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A 78-year-old man presented to our hospital with lung abnormality on his chest radiograph. Computed tomography (CT) showed a mass and obstructive pneumonia in the right upper lobe of the lung. The mass was diagnosed as a pulmonary adenocarcinoma with a bronchoscopy (cT4N2M0, Stage IIIB). CT also revealed multiple hepatic tumors, which were diagnosed as hepatocellular carcinoma (HCC) by dynamic CT and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging(EOB-MRI). First, we treated the lung cancer with a combination of cisplatin and pemetrexed (PEM), but it caused renal dysfunction. Carboplatin (CBDCA) and PEM combination chemotherapy was administered, and not only the lung cancer but also the HCCs decreased in size. There are few reports of synchronous double cancers of HCC and primary lung cancer, and the treatment is not established. We report that platinum-containing anticancer drugs such as CBDCA may be effective against synchronous double cancers of HCC and lung cancer.

Incidence/mortality of liver cancer follow logistic curves because there is a limit reflecting the prevalence of hepatitis virus carriers in the cohort. The author fitted logistic curves to incidence/mortality data covering the nine five-year cohorts born in 1911-1955 of both sexes. Goodness-of-fit of logistic curves was sufficiently precise to be used for future predictions. Younger cohorts born in 1936 or later were predicted to show constant decline in incidence/mortality in the future. The male cohort born in 1931-35 showed an elevated incidence/mortality of liver cancer early in their lives supporting the previous claim that this particular cohort had suffered massive HCV infection due to nation-wide drug abuse in the 1950s. Declining case-fatality observed in younger cohorts suggested improved treatment of liver cancer. This study demonstrated that incidence/mortality of liver cancer follow logistic curves and fitted logistic formulae can be used for future prediction. Given the predicted decline of incidence/mortality in younger cohorts, liver cancer is likely to be lost to history in the not-so-distant future.

Objective: Virtual CT sonography is a system for synchronizing multiplanar reconstructed CT scans with corresponding conventional ultrasound images in real time. The aim of this study was to prospectively evaluate the feasibility of virtual CT sonography for detection of nodules difficult to detect with conventional sonography alone., Subjects and Methods: Fifty-nine patients with 140 nodules were included in the study. All patients underwent CT angiography then conventional sonography and finally virtual CT sonography. The number, location, and echogenicity of nodules and parenchyma were assessed., Results: Among 140 nodules detected with CT angiography, 71 were detected with conventional sonography and another 46 were detected with virtual CT sonography, increasing the overall sensitivity from 50.7% to 83.57%. The average diameter of nodules detected only with virtual CT sonography (9.7 +/- 3.3 mm) was significantly smaller than that of nodules detected with conventional sonography (16.6 +/- 6.2 mm). The results of multivariate analysis suggested that nodule size (p < 0.001), echo pattern (p = 0.004), and location (p = 0.028) are associated with the difference in detection. Interestingly, 87% of the nodules 10 mm in diameter or smaller were already dysplastic or malignant., Conclusion: Nodules 10 mm in diameter or smaller have significant malignant potential and therefore are clinically important. Even though we do not consider virtual CT sonography a screening tool, we conclude it superior to conventional sonography for detection of small hepatic nodules, allowing bedside percutaneous ultrasound-guided biopsy and treatment that would not be possible with conventional sonography alone.

Cimetidine is known to have an anti-tumor effect on certain types of malignancies, though on hepatocellular carcinomas (HCCs), its effect remains unclear. We studied the anti-tumor effects of cimetidine on chemically-induced HCCs in rats. Four-week-old male Wistar rats (n=105) were divided into 4 groups. Those in groups A and B were administered diethylnitrosamine (DEN) intraperitoneally at 100 mg/kg body weight every week for 6 weeks, during which rats in group A were given tap water and those in group B received cimetidine (100 mg/kg/day) in their drinking water. Rats in groups C and D were administered saline instead of DEN and given tap water with 100 mg/kg/day of cimetidine, respectively. The animals were sacrificed at 7, 12, 22 and 32 weeks after the first administration of drugs and examined. Liver nodules were observed only in groups A and B, with the number of nodules, maximum diameter of the largest nodule, and liver weight significantly lower in group B. Immunohistochemistry findings showed that glutathione S-transferase placental-positive preneoplastic foci were significantly decreased in group B. Cimetidine treatment decreased the number of proliferating cell nuclear antigen-positive hepatocytes and tended to enhance natural killer (NK) cell activity in splenic lymphocytes. In addition, flow cytometry revealed that the proportion of NK cells among total splenic lymphocytes was not affected by cimetidine treatment. Our results showed that cimetidine has an inhibiting effect on hepatocarcinogenesis.

Background and Aims: Prognosis after hepatectomy for hepatocellular carcinoma (HCC) has been improved by progress in the evaluation of hepatic functional reserve, surgical techniques and perioperative management. However, even when curative resection is performed at a relatively early stage, a considerable number of patients develop early intrahepatic and/or extrahepatic recurrence postoperatively. This study analyzed the clinicopathologic features of HCC with early recurrence., Methods: We reviewed records of 513 consecutive patients who had undergone liver resection for HCC. There were 48 deaths within a year after surgery from recurrence, including 21 patients with stage II or III HCC (group I). Clinicopathologic parameters of group I patients were compared with those of 188 patients (group II) who developed recurrence following resection of stage II or III HCC and died more than 1 year after surgery., Results: On univariate analysis, age, tumor diameter (phi), alpha-fetoprotein (AFP):phi and protein induced by vitamin K absence or antagonist II (PIVKA-II):phi were significantly greater in group I than in group II. Macroscopic portal vein invasion, microscopic vascular invasion, intrahepatic metastasis, poor differentiation, pleomorphism, sarcomatous change, vascular lake, and angiographic condensed pooling were more frequently observed in group I than group II. Five independent determinants were selected by multivariate analysis: AFP:phi, histologic pleomorphism, sarcomatous change, vascular lake and angiographic condensed pooling., Conclusions: Highly malignant HCC with extremely poor prognosis exhibits peculiar clinicopathologic characteristics, particularly histologic immaturity, and can be predicted by preoperative indicators such as markedly elevated tumor marker concentrations and condensed pooling on angiography.

