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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.

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.

It is accepted that inflammation promotes malignant progression in the development of cancers. Whether, this is true for hepatocellular carcinoma (HCC) remains as an open question. We examined the relationship between the inflammatory histology activity index (HAI) in the background liver cirrhosis (LC) and the histological grading of the HCC in the hepatectomized HCC patients with HCV-associated LC.Out of 264 HCC patients who underwent curative hepatic resection, 197 had HCV-associated LC. Among them, 52 patients with a small solitary HCC nodule (5 cm in diameter) were studied. Inflammation in the background LC was evaluated by modified Knodell's HAI. To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (0-4, each) were estimated. The average HAI was calculated. The grade of malignancy of HCC was determined by WHO classification.The average HAI in the 15 patients with moderately differentiated HCC (4.3 ± 0.8, mean ± SD) was significantly larger than that in 11 patients with well differentiated HCC (3.5 ± 0.6, p = 0.036). The HAI in the 24 patients whose HCC nodules contained poorly differentiated HCC (5.2 ± 1.1) was significantly larger than that in patients with moderately differentiated HCC (p = 0.025). Thus, the HAI order was well differentiated groupmoderately differentiated grouppoorly differentiated group.Inflammation in the background non-cancerous cirrhotic portion would evoke malignant progression in HCC development from HCV-associated LC.

OBJECTIVE Whether severe inflammation in the background liver cirrhosis might correlate with the development of poorly differentiated human hepatocellular carcinoma (HCC) was studied in hepatitis C virus (HCV)-associated liver cirrhosis. METHODS Out of 214 HCC patients who underwent curative hepatic resection, 148 patients were HCV-associated liver cirrhosis (LC) patients. Out of these 148, 31 patients with small solitary HCC nodule (diameter ≤ 3 cm) were included in this study. Inflammation in the background LC was evaluated by modified histology activity index (HAI). To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (each 0-4) were estimated. In each case, the average HAI was calculated. The grade of malignancy of HCC was determined by World Health Organization (WHO) classification. RESULTS The average HAI score in the cirrhotic portion in 17 patients with poorly differentiated HCC (5.21 ± 1.15, mean ± standard deviation (SD)) was significantly larger than that in 14 patients without poorly differentiated HCC (4.05 ± 0.83, p

To examine whether the marked increase in DNA synthesis of hepatocytes in cirrhotic liver might elicit multicentric hepatocarcinogenesis, we examined the relationship between new development of hepatocellular carcinoma (HCC) and the bromodeoxyuridine (BrdU) labeling index (LI) of hepatocytes in the residual liver of hepatectomized patients with liver cirrhosis (LC) and HCC. Eighteen hepatectomized patients with LC and HCC, whose resected liver revealed neither portal nor hepatic vein invasion by histologic examination, were studied (to exclude cases with intrahepatic metastasis). DNA synthesis activity of hepatocytes from the residual cirrhotic liver was measured by a BrdU/anti-BrdU in vitro method. The incidence of HCC recurrence was studied during a 3-year follow-up period. Among 18 patients, 9 patients had recurrence and 9 did not. The average BrdU LI in the recurrent patients was 2.6 +/- 1.3% and was significantly higher than that in patients without recurrence (1.4 +/- 0.5%, P < 0.05). All five patients who had a BrdU LI of 2.4% or above showed recurrence within 3 years, as compared with 4 of 13 (30.8%) patients with BrdU LI of less than 2.4% (P < 0.05). Our data indicate that abnormally high DNA synthesis in hepatocytes in the background cirrhosis might lead to the development of multicentric carcinogenesis in human cirrhotic liver, and in the residual cirrhotic liver of hepatectomized patients with HCC and LC, it may be a predictor of new development of HCC.

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. Methods. The bromodeoxyuridine labeling index (BrdU LI) of hepatocytes was estimated in 38 cirrhotic patients (Child A stage, 23 men and 15 women) using a BrdU/anti-BrdU in vitro method. The incidence of HCC was compared between male and female cirrhotic patients during a 3-year follow-up period. Results. Sixteen of 23 (69.6%) male patients belonged to the high-DNA synthesis group (BrdU LI ⩽ 1.5%), and only 7 (30.4%) were in the low-DNA synthesis group (BrdU LI < 1.5%). Among female patients, only 5 of 15 (33.3%) were in the high-DNA synthesis group, and 10 of 15 (66.7%) were in the low-DNA synthesis group (P < 0.05). Eleven of 23 (47.8%) male patients and 3 of 15 (20.0%) female patients had HCC develop. In the high-DNA synthesis group, 10 of 16 (62.5%) of the men and 3 of 5 (60.0%) of the women had HCC develop during the follow-up period. In contrast, only one of seven (14.3%) male patients and none of ten (0%) female patients in the low-DNA synthesis group had HCC develop. Conclusions. It was concluded that HCC developed frequently (about 60% of the time within 3 years) in patients of both sexes who were in a high-DNA synthesis group. Thus, the larger proportion of men in the high-DNA synthesis group compared with the number of women in the group (69.6% versus 33.3%) might be one possible reason for the male predominance in the development of HCC in cirrhotic patients.

