Comparison of potential fecundity models for walleye pollock Gadus chalcogrammus in the Pacific waters off Hokkaido, Japan.

Potential fecundity models of walleye or Alaska pollock Gadus chalcogrammus in the Pacific waters off Hokkaido, Japan, were developed. They were compared using a generalized linear model with using either standard body length (LS ) or total body mass (MT ) as a main covariate along with Fulton's condition factor (K) and mean diameter of oocytes (DO ) as additional potential covariates to account for maternal conditions and maturity stage. The results of model selection showed that MT was a better single predictor of potential fecundity (FP ) than LS . The biological importance of K on FP was obscure, because it was statistically significant when used in the predictor with LS (i.e. length-based model), but not significant when used with MT (i.e. mass-based model). Meanwhile, DO was statistically significant in both length and mass-based models, suggesting the importance of downregulation on the number of oocytes with advancing maturation. Among all candidate models, the model with MT and DO in the predictor had the lowest Akaike's information criterion value, suggesting its better predictive power. These newly developed models will improve future comparisons of the potential fecundity within and among stocks by excluding potential biases other than body size.

The role of macroscopic classification in nodular-type hepatocellular carcinoma.

BACKGROUND: Little has been reported on the role of macroscopic classification of hepatocellular carcinoma (HCC). We hypothesized that macroscopic classification of HCC might have a strong correlation with long-term prognosis after hepatectomy. METHODS: Four hundred and four patients with a macroscopically nodular type of HCC who underwent a hepatectomy were studied. The patients were divided into three groups: single nodular (SN) group (n = 312); single nodular with extranodular growth (SNEG) group (n = 52); and confluent multinodular (CMN) group (n = 40). Clinicopathological variables were compared among the three groups. The patient survival rate was also compared among the three groups. Finally, a multivariate analysis was performed to clarify the independent significant variables of the long-term prognosis. To confirm the consistency of the results in small-size HCC, the same analyses were made using patients whose tumor size was equal to or less than 3 cm in diameter. RESULTS: The alpha-fetoprotein value, tumor size, and rate of absolute noncurative operation in the SNEG group were higher than in other groups. The positive rate of both portal vein invasion of cancer cells and intrahepatic metastasis in the SN group was lower than those in other groups. The rate of poorly differentiated histology in the SN group was lower than in the other groups. Patient survival in the SNEG group was worst among the three groups. However, patient survival showed no significant difference between the SN and CMN groups. The multivariate analysis showed that the presence of intrahepatic metastasis, the macroscopic classification of SNEG type, and absolute noncurative operation were independent poor prognostic indicators. The results for patients with small HCCs measuring equal to or less than 3 cm in diameter were quite similar to the results for the other patients. CONCLUSIONS: Among the three subtypes of macroscopically nodular type of HCCs, the SNEG type showed higher rates of portal vein invasion of cancer cells, intrahepatic metastasis, and poorly differentiated histology. The patient survival rate in the SNEG type was worst, and the SNEG type was an independent poor prognostic indicator. The macroscopic classification of HCC, especially the SNEG type, helps predict the long-term outcome after hepatectomy.

Characteristics of multicentric hepatocellular carcinomas: comparison with intrahepatic metastasis.

Characteristics of multicentric hepatocellular carcinomas (HCCs) remain obscure. We therefore aimed to clarify them and compare them with HCC with intrahepatic metastases. A series of 118 patients who had definite hepatitis C viral status and multinodular HCC were divided into two groups: a multicentric occurrence (MO) group (n = 38), with multicentric HCCs; and an intrahepatic metastasis (IM) group (n = 80), with HCC having intrahepatic metastases. Clinicopathologic variables, including the patient's survival and disease-free survival rates, were compared between the MO and IM groups. Univariate analysis revealed the presence of esophageal varices, the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, hepaplastin test, gamma-globulin, the histologically active hepatitis, tumor size, des-gamma-carboxy prothrombin > 0.1 AU/ml, positive portal vein invasion, and histologic grade as discriminating factors. The MO score to differentiate multicentric HCCs from intrahepatic metastatic HCCs was determined using the following four independent factors selected by a stepwise regression analysis: the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, tumor size, and histologic grade. The sensitivity and specificity of the MO scores using those factors were 84% and 70%, respectively, when the cutoff value was 0.4. The disease-free survival rate in the MO group was similar to that in the IM group, whereas the survival rate in the MO group was significantly better than that in the IM group. The multivariate analysis revealed the multicentric occurrence of HCC as one of the independent prognostic factors. Clinicopathologic factors differentiating multicentric HCCs from intrahepatic metastatic HCCs were the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, small tumor size, and low histologic grade.

