (ADR) by a central telephone registration. Several clinical characteristics were slightly worse in group A than in group B, but there was no statistically significant difference. The actual doses of FARM and ADR were 72 mg/body and 48 mg/body, respectively. Additional treatments, including repeated TAE or surgery, were given to 248 patients. The 1- and 2-year survival rates were 69% and 44% for group A and 74% and 57% for group B, respectively. The difference was marginally significant (P value in the log-rank test, 0.038). When each group of patients was classified into two subgroups, i.e., high-risk and low-risk categories, based on the severity index calculated by the Cox regression model from significant prognostic factors, the ADR subgroup was significantly superior to the FARM subgroup in the low-risk category, but there was no significant difference between the subgroups in the high-risk category. The change in the serum alpha-fetoprotein level, the extent of Lipiodol accumulation in the tumor, and the extent of tumor reduction did not show any significant difference between the groups. At the above-mentioned doses, ADR seemed to have efficacy almost the same as or slightly superior to that of FARM in L-TAE for the treatment of hepatocellular carcinoma.

Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma. A comparison of L-TAE with farmorubicin and L-TAE with adriamycin (second cooperative study

SummaryA randomized clinical trial comparing L-TAE with Farmorubicin (FARM) and L-TAE with Adriamycin (ADR) in the treatment of hepatocellular carcinoma was conducted from October 1989 through December 1990. In all, 192 hospitals participated in this study and 117 patients were entered. The patients were randomly allocated to group A (L-TAE+FARM) or group B (L-TAE+ADR). There was no significant intergroup difference in background factors. Additional treatment consisting of repeated TAE or surgery was given to 66 patients. Four factors were analyzed in this study: the percentage of reduction in tumor size, the change in the AFP level, lipiodol accumulation, and survival. None of these factors differed significantly between the two groups. The final evaluation of this study will be based on differences in survival after a long-term follow-up. Toxic effects manifested less frequently in group A than in group B, and the decrease in the platelet count in the peripheral blood was significantly lower in group A than in group B. These results suggest that FARM exerts a more favorable effect than does ADR in the treatment of hepatocellular carcinoma.

Estimation of remnant liver function before hepatectomy by means of technetium-99m-diethylenetriamine-pentaacetic acid galactosyl human albumin

To improve the results of hepatectomy in cirrhotic patients, the likely reserve function of the liver was evaluated before surgery. Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific for galactose-terminated glycoproteins. Technetium-99m-diethylene triamine pentaacetic acid-galactosyl human serum albumin (99mTc-GSA) is a newly developed analog ligand to ASPG-R. The probable functional reserve of the remnant liver after hepatectomy was estimated preoperatively as the hepatic binding protein (HBP) concentration specific for ASGP-R on the hepatocellular membrane of the remnant liver. This estimate was based on the effective liver volume rate, obtained by the uptake of99mTc-GSA. In all, 3 normal volunteers, 3 patients with chronic hepatitis (CH), 9 patients with liver cirrhosis (LC), 2 patients with hepatic cystadenoma, 3 patients with hepatocellular carcinoma (HCC) associated with CH, and 21 HCC patients with LC were studied. The mean value ±SD obtained for HBP in normal volunteers (three cases) and in patients with mild (four cases), moderate (two cases), and severe liver damage (five cases) were 0.74±0.03 μM, 0.43±0.042 μM, 0.31±0.05 μM, and 0.20±0.05 μM, respectively. Most of the cases in which the preoperative HBP of the remnant liver was above 0.22 μM had a good postoperative course irrespective of the type of hepatectomy. On the other hand, in subjects with a remnant liver HBP of between 0.22 and 0.11 μM, postoperative severe liver dysfunction occurred in about 50% of cases. In all cases with a remnant liver HBP below 0.1 μM, the prognosis was very poor, indicating that hepatectomy should be avoided. The HBP concentration detected by the99mTc-GSA study is a very sensitive indicator of changes in the hepatic functional reserve, and the HBP value for the functional reserve of the remnant liver is extremely useful for estimating the liver function before and after hepatectomy.

Effects of transcatheter arterial chemoembolization with oral chemotherapy on hepatic neoplasmas

SummaryAn investigation was carried out into the effects of lipiodol-transcatheter arterial chemoembolization (L-TACE) therapy on hepatocellular carcinoma (HCC) and metastatic liver cancer, as well as the effects of oral 5-fluorouracil administration after L-TACE. For L-TACE, lipiodol mixed with adriamycin (doxorubicin) was injected through a catheter inserted into the tumor feeding artery and this was followed by embolization with a gelatin sponge. Twenty national hospitals throughout Japan participated in this multicenter co-operative open trial. A total of 102 patients became the subjects of study, including 75 HCC patients, 12 metastatic liver cancer patients treated with L-TACE, and 15 HCC patients who had hepatectomy after L-TACE. In 22% of the HCC patients and in 42% of the metastatic liver cancer patients, the tumor size was reduced by more than 50% after L-TACE. 73% of the 63 HCC patients showed a more than 50% reduction of the levels of serum α-fetoprotein. Although the survival rates of the HCC patients who had a hepatic resection were better than those who had not, there was no statistically significant difference between the survival rates of the HCC patients and those of the metastatic liver cancer patients treated with L-TACE. The survival rates of the HCC patients after L-TACE did not change as a result of oral 5-fluorouracil administration. It was therefore concluded that L-TACE is an effective way of treating both HCC patients and metastatic liver cancer patients, and that repeated L-TACE should be considered for some patients whose serum levels of α-fetoprotein rose again after L-TACE. Further follow-up studies will be needed to discover the effects of oral chemotherapy after L-TACE.