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. METHODS DNA synthesis activity of hepatocytes from background cirrhotic tissue and HCC cells from cancerous tissue was studied in 30 patients with liver cirrhosis (LC) and HCC who had undergone hepatectomy; the study was done using the bromodeoxyuridine (BrdU)-anti-BrdU in vitro method. The correlation between the BrdU labeling index (LI) of hepatocytes from noncancerous cirrhotic tissue and that of HCC cells was studied. The relationship between both BrdU LI values and the survival after hepatectomy also was studied. RESULTS A significant correlation (r = 0.572; P < 0.001) was identified between the BrdU LI for HCC and that for noncancerous cirrhotic tissue. A significant correlation (r = -0.572; P < 0.05) was found between the BrdU LI of HCC cells and the survival after hepatectomy. A significant correlation (r = -0.678; P < 0.01) was observed between the BrdU LI of the noncancerous cirrhotic tissue and the survival. CONCLUSIONS It was concluded that a significant correlation existed between DNA synthesis of hepatocytes from the background cirrhotic tissue and that of HCC cells and that DNA synthesis activity of hepatocytes from noncancerous cirrhotic tissue and that of HCC cells from cancerous tissue could predict the survival of patients with HCC who had undergone hepatectomy.

The relationship between DNA synthesis activity in hepatocytes from cirrhotic tissue and development of hepatocellular carcinoma was studied in 33 posthepatitic patients with Child's 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.

Bromodeoxyuridine (BrdU) labeling indices (LI) of liver biopsied specimens from 27 control liver cirrhosis patients (control LC) without hepatocellular carcinoma (HCC), 26 cirrhotic patients with HCC, and from 6 control subjects were examined using an in vitro BrdU labeling technique. The mean BrdU LI +/- S.E. of HCC cancerous portion, HCC non-cancerous cirrhotic portion, control LC, and control subjects were 6.6 +/- 0.8%, 2.7 +/- 0.3%, 1.7 +/- 0.3% and 0.25 +/- 0.09%, respectively. Interestingly, there was a significant difference (p less than 0.025) between the non-cancerous LC portion and control LC. While 25 of 26 non-cancerous LC portion of HCC patients were in the high LI group (greater than or equal to 1.4%), 15 of 27 in the control LC were in the low LI group (less than 1.4%) (p less than 0.001). Of the 12 control LC with high LI, 6 developed HCC within 2 years, whereas only one of the 15 control LC with low LI developed HCC (p less than 0.05). In conclusion, HCC may develop in cirrhotic patients with high DNA synthetic potency.

An analysis was performed of the patients with hepatitis C virus-associated liver cirrhosis (HCV-LC) who never developed hepatocellular carcinoma (HCC) for 10 years after the histological diagnosis of LC. Seventy-four consecutive HCV-LC patients of Child stage A were observed for >10 years prospectively for the development of HCC with frequent ultrasonography and magnetic resonance imaging or computed tomography. Of the 63 patients who fulfilled the study, 48 patients were treated and 15 were nontreated because of their stable state. They were subdivided into three groups according to their serum alanine aminotransferase (ALT) levels: the high ALT group comprised of 23 patients whose annual average serum ALT level was persistently high (≧80 IU); the low ALT group comprised of 28 patients whose annual average serum ALT level was persistently low (