Effects of preoperative steroid administration on surgical stress in hepatic resection: prospective randomized trial.

HYPOTHESIS: Preoperative administration of methylprednisolone sodium succinate can control surgical stress in patients undergoing hepatic resection. DESIGN: A prospective randomized trial. SETTING: A university hospital department of surgery. PATIENTS: Thirty-three patients who underwent hepatic resection were classified into 2 groups: a control group (n = 16) and a steroid group (n = 17) in which patients were intravenously administered 500 mg of methylprednisolone 2 hours before surgery. MAIN OUTCOME MEASURES: Perioperative levels of interleukin (IL)-6 and IL-10 (serum and peritoneal), immunosuppressive acidic protein, Candida antigen, and other laboratory and clinical variables were measured. RESULTS: Postoperative levels of serum and peritoneal IL-6 and levels of C-reactive protein were significantly lower in the steroid group than in controls. Furthermore, serum and peritoneal IL-10 levels were significantly higher in the steroid group. The total bilirubin value on postoperative day 1 was significantly lower in the steroid group than in controls. Postoperative immunosuppressive acidic protein levels were also significantly lower in the steroid group, as was the positive rate of serum Candida antigen. No differences were found in the incidence of postoperative complications. CONCLUSIONS: Preoperative steroid administration significantly elevated anti-inflammatory cytokine IL-10 levels, suppressed the levels of inflammatory cytokines IL-6 and C-reactive protein, and prevented postoperative elevation of total bilirubin values. Furthermore, postoperative elevation of immunosuppressive acidic protein levels and the positive rate of Candida antigen were suppressed, indicating that the immune response was maintained by preoperative steroid administration.

Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model.

Applications of nonviral vectors for gene transfer into tumors in vivo have been limited by the relatively low expression levels of the transferred gene. The aim of this study is to evaluate the efficacy of electroporation-mediated interleukin-12 (IL-12) gene therapy for hepatocellular carcinoma (HCC). First, we investigated the optimal conditions of electric pulses (voltage, pulsing duration, numbers of shocks) of in vivo electroporation for gene transfer into HCC established by s.c. implantation of MH134 cells to C3H mice. This process made use of plasmid DNA that express the luciferase gene. We concluded that the optimal conditions for the electric pulses are as follows: voltage at 150 V; pulsing duration at 50 ms; nonpulsing duration at 950 ms; and the number of shocks at 10. Second, we tried to treat s.c. HCC by electroporation using plasmid DNA that expresses the murine interleukin-12 (mlL-12) gene. Intratumoral administration of the mIL-12 vector elevated serum IL-12 and IFN-gamma and significantly inhibited the growth not only of HCC into which the mIL-12 vector had been directly transferred, but also of the distant HCC. In addition, intratumoral administration of the mIL-12 vector inhibited spontaneous lung metastasis and delayed establishment of HCC injected 3 days after mIL-12 gene therapy. The IL-12 gene therapy induced more lymphocyte infiltration by NK cells, CD3+ cells, and Mac-1 positive cells into the tumor and reduced the number of microvessels. Therefore, more terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive tumor cells were found. These results demonstrate that gene therapy for HCC by electroporation in vivo using IL-12 is very efficient and is thus promising for further clinical trial.

Bile leakage after hepatic resection.

OBJECTIVE: To identify the perioperative risk factors for postoperative bile leakage after hepatic resection, to evaluate the intraoperative bile leakage test as a preventive measure, and to propose a treatment strategy for postoperative bile leakage according to the outcome of these patients. SUMMARY BACKGROUND DATA: Bile leakage remains a common cause of major complications after hepatic resection. METHODS: Between January 1985 and June 1999, 781 hepatic resections without bilioenteric anastomosis were performed at the authors' institution. Perioperative risk factors related to postoperative bile leakage were identified using univariate and multivariate analysis. The characteristics of patients with intractable bile leakage and the effect of intraoperative bile leakage test were also examined. Management was evaluated in relation to the outcomes and the clinical characteristics of the patients with bile leakage. RESULTS: Bile leakage developed in 31 (4.0%) of 781 hepatic resections. This complication carried high risks for surgical death (two patients [6.5%] died). The stepwise logistic regression analysis identified high-risk surgical procedure, in which the cut surface exposed the major Glisson's sheath and included the hepatic hilum (i.e., anterior segmentectomy, central bisegmentectomy, or total caudate lobectomy), as the independent predictor of the development of postoperative bile leakage. None of the 102 cases in which an intraoperative bile leakage test was performed were subsequently complicated by postoperative bile leakage, and the preventive effect of the test was statistically significant. Patients with fisterographically demonstrable leakage from the hepatic hilum and with postoperative uncontrollable ascites had poor outcomes. CONCLUSION: Patients with bile leakage from the hepatic hilum and postoperative uncontrollable ascites tend to have a poor prognosis. Therefore, especially when a high-risk surgical procedure is performed in patients with liver cirrhosis, more careful surgical procedures and use of an intraoperative bile leakage test are recommended.

