Teruhisa Nakamura

Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma

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.

Liver resection for hepatocellular carcinoma. Results of 229 consecutive patients during 11 years.

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%). Childs 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. Childs 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.

Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic hepatitis and cirrhosis.

The regenerative process was evaluated in terms of liver size, function, and histology in 28 adults who had major hepatic resection: hepatocellular carcinoma (HCC) in 21, secondary liver cancer from colorectum in four, carcinoma of the gallbladder in one, Klatskin tumor in one, and Carolis disease in one. There were 22 men and six women. Ages ranged from 17 to 74 years with a mean age of 56.7. All patients with HCC had underlying liver disease: liver cirrhosis in 14 and chronic hepatitis in seven. Extended right lobectomy was done on 10 patients, right lobectomy on 16 patients, and left lobectomy on two patients. The residual liver size was serially estimated with computed tomography (CT) in 15 patients: six with normal liver, five with chronic hepatitis, and four with cirrhosis. A complete restoration of the residual liver size was found within 3 months in 3 and 6 months, respectively, in two patients with normal livers. The liver was enlarged in all patients with the parenchymal diseases but obviously more slowly compared with normal liver. Liver functions were restored normally within 2-3 weeks in patients with normal livers, but hyperbilirubinemia persisted longer in those with chronic hepatitis and cirrhosis. A continuous rise of bilirubin was an ominous sign of liver failure and subsequent death, which occurred in five patients with cirrhosis. Serum alpha-fetoprotein did not rise in accordance with the regeneration. Histologically, evidence of active regeneration with increased mitotic activity was found at 10 and 35 days in those patients with normal livers. Mitosis was not seen in a specimen taken at 7 days. Enlarged cuboidal hepatocytes and cells with basophilic cytoplasm or two nuclei were observed more or less in all specimens. The livers with cirrhosis or hepatitis also showed histologic evidence of regeneration during the first 2 months but substantially less compared with normal liver, which was well supported by the volumetric study of the liver remnants with CT.

Lack of intratumoral heterogeneity in DNA ploidy pattern of hepatocellular carcinoma.

BACKGROUND From biological and clinical perspectives, it is important to clarify tumor heterogeneity. This study was aimed to investigate whether or not intratumoral heterogeneity of DNA ploidy pattern exists in hepatocellular carcinoma (HCC). METHODS Using fresh materials resected from 31 untreated patients, DNA ploidy was analyzed at different sites of the same HCC by means of flow cytometry. The tumor size ranged from 1.7 to 25.0 cm. RESULTS There was no case in which euploid and aneuploid HCCs coexisted in the same tumor. The DNA ploidy pattern was euploid in 15 and aneuploid in 16 instances. Of 15 euploid tumors, the areas analyzed were all diploid in 12 and tetraploid in 2 but diploid/tetraploid in 1. Among 16 aneuploid tumors, the DNA indices (DI) at different sites were similar in 9, but apparently, different aneuploid subclones coexisted in 7 cases. The incidence of DI heterogeneity in aneuploid HCCs was similar between small (< 5 cm) and large (> or = 5 cm) tumors; 3 of 7 (42.9%) versus 4 of 9 (44.4%). CONCLUSIONS It is assumed that euploid and aneuploid HCCs develop in their own ploidy pattern and that the evolution of aneuploid subpopulations from euploid HCC is rare, but new aneuploid subclones can evolve from aneuploid HCC due to increased instability of its karyotype.

Androgen and estrogen receptors in hepatocellular carcinoma and the surrounding liver in women

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.

Androgen receptor in hepatocellular carcinoma as a prognostic factor after hepatic resection

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.

Role of estrogen receptors in the growth of human esophageal carcinoma

In order to investigate the role of estrogen receptors (ER) in the growth of human esophageal carcinoma, tumor tissues of ER‐positive but androgen receptor (AR)‐negative line of squamous cell carcinoma (ES‐8) were transplanted in ten male and ten female nude mice. As control, those of a tumor line without both receptors (ES‐13) derived from human esophageal cancer were used. The growth rates of transplanted tumors were estimated up to 5 weeks. The tumor growth of ES‐8 line was significantly greater in males than it was in females. Such a difference was not observed for ES‐13 line. Moreover, in order to investigate the effect of estrogen on the ER, tumor tissues of ES‐8 line were transplanted in six oophorectomized female mice, and next, estradiol (E2) (500 μ/kg, 50 μg/kg, or none) was administrated to five transplanted female mice of each group, respectively. The growth rates of tumors were enhanced in oophorectomized female mice, and significantly suppressed with the physiologic dose (50 μg/kg) of E2 compared to the control. The current results seem to indicate that the inhibitory effect of estrogen on the tumor line is mediated by ER.

The salutary effect of FK506 in ischemia-reperfusion injury of the canine liver.

The present study was designed to elucidate the effect of FK506 on 90 min of warm ischemia of the liver and reperfusion in 30 dogs. Three groups of animals were studied. Group 1 animals received FK (0.15 mg/kg/day) for three days prior to the ischemia and group 2 animals got 2 ml of saline solution for three days instead of FK and were considered controls. In group 3 FK (0.15 mg/ kg/day) was injected immediately upon reperfusion and two days thereafter. Evaluation of the effectiveness of the drug was monitored by measuring the serum activities of AST, ALT, LDH, serum total bilirubin, malon-dialdehyde, and by histopathological examinations of the liver specimens and survival of the animals for 7 days after reperfusion. The 7 day survival of the animals in group 1 (80%) was significantly (P< 0.05) improved compared with those in group 2 (30%) and group 3 (20%). The serum activities of AST, ALT, and LDH and total bilirubin were significantly lower in group 1 than in group 2 and group 3. FK pretreatment significantly prevented hepatocellular necrosis and neutrophilic infiltration in group 1 in comparison with those in group 2 and group 3. Although the malondialdehyde level in hepatic venous blood was relatively lower in group 1, this difference was not statistically significant. Three days FK pretreatment prevented hepatocellular injury and enzyme leakage after 90 min of hepatic ischemia, whereas FK treatment immediately upon reperfusion failed to do so. In conclusion, donor organ pretreatment with FK may become a promising strategy for improved allograft survival in liver transplantation.

Progesterone receptor in hepatocellular carcinoma. Correlation with androgen and estrogen receptors.

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.

Clinicopathologic comparisons between estrogen receptor-positive and -negative hepatocellular carcinomas.

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 and time 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.