Background/purpose: The effect of TNP-470, an angiogenesis inhibitor, on the growth of a hepatoblastoma transplanted into nude mice was examined., Methods: A hepatoblastoma obtained from a 3-year-old girl was serially transplanted into nude mice subcutaneously, and the transplant tumors of the seventh and eighth generations were used for experiments. Expression of various markers in the tumors was examined immunohistochemically. TNP-470 was injected subcutaneously every other day into tumor-bearing mice from 3 weeks after tumor transplantation. The proliferation of tumor cells and endothelial cells was estimated by means of the bromodeoxyuridine labeling index., Results: The original hepatoblastoma showed the histology of the epithelial type, consisting of both the fetal and embryonal subtypes and was positively stained with anti-alpha-fetoprotein (AFP), anti-cytokeratin-19 and polyclonal anticarcinoembryonic antigen antibodies, and an antihuman hepatocyte antibody (hepatocyte paraffin 1). The transplant tumors consisted of solid nests of tumor cells with numerous vascular lakes of various sizes, and showed positive staining with all antibodies that reacted positively with the original hepatoblastoma. Injections of TNP-470 at the doses of 15 mg and 30 mg/kg body weight suppressed the tumor growth and the increase in the serum level of AFP dose dependently. Injections of TNP-470 also suppressed the proliferation of tumor cells and endothelial cells in the tumors., Conclusions: Hepatoblastomas maintained in nude mice retained the immunohistochemical characteristics of the original hepatoblastoma, and TNP-470 suppressed the growth of hepatoblastomas transplanted into nude mice. TNP-470 may be worth investigating further as to its usefulness as a therapy for hepatoblastomas.

Background/aims: One of the unique features of advanced hepatocellular carcinoma (HCC) is the morphological heterogeneity in a single tumor nodule. In order to investigate the intratumoral genomic heterogeneity of HCC, we performed Restriction Landmark Genomic Scanning (RLGS), which allows genomic DNAs to be surveyed at approximately 2000 landmark sites in a single 2-dimensional gel electrophoresis., Methods: RLGS profiles of two regions from a single HCC nodule in six patients were compared with non-tumorous liver tissue. Four HCCs consisting of moderately-differentiated cells were separated into several small parts by thin fibrous septa, but not encapsulated. DNA samples were obtained from both parts of these so-called "nodule-in-nodule" HCC. Two HCCs consisting of well-differentiated cells which did not have a definite partition appeared pathologically homogeneous, and two independent regions of the HCC were used for the analysis., Results: All six HCCs demonstrated different RLGS profiles (in total about 160 different spots) from the corresponding non-tumorous liver, and the number of different spots was greater in the 4 moderately-differentiated nodule-in-nodule HCCs (39-68 spots) than in the 2 well-differentiated homogeneous HCCs (6 and 3 spots). RLGS profiles of the two parts were different to each other in all 4 nodule-in-nodule HCCs. On the other hand, two other homogeneous HCCs showed the same RLGS profiles in the two regions., Conclusion: Thus, intratumoral genomic heterogeneity was demonstrated in the advanced HCC samples, and the genomic alterations may relate to the progression of HCC.

Background: Although there have been extensive studies to determine risk factors affecting survival after resection for hepatocellular carcinoma (HCC), we still do not know which patients can survive disease free after curative resection. This study was undertaken to determine independent risk factors affecting the length of disease-free survival., Methods: 171 patients, who survived disease free more than 1 year after curative resection, were divided into four groups according to the disease-free period: Group I (n = 96) for the patients with intrahepatic recurrence between 1 and 3 postoperative years, Group II(n = 27) for those between 3 and 5 years, Group III (n = 40) for those between 5 and 10 years and Group IV (n = 8) for those without recurrence within 10 years. The 37 variables (host factors, tumor factors, non-tumor liver factors, surgical factors) were compared among the four groups. Activity of hepatitis and hepatic fibrosis was scored by the Histological Activity Index (HAI). In a multivariate study, possible prognostic variables with a statistical difference in the disease-free survival rate among each category were preliminarily selected from the 37 variables and the independent variables were finally selected using a proportional hazard analysis., Results: The patients' age, indocyanine green retention rate, microscopic tumor capsular invasion and portal invasion, cell differentiation, extent of hepatectomy, aggressiveness of chronic hepatitis and inflammatory activity assessed by HAI score were significantly different among the four groups. In the multivariate analysis, the following variables were selected as the independent determinants favorable for achieving a longer disease-free period: younger age, lower indocyanine green retention rate, solitary HCC with expansive growth, no microscopic portal invasion and lower activity of co-existing hepatitis., Conclusions: The importance of inflammatory activity in addition to aging, hepatic reserve and tumor characteristics was confirmed as a risk factor for recurrence by multivariate analysis. To achieve better disease-free survival, not only early detection but also suppression of co-existing hepatitis is necessary.

Little data are available regarding the effects of hepatitis virus serostatus and the severity of coexisting chronic inflammation on intrahepatic recurrence after hepatectomy for hepatocellular carcinoma (HCC). We investigated the extent to which these factors modified the prognosis of hepatectomized patients. A total of 274 patients treated in the period January 1981 to December 1996 were divided into three groups: antihepatitis C-positive (HCV; n = 144), hepatitis B surface antigen-positive and HCV antibody (Ab)-negative (HBsAg; n = 106), and HBsAg-negative and HCV Ab-negative (NBNC; n = 20). Positivity for HBV-related antibody in the HCV group was 76%. Histologic grading of inflammatory activity from coexisting hepatitis was determined according to Knodel's histological activity index (HAI) scoring system. Post-hepatectomy crude survival rates and disease-free survival (DFS) rates were compared, according to tumor characteristics, between the three groups. In the patients overall and also in the patients with a single nodular HCC, the HCV group had significantly higher HAI scores and preoperative serum aspartate aminotransaminase (AST) levels than the other two groups. When the patients were limited to those with a single nodular HCC, the crude survival was similar in the three groups with comparable tumor characteristics; however, the DFS was different (NBNC > HBsAg > HCV). When the patients were further limited to those with a single nodular HCC without microscopic extracapsular spread, in whom removal of the tumor was expected to be microscopically complete, the difference in the DFS became more marked. Irrespective of the viral serostatus, better crude and disease-free survivals were observed in the patients with lower AST levels (< or =50 IU/ 1) than in those with higher AST levels (>50IU/l). In contrast, there were no differences in survivals and HAI scores according to the presence or absence of HBV-related antibody in the HCV group. From our univariate analysis, we can conclude that the severity of virally induced inflammation, which was well correlated with viral serostatus, may be a factor that affects intrahepatic recurrence, which is more likely to originate from metachronous carcinogenesis. Prior co-infection of HBV in HCV patients may not be an adverse risk factor for intrahepatic recurrence.