The importance of hepatic resection for hepatocellular carcinoma originating from nonfibrotic liver.

BACKGROUND: Our study aimed to clarify the characteristics of hepatocellular carcinoma (HCC) in patients with a nonfibrotic liver and the role of surgical resection for HCC in nonfibrotic liver compared with patients with HCC in fibrotic or cirrhotic livers. STUDY DESIGN: A total of 516 patients who underwent hepatectomy between April 1985 and June 1999 were classified into two groups: a nonfibrotic liver group (n=65) and a fibrotic liver group (n=451), which included fibrotic or cirrhotic livers. Clinicopathologic variables were then compared between the groups, including disease-free survival rate and patient survival rate. RESULTS: Only 8 of 65 patients (12.3%) with a nonfibrotic liver showed a histologically completely normal liver. The numbers of men and patients with alcohol abuse in the nonfibrotic liver group were higher than in the fibrotic liver group. The numbers of patients with positive hepatitis B antigen and positive hepatitis C antibody in the nonfibrotic liver group were lower than in the fibrotic liver group. Results of liver function tests in the nonfibrotic liver group were better than those in the fibrotic liver group. The rates of both portal vein and hepatic vein invasion of cancer cells in the nonfibrotic liver group were higher than in the fibrotic liver group. The tumor size in the nonfibrotic liver group was larger than in the fibrotic liver group. The patient survival and disease-free survival rates in the nonfibrotic liver group were better than in the fibrotic liver group. CONCLUSIONS: Hepatic resection can be beneficial for patients with HCC originating from a nonfibrotic liver when compared with fibrotic or cirrhotic patients with HCC.

Characteristics of sarcomatous cholangiocarcinoma of the liver.

BACKGROUND/AIMS: The aim of this study was to clarify the clinicopathological characteristics of intrahepatic cholangiocarcinoma with sarcomatous changes. METHODOLOGY: Four cases of cholangiocarcinoma with sarcomatous change were identified and investigated. The clinicopathological findings, including the results of immunohistochemical staining, were investigated in comparison with those of ordinary cholangiocarcinoma. RESULTS: Two of them exhibited pyrexia as the initial symptom. The serum alkaline phosphatase level in sarcomatous cholangiocarcinoma was significantly lower than that in ordinary cholangiocarcinoma. Both the serum carcinoembryonic antigen and carbohydrate 19-9 level in sarcomatous cholangiocarcinoma also tended to be lower than those in ordinary cholangiocarcinoma. The carcinomatous component of all tumors was mostly poorly differentiated adenocarcinoma. The associated microscopic findings were as follows: lymphocyte infiltration in the tumor, accompanied by both necrosis and extensive lymph node metastases. Three of them predominantly exhibited spindle-shaped sarcomatous changes, whereas the other case predominantly demonstrated pleomorphic-type sarcomatous changes. The sarcomatous area was positive for both vimentin, a mesenchymal marker, and for epithelial markers, furthermore, in 3 of 4 cases, the carcinoma portions were also positive for vimentin. The overall survival curves were not significantly different between the 2 groups, however, no long-term survivor was found in sarcomatous cholangiocarcinoma. CONCLUSIONS: The main characteristics of cholangiocarcinoma with sarcomatous changes are considered to be as follows: 1) often demonstrating pyrexia as a symptom; 2) not always demonstrating remarkable abnormal findings in the laboratory data including tumor markers; 3) histologically showing poorly differentiated adenocarcinoma; and 4) showing a very poor prognosis (especially, in a pleomorphic-type).

Surgical indications for advanced hepatocellular carcinoma.

