Shoji Takemiya

Difference in the in vitro uptake of bromodeoxyuridine between liver cirrhosis with and without hepatocellular carcinoma

With the aim of examining increasing deoxyribonucleic acid (DNA) synthesis of liver cirrhotic tissue when hepatocellular carcinoma (HCC) is developing, bromodeoxyuridine labeling indices (BrdU LI) of liver biopsy specimens from 19 control cirrhotic (control LC) patients without HCC, 19 cirrhotic patients with HCC, and from six control subjects were examined using an in vitro labeling technique. The mean BrdU LI ± SD of HCC cancerous portion, HCC non‐cancerous cirrhotic portion, control LC, and of control subjects were 7.2 ± 2.9%, 3.3 ± 1.5%, 2.1 ± 1.7%, and 0.25 ± 0.09%, respectively. Interesting enough, there was a significant difference (P < 0.05) between the non‐cancerous cirrhotic portion and control LC. Although all 17 non‐cancerous cirrhotic portion belonged to the high LI group (> 1.5%), 10 of 19 in the control LC belonged to the low LI group (>1.5%) (P > 0.001). The authors conclude that HCC would develop in the cirrhotics with high DNA synthetic potency.

Cyclooxygenase‐2 mRNA is up‐regulated in cirrhotic or chronic hepatitis liver adjacent to hepatocellular carcinoma

Background and Aim: Hepatocellular carcinoma (HCC) is unique in that its carcinogenesis is related to inflammatory changes and regenerative activities in the background liver. Although there are some data on cyclooxygenase (COX)‐2 expression in HCC by immunohistochemical studies, little is known about the possible role of COX‐2 in inducing hepatitis and/or carcinoma. To elucidate whether COX‐2 is involved in a part of these processes, we attempted to examine COX‐2 mRNA both in the adjacent non‐tumoral liver and in HCC.

Close association between high serum ALT and more rapid recurrence of hepatocellular carcinoma in hepatectomized patients with HCV-associated liver cirrhosis and hepatocellular carcinoma.

We investigated whether or not a high serum alanine aminotransferase (ALT) level is associated with a more rapid recurrence of hepatocellular carcinoma (HCC) in hepatectomized patients with hepatitis C virus (HCV)-associated liver cirrhosis (LC) (HCV-LC) and HCC. Thirty-three hepatectomized patients with HCV-LC and HCC of a single nodule who had no histologic evidence of portal or hepatic vein invasion and who had been followed up for more than 3 years were included in the study. They were subdivided into two groups according to their serum ALT levels, ALT being a well-known marker of inflammatory necrosis in the liver. Seventeen patients whose serum ALT levels showed several peaks or plateaus above 80 international units (IU) were designated as the high ALT group, and 16 patients whose serum ALT levels showed a sustained low level below 80 IU until the first recurrence were designated as the low ALT group, and the interval between hepatectomy and the first recurrence was observed. In the high ALT group, HCC recurred within 3 years in 70.6% of the patients. In contrast, it recurred in only 18.8% of the low ALT group within the same period (p < 0.05). There was a significant difference (p = 0.0201) between the two groups in the cumulative nonrecurrence rate. The mean interval in recurrent patients between hepatectomy and the first recurrence in the high ALT group (23.6 ± 2.8 months; mean ± SE) was significantly (p < 0.02) shorter than that in the low ALT group (49.3 ± 9.7 months). The expected interval between hepatectomy and recurrence was as short as 2.8 ± 0.5 years (mean ± SE) in the high ALT group, compared with 5.8 ± 0.7 years in the low ALT group (p < 0.05). These results showed that the recurrence of HCC was accelerated in the high ALT group, suggesting that suppression of the rise in ALT level after hepatectomy by treatment with anti-inflammatory drugs may prolong the interval until recurrence by about 2 years in hepatectomized patients with HCC and HCV-LC.

In vitro uptake of bromodeoxyuridine by human hepatocellular carcinoma and its relation to histopathologic findings and biologic behavior

The in vitro uptake of bromodeoxyuridine (BrdU) by hepatocellular carcinoma (HCC) cells was studied in 30 hepatectomized patients. Labeling of the nuclei by BrdU expressed as labeling index (LI) was 5.6 ± 3.2% (mean ± standard deviation), with a considerable variation from case to case. The mean LI in Grade III to IV cancers (less differentiated, by Edmondson and Steiners classification, 11.1 ± 2.1%) was significantly larger (P < 0.001) than that in Grade I to II cancers (more differentiated, 4.5 ± 2.0%). Capsule formation was found in all 17 patients except one (94%) with a low DNA synthetic HCC (LI < 6.0%) compared with seven of 13 (54%) with a high DNA synthetic HCC (LI ± 6.0%, P < 0.02). The 2‐year survival rate after surgery was significantly higher (P < 0.02), and intrahepatic metastasis was significantly less (P < 0.05) in the former group than in the latter. The BrdU LI of HCC tumors showed a strong correlation with histopathologic findings and the biologic behavior of HCC.

The enhancement of tumor growth after partial hepatectomy and the effect of sera obtained from hepatectomized rats on tumor cell growth

In the process of liver regeneration, the participation of various types of growth stimulators and changes in immune responses have been reported. Here, we examined the growth of subcutaneously transplanted AH130 cells and Walker 256 cells after partial hepatectomy. In the case of tumor cells being transplanted on the same day as partial hepatectomy, the increase in tumor size in hepatectomized rats was significantly greater compared with that in non-treated rats or in those having undergone a simple laparotomy. When the transplantation of tumor cells was done on the 7th day after partial hepatectomy, however, the increase was less marked. We also examined the effect of serum obtained from rats after partial hepatectomy on thein vitro growth of these tumor cells. Growth enhancement was observed with medium containing serum drawn from rats 1 to 4 days after partial hepatectomy. These results suggest that the growth of tumor cells was stimulated during liver regeneration and that some humoral factors participated in the process. Furthermore, as the conditions of thein vitro method appear to mimic those of thein vivo method, thein vitro approach should be very useful for analysis of the factors responsible.