This study was designed to clarify what differences the last 25 years have made in surgical results for patients with hepatocellular carcinoma (HCC). We examined results for 716 hepatectomized patients in four treatment eras: first era (1973-1980; n = 58), second era (1981-1985; n = 155), third era (1986-1990; n = 243), and fourth era (1991-1997; n = 260). Patient background, tumor characteristics, type of hepatectomy, treatment for intrahepatic recurrences, and surgical results in the four eras were compared by univariate analysis to clarify the factors that have contributed to or impeded progress in the surgical treatment of HCC. Although there were no significant chronological differences in liver pathology and surgical resectability, operative mortality was reduced to 2% in the fourth era, from 29% in the first era. With an increasing proportion of early-stage HCCs (TNM, stages I and II), the cumulative survival rate at 5 years improved in the course of the eras in our overall population of patients (12%, 31%, 38%, and 51%, respectively, for the first, second, third, and fourth eras) and in a subset of the population divided according to tumor stage. Also, we found a chronological improvement in the survival rate at 3 years after intrahepatic recurrence (10%, 28%, 36%, and 44%, respectively in the first second, third, and fourth eras). This improvement was associated with the establishment of an early detection program for intrahepatic recurrences. However, the recurrence rate was similar in any subset of the population through the four eras. Although this univariate study could not determine independent factors that contributed to the chronological progress in results for HCC surgery in the four eras, it is conceivable that the establishment of indication criteria for hepatectomy, an early detection program for primary and recurrent lesions, and the introduction of multimodal treatment for recurrence were contributory factors in this improvement. A strategy for alleviating the frequent recurrences originating from posthepatectomy metachronous carcinogenesis remains to be established.

Background/aims: The crucial points of hepatic segmentectomy include an accurate mapping of proposed segment(s) to be resected and minimization of intra-operative blood loss. This study reports a surgical technique of hepatic resection for segment 7 and 8, and a benefit of supplemental use of topical cooling during consecutive right hepatic inflow occlusion., Methodology: From January 1993 to December 1996, ten hepatocellular carcinoma patients with pathologic livers underwent hepatic segmentectomy for segment 7 and 8. The mapping of the target segments was guided by en-bloc test occlusion of the relevant portal pedicles and subsequent discoloration, often after the opening hilum method. Of these, five tumors were resected with topical cooling by ice slush seeding during consecutive right inflow occlusion (cooling group) and the remainder without cooling (Normothermic group). In the normothermic group, inflow occlusion was carried out by cyclic clamping and unclamping method., Results: The inflow occlusion time was 54 +/- 9.4 min in the cooling group, much longer than in the normothermic group. Although the post-operative peak transaminase values were twice as high as those in the normothermic group, the blood loss was significantly less, and there was no detrimental effect of prolonged, consecutive ischemia on the other intra- and post-operative data., Conclusions: En-bloc taping of the target portal pedicles with or without the opening hilum method is useful in the mapping of segments, and the use of topical cooling is beneficial in prolonged inflow occlusion during complicated right-sided segmentectomy.

Background and Objectives: Activation of telomerase and stabilization of telomeres are considered necessary for immortalization of tumor cells. Telomerase activity was analyzed in 69 hepatocellular carcinomas and adjacent chronic liver disease tissues. The telomerase activity level was examined in relation to clinicopathologic features., Methods: Telomerase activity was determined by a telomeric repeat amplification protocol. Immature and mature leukocytes were removed from homogenized tissue of adjacent livers using anti-CD45 and anti-CD15 monoclonal antibody-coated magnetic beads., Results: Telomerase activity was detected in hepatocellular carcinomas and leukocytes, but not in liver cells from adjacent chronic liver disease tissues after the separation of leukocytes. All hepatocellular carcinomas displayed telomerase activity, and the activity level correlated with the degree of differentiation (P=0.021) and patient survival (P=0.039)., Conclusions: These results indicate that activation of telomerase may be required as a critical step in hepatocarcinogenesis and tumor development, and detection of telomerase activity with removal of contaminating leukocytes may be useful in the characterization or prognostication of hepatocellular carcinoma.

Treatment of HuH-7 human hepatocellular carcinoma (HCC) cells with 1-10 mM sodium butyrate (SB) resulted in growth inhibition in a dose-dependent manner. At 3 mM and higher concentrations, SB caused nuclear fragmentation and DNA ladder formation characteristic of apoptosis. In the treated cells, the expression of p21 (WAFI/CIPI) increased and that of alpha-fetoprotein (AFP) decreased. These characteristic changes were also observed with 5 other human HCC cell lines with or without mutation of the p53 gene. The ability of these cells to form colonies in soft agar was suppressed by either pretreating the cells with SB prior to soft agar plating or incubating untreated cells in SB-containing soft agar. Direct injection of SB into tumors developed from HuH-7 cells in nude mice resulted in an increase in the p21 level, a decrease in the tumor size and an increase in the survival time of mice. When the inoculation of HuH-7 cells into nude mice was immediately followed by subcutaneous injection of SB, development of tumors was either significantly delayed or completely suppressed. These results suggest that SB induces cellular differentiation and suppresses growth and tumorigenicity of HCC cells in vitro and in viva by a mechanism independent of p53 but possibly dependent on p21.

Mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) is a key molecule in intracellular signal transducing pathways that transport extracellular stimuli from cell surface to nuclei. MAPK/ERK has been revealed to be involved in the physiological proliferation of mammalian cells and also to potentiate them to transform. However, its role in the outgrowth of human hepatocellular carcinoma (HCC) has yet to be clarified. Therefore, in this study, we investigated the activation of MAPK/ERK and its associated gene expression in HCC. MAPK/ERK was activated in 15 of 26 cases of HCC we examined (58%), and its activity level was significantly higher in HCC than in the adjacent non-cancerous lesions. Besides, MAPK/ERK activation in HCC was positively correlated with protein expression of transcription factor c-Fos. Furthermore, in 25 of 26 cases of HCC which genomic DNA was available, 22 cases without genomic DNA amplification exhibited positive correlation, not only between protein expression of c-Fos and cyclin D1, but also between MAPK/ERK activation and cyclin D1 expression. Concerning the relationship between MAPK/ERK activation and the clinicohistopathological features of HCC, the tumor (HCC) versus non-tumor (non-cancerous counterpart) ratio (T/N) of MAPK/ERK activity was positively correlated with tumor size, but neither with the stage of HCC nor the degree of differentiation of HCC. In conclusion, these findings suggest that MAPK/ERK activation in human HCC may play an important role in multistep hepatocarcinogenesis, especially in the progression of HCC; at least in part, through cyclin D1 up-regulation primarily induced by MAPK/ERK via c-Fos.

