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Frequent loss of heterozygosity of microsatellites markers on specific chromosomal region have been reported in various types of primary human cancer. The same loss of heterozygosity has also been identified in the matched plasma/serum DNA. Using 109 microsatellite markers representing 24 chromosomal arms, we have examined the loss of heterozygosity in 21 cases of hepatocellular carcinoma, six of cholangiocarcinoma, and 27 cases of chronic hepatitis or cirrhosis. All cases of the hepatocellular carcinoma showed deletion from two to 10 chromosomal arms, while deletion of chromosomes from two to eight regions was detected in five of six cholangiocarcinoma patients. One or more loss of heterozygosity in the paired serum DNA could be detected in 16 of 25 (76.2%) hepatocellular carcinoma patients. In contrast, no alterations in serum DNA test could be found in cholangiocarcinoma patients. Five of seven (71.4%) hepatocellular carcinoma patients with alpha-fetoprotein levels less than 20 ng ml(-1) produced positive serum DNA test. The profiles of 19 microsatellite markers gave a 100% positive predictive value and an 80.8% negative predictive value for hepatocellular carcinoma. In conclusion, we have determined a profile of microsatellite markers appropriate for differential diagnosis of primary liver cancer. The discovery may permit a high-throughput screening of hepatocellular carcinoma at an early stage of disease., (Copyright 2002 Cancer Research UK)

Using a different fragment DE6 obtained from DD-PCR as probe, a full-length cDNA has been cloned from human liver cDNA library and named as syap1 (Synapse-associated protein 1) because its deduced amino acid sequence is homologous to SAP47 of D. melanogaster. Northern blot analysis reveals that two transcripts of syap1 mRNA are expressed in cultured human liver L-02 cells. Moreover, the syap1 mRNA was also detected in most of adult human tissues by RT-PCR analysis. Down-regulated expression of syap1 mRNA was confirmed by semi-quantitative RT-PCR assay in 5 of 10 (50%) cases of human hepatocellular carcinoma (HCC).

The epidermal growth factor (EGF) is a member of the growth factor superfamily that can stimulate the proliferation of many types of cells. Overexpression of EGF receptor (EGFR) was observed in many types of cancer cells. Anti-EGFR antibodies or antisense nucleic acid sequences of EGFR can suppress the growth of hepatoma cells. In order to further investigate the proteome alterations associated with malignant growth of the human hepatoma cells and the influence of EGFR signal pathway on the cellular proteome, we have comparatively analyzed the proteomes of human hepatoma cells transfected with antisense EGFR sequence (cell strain JX-1) and its control cells (cell strain JX-0) by two-dimensional (2-D) gel electrophoresis and mass spectrometry. Image analysis of silver-stained 2-D gels revealed that 40 protein spots showed significant expression changes in JX-1 cells compared to JX-0 cells. Three of them, including the tumor suppressor protein maspin, changed with tendency to the normal levels. Two protein spots were identified as HSP27 in the same gel, and one of them had a reduced level in JX-1 cells. The apparent alterations of HSP27 in expression level might be the results from their differential chemical modifications, suggesting the effect of dynamic post-translational modifications of proteins on the growth of hepatoma cells. Other proteins such as glutathione peroxidase (GPX-1) and 14-3-3-sigma also exhibited altered expression in JX-1 cells, and their functional implications are discussed.

Angiomyolipoma is a rare lipomatous tumor in the liver. Definitive preoperative diagnosis is becoming easier by the use of ultrasonography, computed tomography, and magnetic resonance imaging techniques. Nonsurgical treatment has been advocated for its benign nature. However, recently we encountered one case of hepatic angiomyolipoma with two concomitant hepatocellular carcinomas on a hepatitis B carrier. Although his serum alpha-fetoprotein was normal, under the above impression these lesions were resected. The pathologic findings showed a typical angiomyolipoma and two well-differentiated hepatocellular carcinomas with marked fatty metamorphosis. This is the first report of angiomyolipoma with concomitant hepatocellular carcinomas in the literature. Nonsurgical treatment of angiomyolipoma in an endemic area for hepatocellular carcinoma should proceed with caution because cases of fat-rich minute hepatocellular carcinomas will make the diagnosis difficult.