DNA synthesis activities of hepatocytes from noncancerous cirrhotic tissue and of hepatocellular carcinoma (HCC) cells from cancerous tissue can predict the survival of hepatectomized patients with HCC

Background. There is a concept that a cancer often maintains some of the traits of the background tissue cells. Thus, the possibility exists that the DNA synthetic activity of the hepatocytes in cirrhotic tissue affects that of hepatocellular carcinoma (HCC) cells.

Overexpressed cyclo‐oxygenase‐2 in the background liver is associated with the clinical course of hepatitis C virus‐related cirrhosis patients after curative surgery for hepatocellular carcinoma

Background:  The probable role of cyclo‐oxygenase‐2 (COX‐2) in the development of hepatocellular carcinoma (HCC) in patients with chronic liver diseases has been accepted to be relevant. The purpose of the present study was to determine whether overexpressed COX‐2 in the background liver affects the clinical course of hepatitis C virus (HCV)‐related cirrhosis patients after curative surgery for HCC.

Serum alanine aminotransferase levels and survival after hepatectomy in patients with hepatocellular carcinoma and hepatitis C virus-associated liver cirrhosis.

We examined whether sustained alleviation of inflammation as monitored by serum alanine aminotransferase (ALT) levels was associated with longer survival in hepatectomized hepatocellular carcinoma (HCC) patients with hepatitis C virus‐associated liver cirrhosis (HCV‐LC). Thirty‐four hepatectomized patients with HCV‐LC and HCC as a single nodule, and for whom more than 5 years had elapsed after the hepatectomy, were studied. They had no histologic evidence of portal or hepatic vein invasion. They were subdivided into two groups according to their serum ALT levels in the 2 years after hepatectomy: the low ALT group comprised 13 patients whose serum ALT levels showed a sustained low level below 80 IU, and the high ALT group comprised 21 patients whose serum ALT levels showed several peaks or plateaus above 80 IU. The patients had been followed‐up prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for recurrence for >5 years. The survival period, non‐recurrence interval and number of recurrences were observed. Recurrences were treated with transcatheter chemoembolization in all cases. The cumulative survival rate in the low ALT group was significantly better than that in the high ALT group (P<0.05). The 5‐year survival in the low ALT group was as high as 92.3% (12 of 13) compared with 33.3% (7 of 21) in the high ALT group (P<0.05). The cumulative non‐recurrence rate in the low ALT group was also significantly better than that in the high ALT group (P<0.01). The survival period correlated well with the interval until the first recurrence (r=0.545, P=0.006). There was a tendency for the number of recurrences in the low ALT group (1.5±0.4, mean±SE) to be fewer than that in the high ALT group (2.2±0.4), although this was not significant. Sustained alleviation of inflammation, as indicated by low ALT levels, provides a survival advantage mainly due to the longer non‐recurrence interval, and possibly because of fewer recurrences, in hepatectomized HCC patients with HCV‐LC.

The Prognostic Value of Number of Lymph Node Metastasis in Colorectal Cancer -Using Cox's proportional hazard model-

目的: 大腸癌におけるリンパ節転移個数の予後予測における有用性を検討する.対象: 1990年から2000年までに治癒切除された大腸癌 (肛門管癌除く) 患者815例 (男性487例女性328例, 62.7歳). stage 0 33例, stage I 174例, stage II 220例, stage IIIa 192例, stage IIIb 136例, stage IV 60例. リンパ節転移個数は0個, 1～3個 (1個, 2～3個), 4個以上の3群 (4群) に分け, n因子は大腸癌取扱い規約に従い検討した.結果: 術後生存日数において単変量解析でn因子はn2, n3, n4の各群間に有意差はみられなかった. リンパ節転移個数は各群間に有意差をみた. 深達度, 肝転移, 腹膜播種, 遠隔転移を加えた多変量解析は両者有意な予後規定因子となったが, n因子のrelative riskはn3とn4の間で逆転したのに対し転移個数は1次関数的に増加した. 無再発日数においても単変量解析で転移個数はすべての群で有意差がみられたが, n因子はn2, n3, n4の間に有意差はみられなかった. 多変量解析ではn因子が有意ではあるがrelative riskはn4群がn3群に比べ低値 (n3 6.760, n4 5.722) となったのに対し, リンパ節転移個数ではすべて1次関数的に増加した.結語: リンパ節転移個数は生存率再発予測について, 単変量でも多変量解析でもn因子より有用である. リンパ節転移についてはその部位と共に転移個数についても考慮すべきであり, これらを術中所見の判定に用いることにより, 適切な大腸癌のリンパ節郭清の一助となると考えられた.

Experimental study of activated carbon adsorbed aclarubicin.

For anticancer effects on metastatic lymph node, activated carbon adsorbed anticancer drugs were injected preoperatively into the present study, the adsorption isotherm of activated carbon adsorbed aclarubicin (ACR) was measured and its stability in solution was investigated. The adsorption isotherms of 5-FU and MMC were prepared and compared with that of aclarubicin. In the adsorption isotherm of CH-40 activated carbon, the amount of ACR adsorbed was better than that of 5-FU and MMC. The amount of ACR adsorbed for CH-1500 activated carbon was also better than that for CH-40 activated carbon. The stability of ACR adsorbed on activated carbon solution decreased as the concentration of the activated carbon increased. The stability when the activated carbon and ACR concentration ratio was constant in saline solution was 100% after 2 hours and 40% after 7 days.