Background/aims: Intratumor heterogeneity of DNA ploidy within a single hepatocellular carcinoma is not well understood. The present study was designed to examine the histologic distribution of intratumor DNA ploidy in hepatocellular carcinomas of different growth types in relation to cell differentiation., Methods: Twenty patients (16 men and four women; mean age, 60.2 years) with hepatocellular carcinoma (mean diameter, 4.3 cm) were studied. One hundred and twenty-seven samples from different sites of each tumor were analyzed by determination of the nuclear DNA content and histological examination., Results: The DNA ploidy was heterogeneous in nine (45%) of the 20 tumors. Five tumors had a mixture of diploid and aneuploid regions, and the remaining four consisted of aneuploid regions with different DNA indices. There was no significant difference in patient characteristics between the heterogeneous and homogeneous groups. A significant correlation was found between tumor growth type and the incidence of heterogeneity. Only 16% of single nodular carcinomas without intratumor septal formation exhibited heterogeneity, while single nodular tumors with septal formation or confluent multinodular tumors were associated with high incidences of different DNA ploidy patterns or DNA indices. There was no aneuploidy in well-differentiated foci, while aneuploidy was frequently found in moderately or poorly differentiated foci (incidences of 67% and 74%, respectively)., Conclusions: Heterogeneity of DNA ploidy may develop along with changes in growth pattern and cell dedifferentiation or by confluence of nodules originating from different tumor cell clones.

Hepatitis B virus is associated with human hepatocellular carcinoma. We performed polymerase chain reaction for the X, C, S, and preS2/S regions of the viral genome in 23 hepatitis B surface antigen-negative hepatocellular carcinomas and adjacent liver. Hepatitis B viral genomes were detected in 17 of 23 tumors and adjacent tissues (73.9%). Among recognized transactivators, the X gene was present in 16 (69.6%) cases of hepatocellular carcinoma, but preS2/S was detected in only 7 (30.4%). Hepatitis B virus C and S regions were detected in 3 (13.0%) and 9 (39.1%) hepatocellular carcinomas, respectively. Serologic study revealed antibodies to hepatitis B surface antigen, hepatitis B core antigen, and hepatitis B e antigen in 14 patients; among these, X-gene DNA was detected in 12 of 14 tumors (85.7%). The X gene was also detected in 4 of 9 tumors of seronegative patients. The X gene, present in many hepatocellular carcinomas, may promote hepatocellular carcinoma in hepatitis B surface antigen-negative patients.

Background/aims: Experimental and clinical studies have found a relationship between blood transfusion and altered immune function. We estimated the risk of transfusions for shorter survival on patients with hepatocellular carcinoma who underwent hepatic resection., Methodology: The impact of perioperative blood transfusions on 235 patients with hepatocellular carcinoma who had resections from January 1981 to December 1988 was retrospectively examined. All patients underwent hepatic resection and received no additional chemotherapy., Results: Using the Cox proportional hazard model, the number of perioperative blood transfusions was found to be a significant prognostic factor for patient outcome (p = 0.03). Overall, patients who received less than 12 transfused units had a significantly better 5-year survival rate than those who received more than 13 transfused units (46.3% vs. 24.5%, p < 0.001). This result was also seen when the patients were subdivided by stage: 5-year survival in the early stage group (57.2% vs. 35.5%, p < 0.01) and in the advanced stage group (30.0% vs. 18.2%, p < 0.05). The number of perioperative blood transfusions also influenced the survival of patients who underwent a curative resection (66.2% vs. 38.5%, p < 0.01), but did not affect the survival of those who received a non-curative resection (7.9% vs. 7.4%)., Conclusion: This study suggests that the number of perioperative blood transfusions is a significant prognostic factor in patients with hepatocellular carcinoma who undergo hepatic resection.

This study was performed to investigate factors determining tumor pressure (TP) in hepatocellular carcinoma (HCC) and a correlation of pressure gradient between TP and portal vein pressure (PVP) with tumor spread. TP and hepatic tissue pressure (HTP) were measured in 70 patients who underwent hepatic resection for HCC. Changes in TP after hepatic artery occlusion (HAO) or portal vein occlusion (PVO) were observed. HTP was elevated with worsening chronic liver disease, and exhibited a significant positive correlation with PVP. The TP was significantly higher in the encapsulated and the nonnecrotic HCCs. The pressure gradient (TP-PVP) was significantly greater in the encapsulated HCCs, especially in those with microscopic portal vein invasion (vp) or intrahepatic metastasis (im). HAO caused a greater decrease in TP than did PVO, with the decrease being particularly marked in the encapsulated HCCs. The TP of HCC was found to be regulated mainly by the presence or absence of a tumor capsule or necrosis, and partly by the hepatic arterial flow and PVP. Our study suggests that TP increases with capsule formation and that the pressure gradient between TP and PVP may be a causal factor in the dispersement of tumor cells into the portal vein.

Background: This study investigated the relationship between clinicopathologic features and various viral serologies in patients who underwent hepatectomy in the treatment of hepatocellular carcinoma (HCC)., Methods: Two hundred two patients were allocated to four groups, according to their positivity or negativity for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb): Group I (HBsAg[-], HCVAb[+], n = 151), Group II (HBsAg[+], HCVAb[-], n = 27), Group III (HBsAg[-], HCVAb[-], n = 20), or Group IV (HBsAg[+], HCVAb[-], n = 4). The mean age of the HBsAg positive patients (Groups II and IV) was 10 years younger than that of the HBsAg negative patients (Groups I and III)., Results: The male-to-female ratio was higher in HCVAb negative groups (II and III). The HCVAb positive groups (I and IV) had a significantly poorer hepatic reserve and smaller resections than the HCVAb negative groups. Because the tumors were more advanced (as determined by TNM staging) in Group II, the 3-year crude and disease free survival rates were lower in Group II than in Group I. However, HCVAb negative groups (II and III), when compared at 5 years with the limited subsets of patients who had tumors at earlier stages or a curative resection, had significantly better crude and disease free 5-year survival rates than the HCVAb positive group (I)., Conclusions: Clinicopathologic features differ from one another in accordance with the viral seromarkers in HCC patients. Significantly better crude and disease free survival after complete resection were promising results for patients with non-HCV-related HCC. By comparison, for patients with HCV-related HCC, the risk of intrahepatic recurrences never subsided even in later years after complete resection. Therefore, posthepatectomy follow-up management should be individualized depending on the viral serologic status of HCC patients.

The c-met proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), a potent mitogen and motogen for epithelial cells. Because of its profound effects on cell growth and motility, HGF may be important in the development of cancer metastases in hepatocellular carcinoma (HCC). In this study, we examined HGF concentration and expression of the c-met-proto-oncogene product (c-met) in 62 patients with HCC to determine the relationship between the level of expression and clinicopathological features, and patient outcome following hepatectomy. Western blotting was used to examine the c-met expression, and HGF concentration in tumors was measured using an enzyme-linked immunosorbent assay. c-met was found to be overexpressed in HCC compared with nontumorous liver tissue (P < .01), and correlated with an increased incidence of intrahepatic metastases (P = .039). Patients were divided into two groups, low c-met HCC and high c-met HCC. Patients with high c-met HCC had a significantly shorter 5-year survival than patients with low c-met HCC (33.5% vs. 80.3%, respectively; P < .05). However, there was no correlation between HGF concentration in the tumor tissue and clinicopathological factors and patient survival. These results indicate that expression of c-met played an important role in tumor growth and metastases in patients who underwent hepatectomy for HCC.