Objective: Recently, tissue polypeptide specific antigen (TPS) has been introduced as a cell proliferation marker. Little is known about its clinical significance in hepatocellular carcinoma (HCC). This study aimed to clarify serum TPS levels and tumor invasiveness of HCC., Methods: Serum TPS levels were determined with a monoclonal TPS IRMA assay in 69 patients with HCC. A correlation between serum TPS levels and clinical, biochemical, and pathological features was sought and compared with that of alpha-fetoprotein (AFP). In 57 healthy subjects, 56 patients with biopsy-proven chronic hepatitis and in 49 patients with liver cirrhosis, serum TPS levels were assayed and compared., Results: Serum TPS levels were significantly correlated with glutamic oxalacetic transaminase (p < 0.0001), glutamic pyruvic transaminase (p < 0.001), and lactate dehydrogenase (p = 0.027). There tended to be a positive relationship between serum TPS levels and tumor size, histological differentiation, capsular invasion, portal invasion, and clinical staging, although it did not reach statistical significance. A significant correlation, however, was observed between AFP and tumor size (p = 0.01), number (p = 0.042), histological grading (p = 0.028), portal invasion (p = 0.009), and clinical staging (p = 0.03). Patients with HCC had significantly higher TPS than healthy subjects (p < 0.001). However, there was substantial overlap between patients with HCC, chronic hepatitis, and liver cirrhosis., Conclusions: Our data suggest that serum TPS is not significantly related to tumor invasiveness in patients with HCC. Serum TPS levels are affected by the proliferative activity of the underlying chronic liver disease, which is frequently associated with HCC in Chinese patients. As a cell proliferation marker, serum TPS should be interpreted cautiously in the presence of chronic liver disease., (Copyright 2001 S. Karger AG, Basel)

Apoptosis plays an important role in embryonic development, tissue remodeling, immune regulation and tumor regression. Two groups of molecules (Bcl-2 family and "Death factor" family) are involved in regulating apoptosis. In order to know about the effect of Bcl-2 on apoptosis induced by Fas, a typical member of "Death factor" family, the transfection experiments with expression vectors pcDNA3-fl and pcDNA3-bcl-2 were performed in BEL-7404 cells, a human hepatocellular carcinoma cell line which expresses endogenous Fas, but not FasL and Bcl-2. The data showed that the expression of FasL in pcDNA3-fl transfected hepatoma cells obviously induced the apoptosis of the cells. However, the overexpression of Bcl-2 in pcDNA3-bcl-2 transfected 7404/b-16 cells counteracted pcDNA3-fl transient transfection mediated apoptosis. Further study by co-transfection experiments indicated that Bid but not Bax (both were pro-apoptotic proteins of Bcl-2 family) blocked the inhibitory effect of Bcl-2 on Fas-mediated apoptosis. These results suggested that Fas-mediated apoptosis in human hepatoma cells is possibly regulated by Bcl-2 family proteins via mitochondria pathway.

Background/aims: Previous clinical investigations suggest that androgen and its receptor (AR) may play an important role in the growth of hepatocellular carcinoma. Few studies are available concerning the effect of androgen manipulation on the growth of AR-positive hepatocellular carcinoma in vivo., Methods: AR-positive (SM10) and AR-negative (SM2) sublines derived from a human hepatocellular carcinoma line KYN-1 were implanted subcutaneously in the lower abdomen of nude mice. The tumour size and expression of proliferating cell nuclear antigen and Lewis Y antigen were examined in intact males, castrated males, intact females, and castrated males with androgen replacement. AR of the tumour was measured with binding assay, ultracentrifugation, and Western blotting., Results: The growth of SM10 was significantly better in intact males and castrated males with 5a-dihydrotestosterone injection than in intact females and castrated males. Castration did not suppress the growth of SM2. The tumour AR level was reduced by castration but maintained by the hormone substitution. Although proliferating cell nuclear antigen expression was closely associated with tumour growth, Lewis Y antigen expression did not differ among the groups., Conclusions: These data may indicate that this hepatocellular carcinoma subline (SM10) is androgen-responsive and that androgen ablation can cause the inhibition of the tumour growth, which might be due to decreased proliferative and not increased apoptotic activities. In addition, such androgen-stimulated tumour growth seems to be mediated through AR.

Background: The long-term survival rate after liver resection of hepatocellular carcinoma (HCC) is far from satisfactory, mainly because of high intrahepatic recurrence (IHR) rates. This study was aimed to clarify clinicopathologic factors relevant to IHR after resection of HCC., Methods: The 10-year cumulative intrahepatic recurrence rates were analyzed in terms of seven clinical and eight pathological factors in 201 patients with curative hepatic resection., Results: IHR was found in 121 patients during the follow-up period. The overall IHR rates were 22% at 1 year, 43% at 2 years, 62% at 3 years, 72% at 4 years, 75% at 5 years, and 75% at 10 years. Age, sex, and serum alpha-fetoprotein level, hepatitis B virus markers, and extent of liver resection were not significantly related to the IHR rate. Postoperative chemotherapy mainly with anthracycline tended to suppress IHR (P = 0.0889), but preoperative chemoembolization did not affect IHR. The presence of cirrhosis, satellite nodules, and venous invasion and the absence of capsule formation were associated with higher recurrence rates throughout the observation. Positive surgical margin (< or = 5 mm) was also associated with a higher IHR rate. Although not significant, well-differentiated HCCs showed a higher recurrence rate in comparison with poorly differentiated tumors. Size and number of tumor did not influence the IHR rate., Conclusions: Accurate patient selection and adequate hepatic reserve are important considerations in the management of HCC by resection.

