Kazunobu Monden

Results of surgical treatment for recurrent hepatocellular carcinoma; comparison of outcome among patients with multicentric carcinogenesis, intrahepatic metastasis, and extrahepatic recurrence

No consensus has been reached on the indications for and effectiveness of surgery for secondary intrahepatic hepatocellular carcinoma (HCC) and extrahepatic metastasis after macroscopically complete removal of primary HCC. Secondary intrahepatic HCCs, usually regarded as recurrence are classified into those arising as a result of multicentric carcinogenesis or intrahepatic metastases derived from the primary HCC. The present study was designed to evaluate the utility of surgical treatment in relation to the pathogenesis of the secondary HCC: classified as multicentric carcinogenesis (MC), intrahepatic metastasis (IM), and extrahepatic metastasis. Thirty patients underwent extirpation of secondary HCC: 22 patients had secondary HCCs in the remnant liver (MC group; n = 8; IM group, n = 14), 6 patients had extrahepatic metastases, and 2 patients had both intrahepatic and extrahepatic metastases. Survival rates after the re-resection in the 22 patients with the secondary intrahepatic HCCs were 94.7% at 1 year, and 50.2% at 3 years postoperatively, and the 8 patients with extrahepatic metastasis had survival rates of 62.5% at 1 year, 37.5% at 3 years, and at 5 years. The survival rates after re-resection in the MC group were 100% at 1 year and 80.0% at 3 years, whereas those in the IM group were 91.7% at 1 year, and 38.1% at 3 years. Surgery can be indicated not only in patients with localized intrahepatic secondary HCCs but also in those with extrahepatic metastasis. In particular, patients with secondary HCCs arising as a result of multicentric carcinogenesis are expected to have a good prognosis.

Pathogenic role of Kupffer cell activation in the reperfusion injury of cold-preserved liver.

The present study was designed to investigate the possible participation of Kupffer cells in the development of reperfusion injury of the cold-stored liver graft. In the cold preservation of Kupffer cells with Euro-Collins solution, the proportion of asialo-GM1-positive cells was significantly increased at 12 and 24 hr of storage, and the TNF alpha-producing activity in these cells was approximately fivefold greater than control. Northern blot analysis demonstrated that TNF alpha mRNA was remarkably elevated in the reperfusion of the cold-preserved liver, although that of the prereperfused graft was only slightly induced. The reperfusion experiments of the cold-stored liver graft showed that addition of anti-TNF alpha antibody to the perfusate suppressed the elevation of the effluent levels of GOT and LDH significantly, and that pretreatment with a Kupffer cell inhibitor, gadolinium chloride, inhibited the increase of these enzymes in the effluents almost completely. Histological study revealed deposition of a fibrinlike substance in the sinusoid and the central veins extensively in the reperfused liver graft, whereas no apparent deposition was observed in the gadolinium-pretreated liver. Thus, the present study showed that Kupffer cells were primed by cold preservation with Euro-Collins solution, and then activated when the reperfusion was done. It seems likely that the Kupffer cell activation induced by cold preservation/reperfusion plays a major role in reperfusion injury with sinusoidal microcirculatory disturbance, and that TNF alpha is responsible for the impairment of the reperfused liver graft.

Enhancement of hepatic macrophages in septic rats and their inhibitory effect on hepatocyte function

In the present study, the function of hepatic macrophages and the modulation of hepatocytes by sepsis-elicited hepatic macrophages were investigated in rats with induced sepsis. The functional state of hepatic macrophages was determined by the following indicators: phagocytic index, protein-synthesizing capacity, and superoxide (O2-) producing capacity. These indices of changes in hepatic macrophages were much higher in rats with sepsis than in healthy controls. Moreover, the activated hepatic macrophages had some biological properties which were different from those of the resident Kupffer cells. It was found that protein synthesis by cultured hepatocytes was inhibited in the co-culture system of hepatocytes and sepsis-elicited hepatic macrophages, and that the supernatant of hepatic macrophages from rats with sepsis also reduced the protein-synthesizing capacity of cultured hepatocytes. Thus, activated hepatic macrophages may play a role in inducing hepatic dysfunction in sepsis.

Depressed function of Kupffer cells in rats with CCl4-induced liver cirrhosis.