Background: A safe limit for normothermic consecutive portal triad occlusion in hepatectomy for the cirrhotic liver was believed to be around 30 minutes. Possibly, the occlusion time can be prolonged by cooling the ischemic liver in vivo. We describe the technique of segmentectomy assisted by topical cooling and its usefulness in prolonging the hepatic inflow occlusion time for cirrhotic livers without causing further ischemic injury., Study Design: Fifty patients with hepatocellular carcinoma and chronic hepatic disease who underwent right-sided segmentectomy under hemihepatic inflow occlusion were divided into two groups: normothermic (n = 27), and hypothermic with hemihepatic topical cooling using ice slush (n = 23). Segmentectomies were carried out in the same way in both groups, guided by initial enbloc ligation of the corresponding portal pedicles., Results: The mean right hepatic inflow occlusion time was significantly longer in the hypothermic group than in the normothermic group (53 +/- 22 minutes compared with 17 +/- 9.3 minutes). Despite the significant difference in occlusion time, no differences were found in the recovery of hepatic functions and the incidence of postoperative complications between the groups. Intraoperative blood loss was significantly less in the hypothermic group., Conclusions: The hepatic right-sided partial inflow occlusion time can safely be prolonged to 60 to 90 minutes in the presence of cirrhosis without causing another injury from ischemia and intermittent reperfusion.

The c-met proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), a potent mitogen and motogen for epithelial cells. Because of its profound effects on cell growth and motility, HGF may be important in the development of cancer metastases in hepatocellular carcinoma (HCC). In this study, we examined HGF concentration and expression of the c-met proto-oncogene product (c-Met) in 62 patients with HCC to determine the relationship between the level of expression and clinicopathological features, and patient outcome following hepatectomy. Western blotting was used to examine the c-Met expression, and HGF concentration in tumors was measured using an enzyme-linked immunosorbent assay. c-Met was found to be overexpressed in HCC compared with nontumorous liver tissue (P < .01), and correlated with an increased incidence of intrahepatic metastases (P = .039). Patients were divided into two groups: low c-Met HCC and high c-Met HCC. Patients with high c-Met HCC had a significantly shorter 5-year survival than patients with low c-Met HCC (33.5% vs. 80.3%, respectively; P < .05). However, there was no correlation between HGF concentration in the tumor tissue and clinicopathological factors and patient survival. These results indicate that the expression of c-Met played an important role in tumor growth and metastases in patients who underwent hepatectomy for HCC.

Multiple tumors within the liver are a characteristic feature of hepatocellular carcinoma (HCC). This study investigated alterations in the histologic type and DNA content of multiple nodules of HCC. Both a pathologic examination and flow cytometric DNA analysis were performed on 49 resected specimens of multinodular HCC. The results showed that 35 cases had multiple metastatic satellite nodules around the main tumor (group 1), while 14 had two solitary nodules in different segments without satellite nodules (group 2). In group 1, 28 out of 35 (80.0%) showed a single DNA index while 7 (20.0%) revealed two different DNA contents in the main tumor. The histological type, cytological grade, and DNA index were equivalent between the main and satellite tumors in 100%, 88.6%, and 97.1% of the cases, respectively. In group 2, all tumors showed a single histological type, cytological grade, and DNA index in each nodule. The histological type was identical in 85.7% of the pairs of nodules, but the cytological grade and DNA index were different in 42.9% and 85.7%, respectively. The patients in group 2 showed a significantly higher 5-year survival rate than that in group I (64.8% vs 27.2%, P < 0.05). This study thus indicates that the cytological grade and DNA content are useful in distinguishing multicentric occurrence from intrahepatic metastasis in HCC.

The mechanism and pathogenesis of the high frequency of intrahepatic metastasis in hepatocellular carcinoma (HCC) has not yet been elucidated. Two hundred and thirty one tumors (< or = 5 cm in diameter) of resected specimens of HCC were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens selected at random from the 231 tumors. The most frequent site for tumor spread in HCC was capsular invasion followed by extracapsular invasion, vascular invasion, and finally intrahepatic metastasis. There was a strong statistical correlation between the presence of intrahepatic metastasis and the frequency of vascular invasion (correlation coefficient = 0.998). Radiopaque material injected directly into 23 resected tumors entered only the portal vein in 17 tumors and into both the portal and hepatic veins in six tumors. In all eight patients with unresectable lesions, radiopaque media injected percutaneously into tumor nodules flowed only into the portal vein. These findings suggest that tumor spread in HCC progresses from capsular invasion to intrahepatic invasion and that the portal vein may act as an efferent tumor vessel.

The present study reports on the usefulness of microwave coagulonecrotic therapy (MCT) as a treatment option for hepatocellular carcinoma (HCC) with poor hepatic reserve. From June 1992 to March 1995, MCT using a microwave electrode was employed on 8 patients using laparoscopic control and 19 with the open method, and wedge resection (Hx) was applied to the 23 patients. All patients had HCC with poor hepatic reserve. Radiation output was 100 watts with a mean radiation duration of about 30 minutes. The severity of liver dysfunction and the regional characteristics of the tumor (tumor size, multiplicity, portal invasion, tumor depth) were comparable between the MCT and Hx groups. The operative time was significantly shorter for the MCT group than the Hx group. The mean blood loss was 1570 ml in the Hx group but negligible in the MCT group. There was no operative mortality in the MCT group in contrast to 4.3% (1 of 23) in the Hx group. Complications were observed in 11.1% (3 of 27) and 34.8% (8 of 23), respectively, for the MCT and Hx groups. The postoperative total bilirubin had lower values and the start of diet was earlier in the MCT group than the Hx group. The 3-year crude and disease-free survival rates were 86% and 44%, respectively, for patients who underwent MCT, which were comparable to 75% and 14% for those with Hx. MCT can achieve long-term results equivalent to those obtained by wedge resections, but it is less invasive and technically easier. Therefore it can be an alternative option in place of limited resection for HCC with poor hepatic reserve.

Background: The mechanism and pathogenesis of the high frequency of intrahepatic metastasis in hepatocellular carcinoma (HCC) has not yet been elucidated., Methods: Two hundred thirty-one tumors ( < or = 5 cm in diameter) of resected specimens of HCC were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens selected from the 231 tumors., Results: The most frequent site for tumor spread in HCC was capsular invasion followed by extracapsular invasion, vascular invasion, and finally intrahepatic metastasis. Radiopaque material injected directly into 23 resected tumors entered the portal vein in only 17 tumors and entered into both the portal and hepatic veins in six tumors., Conclusions: These findings suggest that tumor spread in HCC progresses from capsular invasion to intrahepatic invasion and that the portal vein may act as an efferent tumor vessel.