Objective: This study analyzed the results in 229 patients with primary hepatocellular carcinoma (HCC) who were treated by radical hepatic resection in the past 11 years., Summary Background Data: Due to marked advances in diagnostic and therapeutic methods, the therapeutic strategy for HCC has changed significantly. However, there are still many problems to be solved when hepatic resection is to be performed for HCC associated with chronic liver disease. A satisfactory result may be possible only when all of accurate operative indication, skillful surgical technique, and sophisticated postoperative management are met., Methods: There were 188 men and 41 women. Age ranged from 32 to 79 years averaging 60.8. Underlying cirrhosis of the liver was found in 177 patients, and chronic hepatitis was found in 47 instances. Before surgery, 114 patients had 157 associated conditions; diabetes mellitus in 66, esophageal varices in 42, cholelithiasis in 22, peptic ulcer in 12, and miscellaneous in 15 cases. In addition to various types of hepatic resection, 69 patients underwent concomitant operations such as cholecystectomy, the Warren shunt, splenectomy, partial gastrectomy, and so forth., Results: The 30-day (operative) mortality rate was 7.0%, and there were eight additional late deaths (3.5%). Child's class, bromosulphalein (BSP) test, and the estimated blood loss during surgery were good predictors for operative death. The cumulative 5- and 10-year survival rates for all patients were 26.4% and 19.4%, respectively. At present, 110 patients are alive; 2 more than 10 years and 21 more than 5 years. Younger age, absence of cirrhosis, smaller tumor, and postoperative chemotherapy were associated with increased survival., Conclusions: The results of hepatic resection in 229 patients with HCC were analyzed. Child's class, BSP test, and blood loss during surgery were good predictors for operative death. The 5- and 10-year survival rates were 26.4% and 19.4%, respectively. Age, liver cirrhosis, tumor size, and postoperative chemotherapy were prognostic factors. Multidisciplinary approach with liver resection, postoperative chemotherapy, and liver transplantation will be a realistic direction for the surgical treatment of HCC in future.

Background: Thirty-two patients who were 70 years of age or older underwent hepatic resection in the treatment of hepatocellular carcinoma. There were 25 men and 7 women. Age ranged from 70 to 84 years, averaging 74 +/- 3 years (mean +/- SD). Underlying liver diseases were associated in all patients but one, cirrhosis of the liver in 22, and chronic hepatitis in nine., Methods and Results: The operative mortality rate within 1 month was 12.5%, and the overall in-hospital death rate was 18.8%. The 5-year survival rate was 17.6% for all patients and 24.3% when six hospital deaths were excluded. The Child's grade was a good predictor for early and late morbidity and death, the 5-year survival rate of patients with Child's class A disease being 30%. Retrospective comparisons were conducted between the current patients and patients younger than 50 years old who had been operated on during the same period: resectability rate, 61.5% versus 57.8%; hospital mortality rate, 18.8% versus 11.6%; and 5-year survival rate, 24.3% versus 48.6%, respectively., Conclusions: These results seem to indicate that the treatment policy of hepatocellular carcinoma in the aged should be identical to that in young people.

DNA ploidy of hepatocellular carcinoma (HCC) was studied in 28 patients using a flow cytometric method. Fourteen patients had two HCCs synchronously, and the remaining 14 had tumor recurrence in the remnant liver 3-41 months after curative resection of primary HCCs. DNA ploidy pattern and histopathologic parameters were compared between the synchronous and metachronous HCCs. Among those with synchronous HCCs, both tumors were diploid in 7 cases and aneuploid in 2 instances. Five patients had HCCs of different DNA ploidy pattern. On the other hand, 5 of 14 patients with metachronous HCCs had a consistent DNA ploidy between primary and recurrent tumors. In 4 cases, the first tumor was diploid whereas the recurrent HCC was aneuploid or tetraploid. In the remaining 5 cases, the primary HCC was aneuploid, but the recurrent tumor was diploid. Assuming that the difference in DNA ploidy pattern indicates a different clonal origin, the current results indicate that at least 36% of synchronous HCCs and 64% of recurrent HCCs develop in a multicentric fashion.