SummaryIn the present study, the Kupffer cell function of rats with CCl4-induced liver cirrhosis was tested by analyzing the changes in the host defense system. In rats without liver cirrhosis injected with CCl4 for 3 weeks concomitant with the high opsonic activity the endocytic index was significantly increased. Rats treated for 9 and 13 weeks developed cirrhosis, and their endocytic indices were not increased despite the rise in their opsonic activity. Particularly, the endocytic index of 13-week-treated rats with advanced liver cirrhosis was significantly lower than that of the other groups. The organic distribution of 51Cr-endotoxin injected intravenously exhibited characteristic changes in 9-week- and 13-week-treated rats: decreased hepatic uptake and increased splenic uptake. In contrast, pulmonary uptake was increased in all CCl4-treated rats. The superoxide production by Kupffer cells from 13-week-treated rats was greatly reduced, accompanied by the decreased superoxide dismutase activity of liver homogenate. Thus, results of this study suggest that Kupffer cell dysfunction is one of the main factors affecting host defenses in liver cirrhosis.

The three different phases of reticuloendothelial system phagocytic function in rats with liver injury

In the present study, reticuloendothelial system (RES) phagocytic function of rats with partial hepatectomy or experimentally induced liver cirrhosis was investigated by determining the phagocytic index, the opsonic index, and uptake rate in liver, spleen, and lung of a 51Cr-labeled endotoxin-injected rat. In both the partially hepatectomized and the cirrhotic rats, all three indicators varied markedly according to the elapsed period since liver injury. The changes in RES phagocytic function were classified into three different phases: compromised, compensatory, and enhanced. The compromised phase, consisting of a decrease in the phagocytic index, was observed during the first 24 hr after 67% hepatectomy and in advanced liver cirrhosis. This represented the failure of RES phagocytic function. The compensatory phase, in which the phagocytic index was maintained at nearly normal levels mainly by a compensatory enhancement in the opsonic index, was seen during the first to second postoperative day and in moderate liver cirrhosis. The enhanced phase, with a high phagocytic index, was observed from Day 4 to approximately Day 14 after surgery, and in the cases of mild liver damage. In the compromised and compensatory phases, the liver uptake rate was significantly decreased compared with the control. However, the uptake in the spleen and lung were markedly increased. In conclusion, the phagocytic function of the RES was significantly affected to a degree which changed with the extent of liver damage.

Involvement of thromboxane A2-thromboxane A2 receptor system of the hepatic sinusoid in pathogenesis of cold preservation/reperfusion injury in the rat liver graft.

This study was designed to investigate the possible involvement of the thromboxane A2 (TXA2)-TXA2 receptor (TXA2R) system of the hepatic sinusoid in cold preservation/reperfusion injury in liver grafts. Rat livers were preserved in cold University of Wisconsin solution for either 6 or 24 hr. The number of TXA2Rs in sinusoidal endothelial cells isolated from 0-, 6-, and 24-hr preserved liver specimens was 22.50 +/- 1.80 x 10(3)/cell, 12.66 +/- 1.00 x 10(3)/cell, and 4.17 +/- 0.65 x 10(3)/cell, respectively. Kd and Bmax at 0 hr, 6 hr, and 24 hr of preservation were 8.54 +/- 1.26 nM and 37.34 +/- 3.01 fmol/10(6) cells, 7.08 +/- 1.14 nM and 12.66 +/- 1.00 fmol/10(6) cells, and 1.91 +/- 0.10 nM and 3.88 +/- 0.59 fmol/10(6) cells, respectively. The administration of OKY-046 (inhibitor of TXA2 synthesis) to the University of Wisconsin solution suppressed this reduction in TXA2R number. Furthermore, the concentration of TXA2 in hepatic sinusoid was decreased by OKY-046. In a reperfusion experiment, liver tissue preserved for 24 hr exhibited a higher reperfusion pressure, and effluent levels of both aspartate aminotransferase and lactate dehydrogenase were markedly elevated. The addition of OKY-046 to the preservation solution, however, prevented the rise in reperfusion pressure almost completely and the increase in effluent enzyme levels. This study showed that the TXA2Rs in sinusoidal endothelial cells were internalized through binding with TXA2 during cold preservation, causing activation of the TXA2-TXA2R system. This activation apparently induces an increase in reperfusion pressure, possibly due to sinusoidal contraction, resulting in microcirculatory disturbances.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement and hepatocyte-modulating effect of chemical mediators and monokines produced by hepatic macrophages in rats with induced sepsis.