The Liver Cancer Study Group of Japan registered 11,379 patients with hepatocellular carcinoma (HCC) diagnosed from January 1, 1990 to December 31, 1991 in 536 hospitals throughout the country. This nationwide survey revealed the current status of HCC in Japan regarding the epidemiology, clinical characteristics, histopathological features, diagnosis, surgical and conservative treatments, and the outcome. The survival rates of the HCC patients who received hepatic resection, transarterial embolization (TAE), and percutaneous ethanol injection (PEI) were also calculated based on follow-up from January 1, 1987 to December 31, 1991. Three-year and 5-year survival rates of the patients who underwent hepatic resection were 57.5% and 40.8%, respectively, and those of TAE were 19.5% and 8.0%, respectively. Three-year survival rate of the patients with PEI was 53.2%. Cox's multivariate analysis showed that significant prognostic variables after partial hepatectomy were serum alpha-fetoprotein level, tumor size, number of tumors, associated liver cirrhosis, age, surgical curability, and portal involvement.

To clarify whether pre-operative transcatheter arterial embolization (TAE) improves survival after hepatectomy, a prospective randomized comparative study was done. Of a total of 115 registered patients having solitary hepatocellular carcinoma (HCC) 2 to 5 cm in diameter, 18 (15.7%) were excluded after randomization. As a result, 97 patients were chosen as subjects and divided into two groups: hepatectomy with (group A: n=50) and without (group B: n=47) pre-operative TAE. The period of observation of the patients who survived the surgery was between 4.0 and 6.6 years. The randomization appeared to have provided well-balanced groups of patients and the clinico-pathological characteristics of the two groups were quite similar. The necrotic part of the cancerous lesions, as confirmed by operative specimens, amounted to 74.8+/-33.4% (mean +/-SD) in group A and 6.8+/-7.2% in group B (P<0.01). However, the cancer-free survival rates after hepatectomy in both groups showed little difference (39.1+/-7.0 (%+/-SE) and 31.1+/-0.1, respectively). We speculate that TAE is not effective against such HCC accessory lesions as minute intrahepatic metastasis and tumor thrombus and that pre-operative TAE does not improve post-operative survival.

The efferent vessel of hepatocellular carcinoma (HCC) and the mechanism and pathogenesis of the high frequency of intrahepatic metastasis in HCC has not yet been clarified. Three hundred ninety-three resected specimens of HCC were examined for tumor thrombosis in the portal vein and the hepatic vein: 231 tumors < or = 5 cm in diameter were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens and by percutaneous infusion of radiopaque media into tumor nodules in 8 patients. The mode of tumor spread in HCC progressed from capsular invasion to extracapsular invasion, then to vascular invasion, and finally to intrahepatic metastasis. There was a strong statistical correlation between the presence of intrahepatic metastasis and portal vein thrombosis (p < 0.05, R = 0.998). Radiopaque material injected directly into 23 resected tumors entered only the portal vein in 17 tumors and into both the portal and hepatic veins in 6 tumors. In all 8 patients with unresectable lesions, radiopaque media injected percutaneously into tumor nodules flowed only into the portal vein. These findings suggest that intrahepatic invasion by HCC may occur through the portal vein as an efferent tumor vessel.

The present study reports on the usefulness of laparoscopic microwave coagulonecrotic therapy as a new option in the treatment of hepatocellular carcinoma. Five patients with liver tumors associated with cirrhosis were treated from July 1993 to March 1994 with a microwave electrode (output 100 W, 3 to 4 cm long) devised for laparoscopic use. The tumors, all with diameters less than 3 cm and superficially located, were coagulated for a total radiation period of 20 to 30 min under laparoscopic, intraoperative ultrasonographic control. Postoperative complications were negligible, and laboratory values (glutamate-pyruvate transaminase, bilirubin, prothrombin time, platelet count) returned to preoperative levels within 7 days. Complete necrosis, including the surrounding liver tissue, was confirmed by a follow-up dynamic computed tomography scan during the follow-up period of 6 to 17 months (mean, 13 months). Laparoscopic microwave coagulonecrotic therapy can exert an effect on tumor equivalent to that obtained from a wedge resection but is noninvasive and may represent a new option for unresectable liver cancers.

Hepatectomy was performed under in situ right lobar hypothermic perfusion combined with hepatoprotective agents in six patients who had hepatocellular carcinoma and coexisting liver disease. Following occlusion of the right hepatic vein and the right portal pedicle, in situ cold perfusion was initiated using chilled Ringer's lactate infused through a cannula placed in the right main portal vein. The right superior segments were resected in a bloodless field. The liver was cooled to 22-26 degrees C for 40 to 80 minutes with no significant changes in systemic hemodynamics or body temperature. Postoperative liver functions showed no marked derangement; the mean peak GPT was 221 U and the mean peak total bilirubin 2.3 mg d/l. Local cooling minimizes the risk of ischemia/reperfusion injury in this very vulnerable population, yet gives the surgeon adequate time to perform a challenging resection in a bloodless field.

Objective: This study reports further refinement of a prediction scoring system, which was established in 1980 as a guide to determine a safe limit for hepatectomy, based on 10 years of use., Summary Background Data: In the past, whether major resection was safe was judged empirically from the net resection volume or the residual hepatic volume combined with the patient's liver function. However, such judgment was not based on objectively defined criteria., Methods: Patients with hepatocellular carcinoma (HCC; n = 376) and metastatic cancer (n = 58) who had hepatectomy at some time from 1981 through 1990 were entered into this study. A prediction score (PS) was computed using a multiple regression equation that consists of computed tomographic scan-estimated resection rate, indocyanine green retention rate, and the patient's age. A PS greater than 55 was classified as a risky zone, a PS of 45 to 55 was considered borderline and a PS less than 45 was a safe zone., Results: With HCC and chronic liver disease, all patients in the risky zone died, whereas 33% in the borderline zone died and 7.3% died who were in the safe zone. With metastatic cancer with normal liver, all patients in the risky zone died, whereas no patient in either the borderline or safe zones died. The major cause of death in the risky zone was liver failure due to excessive resection. In the borderline and safe zones, liver failure developed primarily after abdominal sepsis or pulmonary infection, particularly for those with adverse prognostic factors such as disturbed glucose tolerance, lower platelet count, and higher indocyanine green retention rate., Conclusion: Prediction scores can eliminate deaths related to excessive resection for patients with normal or injured livers. When patients have adverse prognostic factors, careful surgery and postoperative management is mandatory to avoid liver failure triggered by intra- or extra-abdominal sepsis, even if the score remains in a borderline or safe zone.