Nuclear DNA content of hepatocellular carcinoma (HCC) was estimated by flow cytometry after hepatic resection in 91 patients during the past 5 years. There were 53 diploid and 38 aneuploid tumours. Clinicopathological features were compared retrospectively between the patients with diploid and those with aneuploid HCC. DNA ploidy did not show any correlation with age, sex, alcohol abuse, hepatitis B virus, serum alpha-fetoprotein level or underlying liver disease. Histopathologically, the incidence of HCC less than 2 cm in diameter tended to be higher in the diploid group but no difference was seen for large tumours (greater than 5 cm). The grade of tumour differentiation also tended to be higher in this group of small HCC. The ploidy pattern did not influence the rate of capsule or daughter nodule formation, or venous invasion. There were no significant differences in survival rate or in the incidence and time of intrahepatic tumour recurrence between the two groups. This study may indicate that nuclear DNA ploidy is not a particularly predictive factor for the surgical treatment of HCC.

Serum samples from 243 cases of primary hepatocellular carcinoma (PHC) and 302 non-PHC hospital controls were tested for hepatitis B virus (HBV) surface antigen (HBsAg), antibody to HBsAg (anti-HBs), antibody to HBV core antigen (anti-HBc), HBV e antigen (HBeAg) and antibody to HBeAg (anti-HBe) with radioimmunoassays using commercial kits. A total of 236 (97%) PHC cases and 302 (100%) hospital controls were positive for one or more HBV markers. While 188 (77%) PHC cases and 57 (19%) controls were positive for HBsAg, 44 (18%) PHC cases and 5 (2%) controls were positive for both BHsAg and HBeAg. Statistically significant associations with PHC were observed for HBsAg and HBeAg with an odds ratio (OR) of 10.0 and 3.2, respectively, when age, sex and other markers were adjusted. The stratification analysis of interactive effects of HBV infection markers on the development of PHC showed that HBeAg carrier status may increase PHC risk associated with HBsAg status.

Progesterone receptors (PgR), estrogen receptors (ER), and androgen receptors (AR) were assayed consecutively for hepatocellular carcinoma (HCC) that was surgically removed from 19 men and three women. The methods of receptor assay were the enzyme immunoassay (EIA) for PgR and the dextran-coated charcoal (DCC) technique for ER and AR. The patients ranged in age from 32 to 77 years (average, 60.3 years). No patients had received any specific anti-cancer therapy before tissue collection. All patients but one had underlying liver disease: cirrhosis in 13 and chronic hepatitis in eight. The positive rate of each receptor was 18% for PgR, 48% for ER, and 82% for AR. The titer was highest for AR, intermediate for ER, and lowest for PgR. The titers of PgR in four PgR-positive patients ranged from only 1.1 to 3.0 fmol/mg of protein. There was no relationship between PgR, ER, and AR in terms of positivity and titer. Also, other clinical and histopathologic data did not influence the positivity or concentration of these three sex hormone receptors. It can be concluded that no or little PgR exists in the cytosol of untreated HCC.

Independent and interactive effects related to the development of hepatocellular carcinoma were assessed using a community-based case-control study for hepatitis B virus, habitual alcohol drinking, cigarette smoking, peanut consumption and history of hepatocellular carcinoma among the immediate family. All 200 male newly diagnosed hepatocellular carcinoma patients were recruited consecutively through the period of study as the case group from two teaching medical centers in northern and southern Taiwan. Healthy community residents matched one-to-one with cases on age, sex, ethnic group and residential area were selected as the control group. The carrier status of HBsAg and HBeAg was determined by blind radioimmunoassays, and other risk factors were obtained through standardized interviews according to a structured questionnaire. Conditional logistic regression analysis showed a significant association between hepatocellular carcinoma and the carrier status of HBsAg and HBeAg with an odds ratio of 16.7 and 56.5, respectively, for carriers of HBsAg alone and for carriers of both HBsAg and HBeAg. There was a dose-response relationship between cigarette smoking and hepatocellular carcinoma with an odds ratio of 1.1, 1.5 and 2.6, respectively, for those who smoked 1 to 10, 11 to 20 and more than 20 cigarettes a day. A significant association with hepatocellular carcinoma was also observed for the habitual alcohol consumer with an odds ratio of 3.4. Those whose immediate family had a history of hepatocellular carcinoma were more likely to have the disease develop, with an odds ratio of 4.6. However, the frequency of peanut consumption was not significantly associated with hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

