Kazuo Tarao

Development of hepatocellular carcinoma associated with increases in DNA synthesis in the surrounding cirrhosis

The relationship between DNA synthesis activity in hepatocytes from cirrhotic tissue and development of hepatocellular carcinoma was studied in 33 posthepatitic patients with Childs grade A cirrhosis. DNA synthesis activity was measured by a bromodeoxyuridine (a thymidine analogue) labeling index, using the bromodeoxyuridine-antibromodeoxyuridine in vitro method, and the patients were followed up prospectively with frequent liver ultrasonography for 2 years. During the 2-year follow-up, 11 of the 33 cirrhotic patients developed hepatocellular carcinoma; they included 8 of the 15 patients (53%) in the high labeling index (greater than 1.5%) group compared with only 3 of the 18 patients (17%) in the low labeling index (less than 1.5) group (P less than 0.05). Five of the latter 18 subsequently had increased synthesis activity. Of these 20 patients who showed high synthesis activities either initially or subsequently, 10 (50%) developed hepatocellular carcinoma, in contrast to 1 of 13 (8%) with persistently low activities (P less than 0.05). Thus, hepatocellular carcinoma seems to develop or may become detectable when DNA synthesis in the background cirrhosis is increasing or remains high.

Noninvasive assessment of tumor vascularity by contrast-enhanced ultrasonography and the prognosis of patients with nonresectable pancreatic carcinoma.

Studies have shown that angiogenesis is one of the factors that influences the prognosis of patients with solid tumors, including pancreatic carcinomas. However, none have assessed noninvasively the relation between angiogenesis and prognosis in patients with pancreatic carcinoma. Contrast‐enhanced ultrasonography (US) not only is a convenient, harmless, and noninvasive imaging modality, but it also provides detailed information on tumor vascularity. The objectives of this study were to assess the vascularity of pancreatic carcinoma noninvasively by contrast‐enhanced US and to clarify the prognostic value of tumor vascularity in patients with nonresectable pancreatic carcinoma.

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.

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 male preponderance in incidence of hepatocellular carcinoma in cirrhotic patients may depend on the higher DNA synthetic activity of cirrhotic tissue in men

Background. The relationship between the DNA synthetic activity of hepatocytes from cirrhotic liver tissue and the incidence of hepatocellular carcinoma (HCC) during a 3‐year follow‐up period was studied in male and female patients with posthepatitic cirrhosis.

Increased uptake of bromodeoxyuridine by hepatocytes from early stage of primary biliary cirrhosis.

The relationship between DNA synthesis activities of hepatocytes in biopsied specimens and liver volume was studied in various stages of primary biliary cirrhosis using an in vitro bromodeoxyuridine (a thymidine analogue)-anti-bromodeoxyuridine reaction and computed tomography. The mean bromodeoxyuridine (+/- SE) labeling index for 10 patients in an early histological stage (stage I, 4, and stage II, 6, 3.4% +/- 0.4%) of primary biliary cirrhosis was 17 times that for 6 control subjects (0.2% +/- 0.1%, P less than 0.001), and was significantly higher than that for 19 female patients with chronic aggressive hepatitis (0.9% +/- 0.2%, P less than 0.001), 14 compensated cirrhotic patients of viral origin (all female, 1.1% +/- 0.3%, P less than 0.01), and 5 patients with stage III primary biliary cirrhosis (0.5% +/- 0.1%, P less than 0.001). The mean (+/- SE) liver volume in the early stage of primary biliary cirrhosis (1225 +/- 40 cm3) was about 1.5 times that in control subjects (835 +/- 42 cm3, P less than 0.001). These results suggest that liver volume has already become large in the early stage of primary biliary cirrhosis perhaps because of markedly increased DNA synthesis in hepatocytes.

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.

High serum alanine aminotransferase levels for the first three successive years can predict very high incidence of hepatocellular carcinoma in patients with Child Stage A HCV-associated liver cirrhosis.

Abstract Objective. To assess retrospectively whether continuously high serum alanine aminotransferase (ALAT) levels (<80 IU) in the first three successive years after the diagnosis of liver cirrhosis (LC) are predictive of a subsequent high incidence of hepatocellular carcinoma (HCC) in patients with Child Stage A hepatitis C virus (HCV)-LC. Material and methods. The study comprised 132 HCV-LC (Child Stage A) patients who had not received interferon therapy but had been treated with anti-inflammatory agents. At the end of a 3-year follow-up after the diagnosis of LC, the patients were subdivided into three groups according to their serum ALAT levels and the subsequent incidence of HCC was assessed. Results. The cumulative incidence of HCC starting from 3 years after the diagnosis of LC in the continuously high ALAT group (annual average over 3 years always ≥80 IU; n=41; Group A) was markedly higher than that in the continuously low ALAT group (always <80 IU; n=48; Group B) (p<0.005) during an observation period of 7.9±3.7 years. The incidence of HCC in Group A was 11.8%/year. The odds ratios of developing HCC in Group A and Group C (mixed high and low ALAT levels; n=43) were 5.1-fold and 1.5-fold that of Group B, respectively. A multivariate analysis revealed that the ALAT group was independently associated with HCC development. Conclusions. Continuously high ALAT levels for three successive years following the diagnosis of LC can be predictive of a very high incidence of HCC in Child A HCV-LC patients. Prospective trials using therapeutic approaches aimed at decreasing ALAT levels are necessary in order to confirm a positive impact of ALAT reduction on the incidence of HCC in patients with HCV-LC.