For the purpose of achieving emergency hemostasis of a ruptured hepatocellular carcinoma (HCC) or prevention of such rupture, we applied a new method of transcatheter therapy: intra-arterial alcoholization. Five patients with a ruptured HCC and 42 with an impending rupture were treated by intra-arterial injection of absolute ethanol mixed with an equal volume of iodized oil, Lipiodol (EtOH-Lp). The tumor size ranged from 4 to 26 cm (mean 7.8 cm) in diameter. The catheter tip was placed in the segmental branch or a more distal position of the hepatic artery, and 2-40 (mean 10.6) ml of EtOH-Lp was infused under fluoroscopic guidance. Infiltration of ethanol into the HCC mass was recognized as a dense deposition of Lipiodol on plain abdominal X-rays and computed-tomography. In all five cases of ruptured HCC, hemostasis was achieved. In all 42 cases of impending rupture, tumor rupture was prevented, and all except 3 patients could be discharged. No significant complication of the gastrointestinal tract or biliary tract was seen. The incidence and severity of postembolization syndrome was markedly lower than those seen in cases treated with Gelfoam embolization.

A case of primary carcinoid tumor arising in the liver of a 69 year old woman with no endocrine symptoms is reported. Histopathologically, the tumor was diagnosed initially as a hepatocellular carcinoma in the biopsy specimen, and was shown subsequently to be a carcinoid tumor, demonstrating diffuse positive staining with Grimelius method. Mucin stained with periodic acid-Schiff (PAS), alcian-blue, and mucicarmine, and was shown partially in the glandular structures. Immunohistochemically, most of the tumor cells stained positively for chromogranin-A, epithelial membrane antigen (EMA) and neuron specific enolase (NSE). Ultrastructural examination revealed electron-dense core granules, measuring 40-120 nm in diameter in some of the tumor cells. Intensive and careful searches pre- and post-operatively revealed no other primary source of tumor other than the liver. The patient was reported well with no symptoms 3 1/2 years after the operation. This case is considered to be a primary hepatic carcinoid tumor. The recent literature is reviewed, and the possible histogenesis of hepatic carcinoid tumor is discussed.

Purpose: Although autotransfusion is used in a wide variety of surgical procedures, it is largely unexplored for use in oncologic operations. This study evaluates the impact of autotransfusion in hepatectomy for hepatocellular carcinoma., Patients and Methods: Fifty-four patients with hepatocellular carcinoma underwent hepatectomy by receiving autologous blood transfusion (group 1). Fifty patients receiving homologous blood without any autologous blood were matched for comparison (group 2)., Results: No statistical differences were found between group 1 and group 2 patients in cumulative recurrence rates (62.8% vs 67.3%, respectively) or cumulative survival rates (61.9% vs 52.8%). Autologous transfusion reduced the mean volume of homologous blood used (814 mL vs 3466 mL). The mean postoperative hemoglobin level, platelet count, prothrombin time, and partial thromboplastin time were comparable between groups., Conclusions: Autotransfusion is a safe and effective procedure in patients with hepatocellular carcinoma undergoing hepatectomy.

From retrospective analysis of 174 formalin fixed, paraffin-embedded, HCC tissue samples, the possible correlation was investigated between the CV determined by FCM and the duration of formalin fixation. An adverse effect of prolonged formalin fixation on CV and fluorescence intensity in liver tissue was investigated prospectively in samples from 4 patients.

A monoclonal antibody (MoAb HG1-219) against a human gastric cancer cell line (HuG-1) and its shedding antigen (HG1-219 Ag) was generated and a solid-phase sandwich enzyme immunoassay (EIA-219) was developed. The mean serum HG1-219 Ag concentration in normal individuals was 30.5 +/- 14.5 U/ml measured by EIA-219. When the mean +3 SD of the antigen concentration in normal individuals was used as a cut-off level, 4.3% (2/47) of patients with chronic hepatitis, 9.1% (4/44) of cirrhotic patients and 37.5% (18/48) of patients with hepatocellular carcinoma (HCC) had HG1-219 Ag above the cut-off value. The positive rates of a-fetoprotein (AFP) (> 400 ng/ml) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) for HCC were 26.7% (12/45) and 33.3% (12/36), respectively. There was no significant correlation between HG1-219 Ag and AFP or PIVKA-II in patients with HCC. The combination assay of EIA-219, AFP and PIVKA-II for HCC gave the positive rate of 75% (27/36). The effect of periodic acid on the HG1-219 Ag and the inhibition of EIA-219 by CA 19-9 suggest that the epitope of HG1-219 Ag is a suger chain similar to CA 19-9.

Background: The current study was undertaken to investigate whether or not tumor cells are dislodged into the portal venous stream during hepatic resection for hepatocellular carcinomas., Methods: A catheter was placed using echo guidance into the portal branch through the mesenteric vein in 31 patients. Cytologic examinations were done on multiple blood samples at various operative stages., Results: Tumor cells were recovered in 7 of 31 patients in whom the tumor sizes were more than 5 cm and portal invasions were found microscopically and/or macroscopically. By contrast, the remaining 24 tumors were less than 5 cm in size and showed negative portal invasions. Recovery of the tumor cells was found, not during the earlier operative stage of mobilization or rotation of the hepatic lobe, but during the later stages of hilar dissection or hepatic parenchymal dissection., Conclusions: The portal pedicles should be divided before hepatic dissection in segmentectomy and lobectomy to lessen the chance of dissemination of intravasated tumor cells.

Flow cytometric DNA analysis was done on 302 resected hepatocellular carcinoma and 30 specimens by fine needle aspiration biopsy. Patients with DNA aneuploid tumors had a significant worse prognosis than those with DNA diploid tumors in subdivided groups by curability (p less than 0.01). The recurrence after hepatectomy occurred frequently in DNA aneuploid or non-curative resected group. In a cox multivariate analysis, nuclear DNA content provided significant prognostic value (p = 0.008) as did vascular invasion and intrahepatic metastasis. For the multiple tumors of hepatocellular carcinoma, it is helpful to get the DNA ploidy pattern to diagnose tumors with intrahepatic metastasis or multicentric origin. Nuclear DNA analysis by fine needle aspiration biopsy was useful to determine the treatment method of hepatocellular carcinoma.

Experimental data of autotransfusion in hepatectomy for hepatocellular carcinoma and clinical data from forty-eight patients were analyzed. By a density gradient medium, cancer cells banded at a lower density (1.056 g/ml: mean) than red blood cells (1.105 g/ml: mean). The centrifuge autotransfusor separated the red blood cells from cancer cells and all sections of cell blocks of the blood harvested intraoperatively in 20 cases revealed no malignant cells. The average requirement of bank blood was significantly reduced in these patients than in patients without autotransfusion during one year before, 1573 ml to 478 ml (whole blood of concentrated red blood cells) (p less than 0.05). These findings indicate that autotransfusion in hepatectomy for hepatocellular carcinoma is safe and practical.