From 1980 to 1988, 161 patients underwent total extirpation of primary hepatocellular carcinoma. There were 18 operative or hospital deaths. Recurrence of tumor was diagnosed in 69 of the remaining 143 patients during follow-up treatment with monthly serum alpha-fetoprotein measurements and imaging studies that were performed every three months. There were 61 men and eight women whose ages ranged from 33 to 78 years. The histologic factors noted were cirrhosis of the liver in 60 patients and chronic hepatitis in nine. There were multiple or diffuse recurrences (Type A) in 34 instances, one to three nodular recurrences (Type B) in 21, marginal recurrences (Type C) in 11 and a mixed form of the latter two in three instances. Two-thirds of the recurrences were found within 1.5 years and the second peak was noted between 2.0 and 2.5 years. Sex of patient, hepatitis B virus, type of tumor, capsule, extent of hepatic resection and postoperative chemotherapy did not influence the rate of recurrence, but cirrhotic livers had a significantly higher recurrence rate. A second hepatic resection was performed upon 20 patients with a five year survival rate of 26.8 per cent. Good results were obtained by chemoembolization of the hepatic artery. Prevention and adequate treatment of intrahepatic recurrence are of paramount importance in achieving better surgical results for hepatocellular carcinoma.

During the past 8 years, estrogen receptors (ERs) in the cytosol of hepatocellular carcinoma (HCC) were assayed in 66 unselected patients without preceding treatments on whom radical hepatic resection was performed. Twenty-six patients had ERs of 0.9 to 13.4 fmol/mg protein with a mean dissociation constant of 7.8 x 10(-10) M. The remaining 40 patients had no detectable amount of the receptor. There were no substantial differences between the ER-positive and ER-negative groups in preoperative clinical and laboratory data such as sex, age, alcohol abuse, underlying liver disease, and hepatic functions. Large tumors were more common in the ER-negative group and therefore the incidence of major hepatic resection was significantly higher in this group. Histopathologic studies revealed no substantial differences between the two groups. Operative mortality rate was 11.5% in the ER-positive and 12.5% in the ER-negative group. Excluding eight operative deaths, the rate of tumor recurrence in the residual liver and long-term survival rate were identical for the two study groups. The current results may indicate that the presence or absence of ERs in human HCC does not correlate to either biologic or pathologic characteristics of this tumor, but the true role of ERs in human HCC remains to be elucidated.

During the last 6 years, 205 patients with primary hepatocellular carcinoma (HCC) were admitted to our surgical departments. Thirty-eight had HCC smaller than 3 cm in diameter. There were 34 men and 4 women with an average age of 56.5 years. All patients had underlying hepatic disease: liver cirrhosis in 35 patients and chronic active hepatitis with fibrosis in the remaining 3. Pre-operative complications included: oesophageal varices in ten, cholelithiasis in five, peptic ulcer in two, gastric cancer in one, and severe hypersplenism in one instance. A radical resection was performed in 32 cases and palliative resection in 6. Simultaneous operations were carried out for the above mentioned associated conditions: distal splenorenal shunt in six, Hassab's devascularization procedure in one, splenectomy in one, cholecystectomy in four, cholecystolithotomy in one, and partial gastrectomy in one. Four patients had postoperative complications: liver failure, rebleeding, right haemothorax, and upper gastrointestinal bleeding from acute mucosal lesion of the stomach. One patient with liver failure died in coma within 1 month. The operative and in-hospital mortality rates were 2.6 and 7.9 per cent, respectively. Survival rates during the first 4 years in 32 patients with radical hepatic resection were 89.9, 67.2, 58.8, and 58.8 per cent, respectively. We suggest that hepatic resection should be the first choice of treatment for minute HCC even in the presence of liver cirrhosis.

During the past 8 years we have treated 268 patients with primary hepatocellular carcinoma (HCC); total extirpation of the tumor was carried out in 138. Thirty-one of the patients with resectable HCCs had already been treated with transcatheter arterial embolization (TAE) of the liver before they were referred to us. The clinical values of preoperative TAE were retrospectively evaluated for those 31 patients and for the remaining 107 patients without TAE. There were no substantial differences between the two study groups in the clinical and histopathologic backgrounds. No differences were observed in the extent of liver resection, estimated blood loss during surgery, and operation time. During surgery, however, troublesome intra-abdominal complications relevant to TAE were encountered in 15 patients, and detection of tumors was impossible, even with intraoperative ultrasonography, in five patients in the group with TAE. Such findings were not present in any of the patients without TAE. Postoperative morbidity and mortality rates were similar in the two groups. There was no significant difference in the rate of recurrence of tumor in the liver, but the recurrence time was significantly shorter in the group with TAE. TAE did not improve the long-term survival rates in patients either with or without cirrhosis. Results of our study seem to indicate that preoperative TAE is meaningless in the treatment of resectable HCCs and therefore should be avoided, particularly in patients with advanced cirrhosis of the liver.