SummaryWe investigated the production of chemical mediators by hepatic macrophages from rats with sepsis and the modulation of hepatocyte function by these hepatic macrophages. The chemical mediators we measured were superoxide (O2−), TNF, IL-1, and PGE2. Production of these mediators by hepatic macrophages from rats with sepsis was significantly increased. Furthermore, protein synthesis by cultured hepatocytes was inhibited in a co-culture system of hepatocytes and hepatic macrophages from rats with sepsis, and it was even inhibited by the supernatant of cultured hepatic macrophages from septic rats. These results demonstrate that hepatic macrophages are activated in sepsis and may play a role in inducing hepatic dysfunction in sepsis.

Chemical mediator release and surface marker expression of hepatic macrophages in rats with CCl4-induced liver cirrhosis

The present study was performed to analyze possible functional alterations of hepatic macrophages (HM phi) in rats with carbon tetrachloride (CCl4)-induced liver cirrhosis. HM phi from rats injected with CCl4 for 13 weeks and cultured for 24 hours released less than normal amounts of prostaglandin E2 (PGE2) and tumor necrosis factor (TNF) and very large amounts of interleukin-1 (IL-1). In rats injected with CCl4 for 9 weeks, only PGE2 production was reduced. Interleukin-2 receptor (IL-2R), Ia antigen and asialo GM1 antigen expressions on HM phi from both the 9- and 13-week groups were significantly decreased. IL-2R and Ia antigen expressions showed larger decreases in the 13-week group. Thus, it is concluded that HM phi derived from CCl4-induced cirrhotic livers show a functional alteration in the release of cytokines (except for IL-1) and a decrease in surface marker expression, as cirrhosis advances. These results should provide a basis for further investigation into the host-compromised status in the presence of liver cirrhosis.

A retrospective study of the preventive effect of transarterial chemotherapy for intrahepatic recurrence of hepatocellular carcinoma after partial hepatectomy

A major problem in treating hepatocellular carcinoma (HCC) is intrahepatic recurrence after partial hepatectomy, despite the relatively early detection now possible due to recent developments in non-invasive diagnostic modalities. The present study evaluated the usefulness of preventive therapy for intrahepatic recurrence of HCC. In order to suppress intrahepatic recurrence in HCC patients at high risk of recurrence after tumor removal, we performed preventive transarterial chemotherapy in 23 such patients. Doxorubicin, at a dose of 0.5 mg/kg body weight, was administered, via a catheter inserted at the junction of the common hepatic artery and the gastroduodenal artery, every 2 weeks for the first 2 months, and every month thereafter for at least 1 year. The control group consisted of 30 patients with similar risk of recurrence who underwent partial hepatectomy during the same period without receiving transarterial preventive therapy. The 1-, 2-, 3-, and 5-year cumulative cancer-free survival rates in patients who received transarterial preventive chemotherapy after partial hepatectomy were 87.0%, 47.1%, 21.2%, and 21.2%, respectively, compared to 53.3%, 30.0%, 20.0%, and 13.3%, respectively, in the control group (P<0.05). The 1-, 2-, 3-, and 5-year cumulative overall survival rates were 95.7%, 81.2%, 58.4%, and 48.7%, respectively, in the preventive chemotherapy group, compared to 70.0%, 49.4%, 41.7%, and 19.5%, respectively, in the control group (P<0.05). Thus, the present study demonstrates the limited but significant effect of preventive transarterial chemotherapy for the intrahepatic recurrence of HCC after partial hepatectomy.

Enhancement of rat hepatic macrophages by treatment with interleukin-2 and streptococcal preparation OK432, with reference to antitumor activity, soluble factor production and Ia expression

SummaryThe effect of biological response modifiers, such as interleukin-2 (IL-2) and streptococcal preparation OK432, on the functions of hepatic macrophages was investigated. The macrophages, even with no exogenous stimulation, produced superoxide anion (O2-) and tumor necrosis factor (TNF), displayed cytotoxicity against K562 cells and cytostasis against P815 cells and expressed immune-region-associated antigen (Ia). IL-2 administered in vitro or in vivo enhanced O2- production by hepatic macrophages and the intravenous injection of OK432 also enhanced O2- production. Furthermore, IL-2 added to the culture medium of hepatic macrophages isolated from OK432-injected rats augmented O2- production even more. The TNF production and Ia expression of the macrophages were also increased by the intravenous injection of OK432. As with O2- production, the cytotoxicity of the cells was enhanced by OK432 injection or by IL-2 added to the culture medium and the combination of OK432 and IL-2 augmented their cytotoxicity even more. Thus, the present study suggested that IL-2 and OK432 induce the augmentation of the antitumor activity of hepatic macrophages, partly as a result of the increase in production of O2- and TNF and Ia expression.