Multicentric development of hepatocellular carcinoma (HCC) is a characteristic feature of hepatitis C virus (HCV)-associated cirrhosis (HCV-LC). In this study, the objective was to determine whether the persistent elevation of the serum alanine aminotransferase (ALT) level, which represents the inflammatory necrosis of hepatocytes, is correlated with the multicentric development of hepatocellular carcinoma (HCC) in patients with early-stage HCV-LC.Ninety-three consecutive patients with biopsy proven HCV-LC (Child Stage A) who had been followed for5 years for the development of HCC were studied. They were subdivided into three groups according to their serum ALT level: Group A included 33 patients with annual average serum ALT levels that were persistently high (or = 80 IU; high ALT group), Group B included 41 patients with annual average serum ALT levels that were persistently low (80 IU; low ALT group), and Group C included 19 unclassified patients. The patients had been studied prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography (CT) scans for5 years. When the development of HCC was suspected, angiography, infusion of lipiodol into the hepatic artery, and lipiodol-CT scans were performed in all patients to determine the number of HCC nodules.In Group A, 27 patients (81.8%) developed HCC. Seventeen of 27 patients (63.0%) had multiple nodules. In contrast, in Group B, only 12 patients (29.3%) developed HCC, and only 1 of these 12 patients (8.3%) had multiple nodules. There was a significant difference between Groups A and B in the incidence of developing HCC (P0.001) and developing multiple nodules (P = 0.006). In addition, among the male patients, the incidence of developing multiple HCC nodules in Group A (12 of 19 patients; 63.2%) was significantly higher (P0.05) compared with the incidence in Group B (0 of 6 patients; 0%). The same tendency was observed among the female patients.These results showed a close correlation between multicentric hepatocarcinogenesis and sustained necroinflammation of the liver in patients with HCV-LC.

Many studies have demonstrated in animal experiments that persistent inflammation may accelerate the development of carcinoma. In this article, the question of whether the persistent elevation of serum alanine aminotransferase (ALT) levels (which represents the inflammatory necrosis of hepatocytes) correlates with the development of hepatocellular carcinoma (HCC) was studied in patients with early stage hepatitis C virus (HCV)-associated cirrhosis.Sixty-nine consecutive patients with biopsy proven HCV-associated cirrhosis (mostly Child's Stage A) who had been followed for5 years for the development of HCC were studied. They were subdivided into 3 groups according to their serum ALT levels: Group A was comprised of 28 patients whose annual average serum ALT level was persistently high (/= 80 IU) (high ALT group), Group B was comprised of 28 patients whose annual average serum ALT level was persistently low (80 IU) (low ALT group), and Group C was comprised of 13 unclassified patients. The patients had been studied prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for5 years.In the high ALT group HCC developed in 71.4% of patients compared with 25.0% in the low ALT group over the observation period (P0.005). The 5-year rate of incidence of HCC in the high ALT group was as high as 53.6% compared with only 7.1% in the low ALT group (P0.001). The expected interval between the diagnosis of cirrhosis and the development of HCC was 6.0 +/- 0.7 years (mean +/- standard error) in the high ALT group and 12.7 +/- 1.2 years in the low ALT group (P0.001).The results of the current study demonstrated that the development of HCC was more rapid in the high ALT group with HCV-associated cirrhosis.

The relationship between the recurrence of hepatocellular carcinoma (HCC) and the serum alanine aminotransferase (ALT) level was studied in hepatectomized patients with hepatitis C virus (HCV)-associated cirrhosis and HCC.Twenty-six hepatectomized patients with HCV-associated cirrhosis and HCC whose resected specimens showed neither portal vein nor hepatic vein invasion by HCC histologically were divided into 2 groups: 15 patients who had no recurrence 3 years after surgery (Group A) and 11 patients whose disease recurred 1-3 years after surgery (Group B). The patients' serum ALT levels during this period were examined.In Group A, serum ALT generally showed sustained low levels80 international units (INU) in 12 patients (80%). In contrast, ALT levels in Group B showed several peaks or plateaus80 INU in all patients except 2. The recurrence rate of HCC in the hepatectomized patients with sustained low levels of ALT was 14.3% (2 of 14 patients) at 3 years, and was significantly lower (P0.01) than that in those patients whose ALT levels showed several peaks or plateaus80 INU (9 of 12 patients; 75.0%). The average level of mode of ALT in Group A (48.8 +/- 26.0 INU) was significantly smaller than that in Group B (101.1 +/- 47.3 INU) (P0.005).The importance of hepatocytic necrosis in the recurrence of HCC in hepatectomized patients with cirrhosis and HCC of HCV origin was demonstrated and the significance of subsiding hepatic necroinflammatory process in the prevention of HCC recurrence suggested.