Major hepatic resection was carried out on 23 adult patients with hepatocellular carcinoma (HCC) and underlying cirrhosis of the liver (macronodular in six cases, micronodular in 11 and mixed type cirrhosis in six). Pre-operative liver functional state was Child's class A in 19, class B in three, and class C in one. The operations performed were extended right lobectomy in four patients, right lobectomy in 10, left found in 10 patients, five of whom had duplicated complications and finally died of liver failure 15-65 days after operation. In three of those five patients, other complications (hemorrhagic shock in two and portal thrombosis in one) had preceded liver failure. Eighteen patients tolerated the resection and were discharged from hospital. However, among 13 noncirrhotic patients with HCC who had undergone major hepatic resection during the same period of time, only two had postoperative complications and all patients were discharged from hospital. The 1-, 2- and 3-year survival rates in the 23 cirrhotics were 60.9%, 37.5% and 24.9% respectively, whereas the 1-5-year survival rates were all 61.5% in the 13 noncirrhotics. Thus, major hepatic resection may be indicated in selected patients with HCC and associated cirrhosis, but meticulous managements during and after operation are mandatory to prevent fatal postoperative liver failure.

During the recent 5 2/3 years, hepatic resection was performed on 118 patients with hepatocellular carcinoma. Ages ranged from 17 to 78 years with an average of 57 years. There were 101 males and 17 females. Underlying cirrhosis of the liver was found in 101 cases, and chronic hepatitis was found in 16 cases. Before surgery 62 patients had 71 associated conditions such as esophageal varices, diabetes mellitus, cholelithiasis, or peptic ulcer. Operations for the varices and cholelithiasis were performed simultaneously with hepatic resection in 15 and six patients, respectively. The operative mortality rate within 1 month was 7.6%, and the overall in-hospital death rate was 14.4%. In 94 patients with curative resection, the 2-year survival rate was 81.2% in patients without cirrhosis and 55.4% in patients with cirrhosis. The 4-year survival rate was 81.2% in the former and 34.8% in the latter group. The prognosis was significantly better in patients without cirrhosis than in those with cirrhosis. On the contrary, 21 of 24 patients with palliative resection died within 2 years despite extensive chemotherapy. The present results may indicate that the resectability rate of hepatocellular carcinoma is currently increasing, even in the presence of cirrhosis of the liver due to early detection of the tumor by current advances in diagnostic methods and also that major hepatic resection is possible in selected patients with cirrhosis.

Androgen receptors (AR) and estrogen receptors (ER) were consecutively assayed for hepatocellular carcinoma (HCC) and the surrounding liver was removed surgically from 19 female patients. Patient age ranged from 43 to 79 years, with an average of 61 +/- 9 years. All patients had underlying liver disease (liver cirrhosis in 16, liver fibrosis in two, and chronic hepatitis in one). Seven (37%) of 19 HCC had AR ranging from 2.3 to 82.6 fmol/mg of cytosol protein. The AR titer was higher in the HCC than in the liver in these cases. Three cases also had ER. ER existed in seven (37%) tumors (range, 2.4 to 25.6 fmol/mg of protein). AR and ER were detected in 11 (65%) and ten (58%) of 17 nonneoplastic liver tissues, respectively. Serum alpha-fetoprotein (AFP) level, hepatitis B virus markers, or histopathologic types of HCC had no correlation with the presence or absence of AR or ER and their titers. Also, there was no correlation between the AR and ER positivities. Further studies are mandatory to determine the genuine role of sex hormone receptors in the development and growth of HCC in humans.

Total serum ferritin concentrations were serially estimated in 24 patients with primary hepatocellular carcinoma (HCC) for 4 to 8 weeks after resection of the tumor. The patients were divided into four groups according to the tumor size and the result of ferritin was compared with that of serum alpha-fetoprotein (AFP) levels. All patients had underlying parenchymal diseases of the liver (liver cirrhosis in 19 and chronic hepatitis in 5 cases). The serum ferritin levels did not reflect the therapeutic result of hepatic resection in most of the patients of all groups. Serum AFP levels, which were measured simultaneously with ferritin levels, were much superior to the ferritin estimation. The current study may indicate that ferritin cannot be used as a tumor marker in the follow-up of Japanese patients with HCC and associated liver disease. Acidic isoferritin, which is known to be produced in and secreted from HCC, should be measured for this purpose.

It has been pointed out that hepatocellular carcinoma (HCC) develops more frequently in cirrhotic liver with siderosis than in liver without iron deposition, that excess copper in hepatocytes inhibits hepatocarcinogenesis, and that an increase in copper and a decrease in zinc are seen in the sera of patients with various malignant tumors. Iron, copper and zinc concentrations in the serum and liver were estimated in normal subjects and cirrhotic patients with and without HCC. Serum copper level was significantly higher in cirrhotic patients with or without HCC than in normal subjects. No significant differences were observed in the levels of these trace elements in the serum and liver of cirrhotic patients with and without HCC. The current study seems to indicate that iron, copper and zinc do not play an important role in the development of HCC in cirrhotic patients in Japan.

