Setsuo Tamai

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.

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.

Sustained low alanine aminotransferase levels can predict the survival for 10 years without hepatocellular carcinoma development in patients with hepatitis C virus-associated liver cirrhosis of child stage A.

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 (<80 IU), and the unclassified ALT group comprised of 12 patients. In the low ALT group, as high as 71.4% of patients had never developed HCC for 10 years, in contrast to only 17.4% in the high ALT group (p < 0.001). In the 30 patients who never developed HCC for 10 years, 20 patients belonged to the low ALT group, in contrast to only 4 belonging to the high ALT group. Sustained low ALT levels were important to survive for 10 years without developing HCC in the HCV-LC patients of Child stage A.

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.

Postoperative complications in patients of esophageal cancer after neoadjuvant chemotherapy

We examined the effects of neoadjuvant chemotherapy on surgery by evaluating postoperative complications in 50 patients who had undergone neoadjuvant chemotherapy (Group A) and in 108 patients who had undergone surgery without neoadjuvant chemotherapy (Group B). Toxicity of grade 3 by chemotherapy were WBC in 3 patients (6%), alopecia in 3 patients (6%), and anorexia in 22 patients (44%). There were 4 patients with anastomotic leakage (8%) (all in minor), 5 patients with infection of wound (10%), 6 patients with arrhythmia (12%), no patients with postoperative bleeding, 2 patients with respiratory complications (4%), and no patients who died due to complications in Group A. In Group B, there were 13 patients with anastomotic leakage (13%) (all in minor), 12 patients with infection of the wound (11%), 11 patients with arrhythmia (10%), 2 patients with postoperative bleeding (2%), 8 patients with respiratory complications (7%), and 2 patients who died due to complications (2%). There was no significant difference in the incidence of postoperative complications between the patients who had undergone surgery after neoadjuvant chemotherapy, such as CDDP + 5FU therapy and FAP therapy, and the patients who had undergone surgery without neoadjuvant chemotherapy, in patients who had been diagnosed as being able to undergo relative non-curative resection or better, who had Ccr 60 ml/min or more and no severe complication, and whose stomach could be used for reconstruction of the esophagus, on the condition that surgery would be performed on NC patients at the end of first-course treatment.

Sex Difference in the Laparoscopic Appearance of the Cirrhotic Liver in Child A Stage

The ratio of the number of cases of slightly elevated (flat shaped) nodules to hemispherical nodules on laparoscopical examination was studied in male and female histologically proven cirrhotic patients in Child A stage. The bromodeoxyuridine labeling indices (BrdU Lis) of all of the cirrhotic patients were examined using an in vitro labeling technique. Liver biopsy specimens obtained by a Tru‐cut needle were immediately incubated for 45 min. in 0.1% BrdU solution in RPMI 1640 at 37°C under a pressure of 3 atmospheres in a mixture of 95% O2 and 5% CO2. Immunohistochemical detection of BrdU was performed using the ABC method. In the 18 male cirrhotic patients in Child A stage, 12 (67%) were found to have hemispherical nodules, and 6 (33%) were found to have slightly elevated nodules. In the 18 female cirrhotic patients, 5 (28%) had hemispherical nodules, and 13 (72%) had slightly elevated nodules (p< 0.05). The mean BrdU LI in male cirrhotic patients (2.07 ± 0.36%, SE) was greater than that of the female patients (1.21 ± 0.31%). The average BrdU LI of the hemispherical cirrhotic group (2.41 ± 0.39%) was significantly (p< 0.005) greater than that of the slightly elevated cirrhotic group (0.98 ± 0;21%). We found that about 70% of the male cirrhotic patients in Child A stage had a laparoscopically hemispherical nodular liver, as compared to about 30% of the female cirrhotic patients (p<0.05), and that the proliferation of hepatocytes in the hemispherical nodular liver was significantly increased compared with that of the slightly elevated (flat shaped) nodular liver (p<0.005).

A Survey of Regenerating Capacity in Patchy Liver and in Nodular Liver—with Special Reference to DNA Synthesis Estimated by BrdU Labeling Index—

Abstract: Laparoscopically, patchy liver and nodular liver were considered as features of regeneration of liver cells. In this study, the regenerating capacity of liver cells obtained by a liver biopsy from laparoscopically identified patchy liver and nodular liver was estimated by Bromodeoxvuridine (BrdU)‐anti‐BrdU method. BrdU labeling indices (L. I.), of liver cells in biopsy specimens from 6 normal livers, 12 patchy livers, and from 15 nodular livers were examined using an in‐vitro labeling technique. Liver biopsy specimens obtained by a Tru‐cut needle were immediately incubated for 45 min. in 0.1% BrdU solution in RPMI 1640 at 37°C under a pressure of 3 atmospheres in a mixture of 95% O2 and 5% CO2. Immunohistochemical detection of BrdU was performed by the Avidin‐Biotin‐Peroxidase Complex (ABC) method. The mean BrdU L. I. (±SE) of normal liver, patchy liver, and of nodular liver was 0.25±0.09%, 1.4±0.2%, and 1.7±0.4% respectively. Among the nodular liver, flat shaped ones showed a low level (0.5±0.1%), in contrast to the high level (2.4±0.7%) in the semispherical nodular liver. The BrdU L. I. of both the patchy liver and the nodular liver was significantly higher than that in the normal liver (p<0.001, p<0.01 respectively).

Increased Deoxyribonucleic Acid Synthesis in Primary Biliary Cirrhosis with the Laparoscopical Hallmark of “Reddish patch”

Abstract: The deoxyribonucleic acid (DNA) synthetic potency of hepatocytes in liver biopsy specimens was investgated in: 6 patients with primary biliary cirrhosis (PBC) with a laparoscopical finding of a “reddish patch”, 5 patients with PBC without a “reddish patch”, 10 patients with chronic aggressive hepatitis with a typical “patchy liver” as seen on laparoscopy, 14 patients with cirrhosis of a viral origin with a laparoscopic “nodular liver”, and in 6 patients with gastric cancer without liver involvement (control subjects). The bromodeoxyuridine (BrdU, a thymidine analogue) ‐anti‐BrdU method was used. The mean BrdU L. I. (±SE) of the PBC patients with a “reddish patch”, PBC patients without a “reddish patch”, patients with a “patchy liver”, patients with a “nodular liver” and of the control subjects was 3.5±0.6%, 0.5±0.1%, 1.3±0.3%, 1.1±0.3%, and 0.2±0.1% respectively. The BrdU L.I. of the PBC patients with a “reddish patch” was significantly greater than that of the PBC patients without a “reddish patch” (p>0.001) and greater than that of patients with a “patchy liver” or a “nodular liver” (p>0.001, respectively). It was the greatest in all of the benign liver diseases examined. Thus, the so‐called laparoscopical finding of a “reddish patch” in PBC may represent a marked regeneration of hepatocytes.