Background. The relationships between echosonographic patterns of patients with cirrhosis who are antihepatitis C virus (HCV)-positive, the DNA synthesis of hepatocytes, and the risk for HCC were studied. Methods. Thirty-eight patients with anti-C-100 antibody-positive and Child's grade A posthepatitic cirrhosis were studied. DNA synthesis activity was measured by a bromodeoxyuridine (BrdU, a thymidine analogue)-labeling index (LI), using the BrdU-anti-BrdU in vitro method, and the patients were followed prospectively by frequent liver ultrasonography for 3 years. The ultrasound patterns were classified into fine, coarse, and coarse-nodular (CN) patterns, and the reproducibility of the classification in practical use also was confirmed. Results. Of the 21 patients with high DNA synthesizing cirrhosis (BrdU LI ⩾ 1.5%), 10 (48%) showed coarse-nodular, 5 (24%) coarse, and 6 (29%) fine pattern in ultrasonography. Conversely, of the 17 patients with low DNA synthesizing LC (BrdU LI < 1.5%), only 1 (6%) showed coarse-nodular, 2 (12%) coarse, and 14 (82%) fine pattern.A significant relationship was found between the two groups of BrdU LI and ultrasound imaging patterns [P < 0.05). The incidence of CN pattern was significantly higher (P < 0.01) in the high DNA synthesizing group than in low DNA synthesizing group. Of the 11 patients with CN pattern by ultrasound imaging, 10 (91%) were in the high DNA synthesizing group, and 9 (82%) developed HCC during the follow-up period, compared with 3 of 7 (43%) with coarse, and only one of 20 (5%) with fine pattern developed HCC. The incidence of HCC was significantly higher (P < 0.01) in patients with a CN cirrhosis pattern than in those with a fine pattern. Conclusions. In patients with cirrhosis who are anti-HCV-positive, the CN pattern by ultrasound imaging indicates increased DNA synthesis of hepatocytes and a high risk for developing HCC. Cancer 1995;75:1255-62.

To clarify sex differences in DNA synthesis in hepatocellular carcinoma (HCC), bromodeoxyuridine labeling indices (BrdU LI) of HCC cells included in tumor biopsy specimens from 12 consecutive male patients and from 5 consecutive female patients all with liver cirrhosis and HCC were examined using an in vitro labeling technique. The mean BrdU LI +/- SE of HCC from male patients (7.7 +/- 0.8%) was significantly (P less than 0.05) higher than that from female patients (4.4 +/- 1.0%). While 7 of the 12 male HCC patients belonged to the high DNA synthesis group (BrdU LI greater than or equal to 7.0%), none of the 5 female HCC patients showed high DNA synthesis (P less than 0.05). We conclude that DNA synthesis in HCC was higher in males than in females.

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 less than 0.05) between the non-cancerous cirrhotic portion and control LC. Although all 17 non-cancerous cirrhotic portion belonged to the high LI group (greater than or equal to 1.5%), 10 of 19 in the control LC belonged to the low LI group (less than 1.5%) (P less than 0.001). The authors conclude that HCC would develop in the cirrhotics with high DNA synthetic potency.

ThymidineのanalogueであるBrdUに対するモノクローナル抗体を用いて肝細胞癌(以下HCC),肝硬変(以下LC),慢性活動性肝炎(以下CAH),アルコール性肝線維症(以下Al-F)等の各種肝疾患時の肝のDNA合成を免疫組織学的に検討した.即ち,上記疾患の肝生検組織をBrdUを含んだ培養液とincubationしBrdU摂取をin vitroで測定した.取り込みが最も高率であったのはHCC癌部でL.I.は5.7±0.9%であり,次いでHCC非癌硬変部(3.4±0.4%),さらにHCCの無いLC (2.3±0.7%), Al-F (2.4±0.7%)であった.一方,CAHでは1.0±0.1%と予想外に低かった.HCC癌部は,HCC非癌硬変部(p

ThymidineのanalogueであるBromodeoxyuridine(以下BrdU)に対するモノクロナール抗体を用いて原発性肝癌(以下HCC) 16例の腫瘍細胞のDNA合成を免疫組織学的に検討した.方法は0.1%にBrdUを含んだRPMI1640液と肝生検組織をincubationし,BrdU摂取率をin vitroで測定した.Labeling Index (L.I.)のMean±SEは7.06±2.71%で症例間で2.6%から12.7%と大きな差異がみられた.又,HCCのL.I.は他の消化器癌に比べて概して低値であった.次にHCCの組織学的差異によるBrdU L.I.の検討ではL.I. 5%未満では全てtrabecular typeであったのに対し,5%以上ではpseudoglandular typeやsolid typeが高頻度にmixしていた.一方,Edmondson & Steiner'sの異型度分類とBrdU L.I.との関係では,より異型度の高いIII型がL.I. 10.64±2.10%で,I～II型の5.87±1.61%に比べ有意に高く,異型度とDNA合成能との相関が示唆された.