Preoperative detectability rates of hepatocellular carcinoma smaller than 5 cm in 113 cirrhotic patients were 91 percent by ultrasonography, 93 percent by computed tomography, and 92 percent by selective angiography. The combination of two methods produced detectability rates of 97 to 99 percent. One hundred three patients underwent various types of hepatic resection with the aid of intraoperative ultrasonography. Forty-four tumors (43 percent) were embedded in the liver, and these tumors were not detected by conventional surgical exploration. The detectability rates were 38 percent for hepatocellular carcinomas smaller than 2 cm, 57 percent for 2 to 3.5 cm tumors, and 71 percent for 3.5 to 5 cm tumors. All undetectable hepatocellular carcinomas were identified by intraoperative echography. The overall detection rate by this method was 98 percent, which was substantially higher than the preoperative rate. Intraoperative ultrasonography is a useful and indispensable method for performing atypical minor hepatectomy for the treatment of small hepatocellular carcinomas associated with liver cirrhosis.

During a recent 6-year period we have encountered 10 patients with 'hepatocellular pseudotumour in the cirrhotic liver' (regenerating hyperplastic nodule). The patients were all male, aged 40-82 years. Seven were chronic alcohol consumers. None was positive for HBs-Ag but seven had either anti-HBs or anti-HBc. Serum AFP level ranged from 4 to 28 ng/ml in six patients who did not have hepatocellular carcinoma at the time of the diagnosis of the pseudotumour. The lesions were depicted by ultrasonography in seven, by computed tomography in two, and by angiography in one case. Liver scan was negative in all five cases investigated. The pre-operative diagnosis was definitely or highly suspicious of hepatocellular carcinoma in three, of pseudotumour in the cirrhotic liver in three, and of recurrent carcinoma in one. In another three patients, pseudotumour was coincidentally discovered in resected specimens with hepatocellular carcinoma. The histopathological and follow-up studies demonstrated synchronous or metachronous development of carcinoma in seven patients. Whether or not these lesions in the cirrhotic liver are premalignant remains to be elucidated.

Hepatocellular carcinoma (HCC) is more prevalent in males than it is in females, which has often been explained by the fact that alcoholism and chronic hepatitis B virus infection are more prevalent among males. The current studies, using biochemical and autoradiographic methods, verified that HCC contains higher concentrations of androgen receptors than the surrounding liver parenchyma and that extrinsically given testosterone are actively taken up by such tumors. These results may suggest that HCC is an androgen-dependent tumor and that, therefore, this tumor is more prevalent in males than it is in females.

An analysis of 27 recurrent cases after partial hepatic resection for hepatocellular carcinoma, closely followed-up with various diagnostic imagings, is reported. The patients comprised 22 males and 5 females. Their ages ranged from 34 to 76 years, with an average of 57.8 years. Twenty-five had underlying cirrhosis and 2 presented chronic hepatitis histologically. The 27 patients were classified into the following three types. Type I comprised 18 patients with local recurrence. Local recurrence means that the tumor recurred in an adjacent segment to that initially affected or in the same segment. Thirteen of these patients had a recurrence within a year-after the initial operation. Type II comprised 6 cases of multiple intrahepatic metastases, and Type III 3 cases which were thought to represent a metachronous occurrence. Five of the 6 cases of Type II had multiple intrahepatic metastases within 3 months after the initial operation. The results of the present series indicate that when patients with hepatocellular carcinoma are operated on, manipulation should be as careful as possible in order not to disperse the cancer cells, and close follow-up with imagings more than once every three months, especially in the first year after the initial operation should be ensured wherever possible.

Seven Japanese patients showed a gradual rise in serum alpha-fetoprotein (AFP) levels for periods of 4 to 14 weeks after partial hepatectomy for hepatocellular carcinoma. These levels then gradually decreased, but not always to a normal level, and various procedures after surgery failed to detect tumor recurrence. All the cases were complicated with liver cirrhosis. It is suggested that the postoperative elevation in the AFP level may have been caused by hepatic regeneration as a result of the intervention chemotherapy and/or surgery, but it does not exclude the possibility of a tumor recurrence.