The usefulness of transcatheter arterial chemoembolization (TACE) of the hepatic artery was retrospectively evaluated in 66 patients who underwent the procedure for treatment of hepatocellular carcinoma that recurred after partial hepatectomy. The materials infused were Gelfoam sponge or Gelfoam sponge plus Lipiodol and an anticancer agent. A control group of 15 patients with recurrent tumor received oral anticancer agents alone. The cumulative survival rate for the TACE group was 88% for the first year, 57% for 2 years, 42% for 3 years, and 27% for 5 years, whereas that of the control group was 80% for the first year, 27% for 2 years, and 18% for 3 years. Thus, the prognosis of the TACE group was significantly better (p less than or equal to .01, log-rank test) than that of the control group. The survival rate was inversely correlated with the ratio of the volume of the recurrent tumor to the volume of the whole residual liver. These results suggest that TACE is more effective than oral chemotherapy for treatment of hepatocellular carcinoma that recurs after partial hepatectomy.

The prognostic value of nuclear DNA content was studied retrospectively using flow cytometry in 203 cases of resected hepatocellular carcinoma. The occurrence of DNA aneuploidy, which was detected in 50% of patients, correlated significantly with tumor size and the presence of vascular invasion or intrahepatic metastasis. Overall, patients with DNA aneuploid tumors had a significantly worse prognosis than those with DNA diploid tumors (P less than 0.001) and, also in subdivided groups by tumor size (P less than 0.01). Among DNA aneuploid patients, the survival times were significantly shorter for patients with a low DNA index (less than 1.5) than for those with a high DNA index (greater than or equal to 1.5) (P less than 0.05). In a Cox multivariate analysis, nuclear DNA content provided significant prognostic value (P = 0.008), as did vascular invasion (P = 0.001) and intrahepatic metastasis (P = 0.005). These results indicated that nuclear DNA content has an important prognostic value in hepatocellular carcinoma.

Accumulation of mutations in oncogenes and tumor suppressor genes transforms a normal cell to a malignant cell by allowing it to escape from normal control of growth. In order to learn (a) how many tumor suppressor genes are involved in the tumor progression of hepatocellular carcinoma, (b) whether there is any association among allelic losses of chromosomes, or (c) whether integration of hepatitis B virus into host DNA influences any particular chromosomal losses, we have examined loss of heterozygosity with 44 restriction fragment length polymorphism markers in 46 cases of hepatocellular carcinoma. The markers represented all chromosomal arms except 5p, 8p, 9p, 18p, and acrocentric chromosomes. Allelic losses in tumors indicated that five tumor suppressor genes, located on chromosomes 5q, 10q, 11p, 16q, and 17p, may be involved in this cancer. However, no significant associations were observed among the various allelic losses or between the integration of hepatitis B virus and chromosomal losses. Furthermore, a deletion map for chromosome 16q indicated the localization of a tumor suppressor gene between q22 and q24 and that for chromosome 17p suggested the existence of a second tumor suppressor gene in addition to the p53 gene.

The current study determines the prognostic factors after hepatectomy for hepatocellular carcinomas. The 295 patients who underwent hepatectomy from 1973 through 1987 were included for a univariate and a Cox multivariate analysis. The favoring conditions were determined as follows. The essential requirements are (1) the absence of tumor thrombi; (2) no intrahepatic metastasis, but even when present, it should be close to the main tumor and removed with a massive resection; and (3) retention rate of indocyanine green dye (ICG) at 15 minutes should be within 14 +/- 4.2% (M +/- SD) to allow that resection. The desired requirement is that the tumor size should preferably be less than 5 cm; a wider free margin from tumors (greater than or equal to 1 cm) is recommended, but not determining factor. The eligible patients, having no thrombi, no intrahepatic metastasis, a tumor size of 5 cm or less, negative surgical margin (greater than or equal to 1 cm), had achieved a 5-year survival of 78%. In conclusion, resection therapy is the first option for patients with those requirements.

The levels of a variety of immunological parameters were examined in 203 preoperative patients with hepatocellular carcinoma (HCC) at various stages (I-IV). The changes in the peripheral blood lymphocyte (PBL) count, the serum level of immunosuppressive acidic protein and the degree of the skin reaction to purified protein derivative were associated significantly with the stage of HCC progression. However, the percentages of lymphocyte subsets, mitogenic responsiveness of PBL and serum immunoglobulin concentration remained at the levels of stage I. Further study demonstrated that in patients undergoing hepatic artery ligation, there were statistically significant correlations between the PBL count, immunosuppressive acidic protein concentration and intensity of the skin reaction to purified protein derivative, assayed 1 month after surgery, and the prognosis. HCC-specific immunity was examined in 34 patients treated by hepatic resection or hepatic artery ligation using in vitro responses of PBL to HCC extracts (ATS test). This test was performed using culture medium containing added arginine. None of the PBL from the patients showed a positive response to allogeneic HCC extracts, but the PBL from 12 patients (9 hepatic resections, 3 hepatic artery ligations) were stimulated significantly (SI greater than or equal to 2.5) with autologous HCC extracts. In 7 of 9 hepatic resection patients who were positive in the ATS test, tumor recurrence was identified. Statistical analysis indicated that the ATS test result was significantly correlated with tumor recurrence in hepatic resection patients. Autologous-PBL-stimulating activities were isolated in a fraction at pH 8.3 and in fractions at pH 6.7-7.0 by chromatofocusing of the crude extract. Although identification of the HCC-specific antigen remains to be done, use of the above fractions may simplify the ATS test procedure and improve its sensitivity.

Retrospective DNA ploidy studies of paraffin-embedded blocks were performed by flow cytometry on 212 surgically resected hepatocellular carcinoma. One hundred and sixty-four of 212 specimens yielded evaluable DNA histograms. Eighty-three cases showed a DNA diploid pattern and 81 a DNA non-diploid pattern. The incidence of non-diploid pattern increased with the tumor size. (2cm; 15.4%, 2-5; 42.3%, 5-10; 70.8% greater than 10; 73.3%). The DNA pattern correlated with the backgrounds, the degree of vascular invasion, intrahepatic metastasis and serum AFP levels. Survival of patients with non-diploid pattern was significantly less than those with diploid patients in any different stage. Of thirty who survived three years with disease free condition, 20 patients showed diploid patterns. Though remaining 10 patients were non-diploid patterns, 9 were high DNA index more than 1.5. It is concluded that flow cytometric DNA ploidy study had prognostic value for patients with surgically resected hepatocellular carcinoma.