During the period between January 1980 and December 1987, 229 male and 39 female adult patients with primary hepatocellular carcinoma (HCC) were hospitalized in our unit. Radical hepatic resection was carried out in 90 (39.3%) males and 17 (43.6%) females in whom no specific cancer treatment had been attempted preoperatively. The 1-, 3-, and 5-year survival rates in the male and female patients were 78% and 70%, 45% and 52%, and 19% and 52%, respectively. The difference was significant after 47 months. No substantial differences were found between the two groups with respect to age, preoperative clinical condition and laboratory data, method of liver resection, postoperative morbidity and mortality, postoperative adjuvant chemotherapy, and histopathology of HCC and the liver. Only the incidence of alcohol abuse was significantly different, being higher in male than in female patients. However, the survival analysis demonstrated that alcohol abuse had had no influence on recurrence rate and long-term survival in either male or female patients. As a control, survival was analyzed for the patients with similar clinicopathological background but without HCC who had undergone distal splenorenal shunt for esophageal varices. There was no significant difference between the male and female patients. The current clinical results seems to support our hypothesis based upon sex hormone receptor studies that HCC may be androgen-dependent.

Eight cases of hepatocellular pseudotumours (HPT) were encountered in 6 years during which time 140 hepatectomies were performed for hepatocellular carcinoma (HCC). All were found during screening of cirrhotic patients. The ultrasonographic pattern of HPT was similar to that of HCC and their correct diagnosis was impossible by ultrasonography alone. A space-occupying lesion in the cirrhotic liver which is detected by ultrasonography but not by computed tomography and angiography may be a hepatocellular pseudotumour. This diagnosis is particularly likely if the serum alpha-fetoprotein level is normal.

Ten patients with both hepatocellular carcinoma (HCC) and esophageal or esophagogastric varices were concurrently treated by partial hepatic resection and distal splenorenal shunt. All the patients were men aged from 45 to 71 years. Four patients had had recent episodes of variceal bleeding. Six patients were considered to be at high risk for bleeding, as their varices were large and had "red color signs" endoscopically. Liver cirrhosis was associated with all cases. The grade of hepatic dysfunction was Child A in seven and Child B in three patients. As the HCCs were relatively small, partial wedge hepatectomy was carried out in all patients. Five patients underwent the original Warren shunt, but the remaining five had modified shunts with expanded polytetrafluoroethylene (Gore-Tex) interposition. There was no operative mortality within one month. Nine patients with patent shunts had no variceal bleeding despite the fact that three of them had tumor recurrence in the liver. Hepatic encephalopathy occurred transiently in only one instance. Six patients were alive at the time this report was written, eight to 49 months after operation. Five were free of cancer and one had tumor recurrence. This result may indicate that relatively small HCCs and esophageal varices can be simultaneously treated by limited hepatic resection and distal splenorenal shunt in patients with Child A or B liver disease.

During the last 5 years, radical hepatic resection was performed in 91 patients with hepatocellular carcinoma (HCC). Thirty-one of them had tumour recurrence in the remaining liver during the follow-up period. Second hepatic resection was carried out on nine of them 4-38 months after the first hepatectomy. The ages of these patients ranged from 39 to 65 years with an average of 53.7. There were six men and three women. Eight patients had underlying cirrhosis of the liver and one chronic active hepatitis. Six patients are alive, four being free of HCC and two with disease, for 15-45 months after the first operation. Two patients died of systemic cancer dissemination. The remaining patient had tumour recurrence in the liver again and died of hepatic failure after the third laparotomy. The survival rate of these nine patients was significantly better than that of twenty-two patients who were treated by other palliative methods. The present result shows that a second hepatic resection is a possible and meaningful method of treatment for the patients with recurrent HCCs in the liver remnant.

Androgen receptors (AR) in the cytosol of hepatocellular carcinoma (HCC) were assayed in 45 unselected patients in whom radical hepatic resection was performed. Thirty-one patients had detectable amounts of ARs in tumors, ranging from 2.3 to 82.6 fmol/mg protein with the dissociation constants (Kd) of 4.1 - 30.9 x 10(-10) M. The receptor was not found in the remaining 14 cases. AR negative HCCs were significantly more common among women and nonalcoholic patients. Otherwise, there were no significant difference in the clinicopathologic background between patients with AR positive HCCs and those with AR negative tumors. Three patients died of liver failure in the former group, whereas two died in the latter; one patient died of liver failure and the other died of pneumonia (results were not statistically significant). Excluding those five operative deaths, the recurrence rates were 67.9% in the group of patients with AR positive HCCs and 33.3% in the group of patients with AR negative tumors (0.1 less than p less than 0.05). The 5-year survival rate was significantly better (p less than 0.05) in patients with AR negative HCCs (62.2%) than in those with the positive tumors (17.3%). In light of the current results and previous experimental works by others, it is likely that testosterones enhance the growth and invasiveness of human HCC, which is mediated by AR in the tumor.