BACKGROUND/AIMS: The aim of this study is to clarify the limitations of hepatectomy for advanced hepatocellular carcinoma. METHODOLOGY: Fifty-six patients with Stage 4 hepatocellular carcinoma were retrospectively studied, and the prognostic factors were both univariately and multivariately analyzed. The VI score, which was defined as the degree of portal vein invasion (VP) multiplied by the degree of intrahepatic metastases (IM), was introduced as a new prognostic indicator. RESULTS: A univariate analysis revealed the following significant variables: hypertension, esophageal varices, Child's classification B or C, a bilirubin value of over 1.0 mg/dL, a albumin value of below 3.5 g/dL, a GOT value of over 100 IU/L, an AFP value of over 1000 ng/mL, a history of tumor rupture, Stage 4B, a tumor size of over 5 cm, VP3, IM3, and the VI score of no less than 6. A multivariate analysis demonstrated the following 4 variables to be independent prognostic indicators: a Stage of 4B, a VI score of no less than 6, a Child's classification of B or C, and a tumor size of over 5 cm. Furthermore, no long-term survivors were found in patients with either Stage 4B HCC or a hepatocellular carcinoma having a VI score of more than 6. At the present time, either Stage 4B or a hepatocellular carcinoma having a VI score > or = 6 are considered to be factors which means the limitation of hepatectomy alone. Furthermore, an advanced hepatocellular carcinoma with either poor liver function or a hepatocellular carcinoma with a size of over 5 cm should be carefully evaluated before determining its appropriateness for hepatectomy. CONCLUSIONS: The VI score is therefore suggested to be a useful prognostic indicator for determining the surgical indications for advanced hepatocellular carcinomas.

Hepatic sclerosing hemangioma mimicking a metastatic liver tumor: report of a case.

We present herein the case of a sclerosing hemangioma of the liver which was extremely difficult to differentiate from liver metastasis of rectal cancer, in a 67-year-old woman. All the radiological findings were compatible with liver metastasis; however, marginal pooling of the tumor revealed by computed tomographic angiography and magnetic resonance imaging scans was inconsistent with a diagnosis of liver metastasis. At laparotomy, the tumor was macroscopically unusual in that it was yellowish elastic-hard with a very clear margin, and thus, it did not have the appearance of a metastatic tumor. Mile's operation and a partial hepatectomy were performed, followed by an uneventful postoperative course and no signs of recurrence. The carcinoembryonic antigen (CEA) level in the peripheral blood was not elevated at any time. The postoperative pathological diagnosis was a rare hepatic tumor, namely, a "sclerosing hemangioma," based on the findings of cellular fibrous stroma containing vascular channels with flattened endothelial cells. Preoperatively differentiating between sclerosing hemangioma and a metastatic liver tumor from colorectal cancer may be very difficult; however, this case demonstrated some interesting characteristics, namely, the serum CEA level was not elevated, marginal pooling of the tumor was found in the enhanced radiological findings, and the tumor was macroscopically unusual. Therefore, the possibility of sclerosing hemangioma should be borne in mind when considering the differential diagnosis of patients suspected of having colorectal liver metastasis. A preoperative biopsy should be carried out and when a laparotomy is performed under the misdiagnosis of colorectal liver metastasis, it is advisable that either an intraoperative needle biopsy or a frozen histological analysis be undertaken to avoid unnecessary extended hepatic resection of this rare benign hepatic tumor.

The role of des-gamma-carboxy prothrombin levels in hepatocellular carcinoma and liver tissues.

We aimed to clarify the clinical significance of des-gamma-carboxy prothrombin (DCP) levels in both hepatocellular carcinoma (HCC) and liver tissues with a special reference to the relationship between DCP level in non-cancerous parts of the liver and the multicentric occurrence of HCC. Twenty-eight patients with HCC, who underwent hepatectomy, were studied. Surgical specimens were obtained from both HCC and non-cancerous liver of each patient. After the preparation of the liver tissues, including tissues with HCC, the DCP levels both in HCC and non-cancerous liver tissue were measured using an electro-chemiluminescence immunoassay. The correlation was investigated between DCP levels and other clinicopathological factors. The DCP level of HCC ranged from 55 to 77735 U/0.1 g tissue weight, with a median of 2801, while the DCP level of non-cancerous parts of the liver ranged from 24 to 721 U/0.1 g tissue weight, with a median of 86. The DCP level in the liver tissue in patients having a multicentric occurrence of HCC was significantly higher than that in patients without multicentric occurrence of HCC. The logarithm of the plasma DCP level correlated with that of the DCP level in HCC (correlation coefficient =0.46; P<0.05). No significant correlation was found between the DCP level in HCC and other clinicopathological parameters. The DCP level in non-cancerous parts of the liver with simultaneous multicentric occurrence of HCC was significantly higher than that in the liver without multicentric HCC. Furthermore, the DCP level in non-cancerous parts of the liver was one of the most important predictable factors of the multicentric occurrence of HCCs among various clinicopathological factors. Therefore, the DCP level may have an important role in hepatocarcinogenesis.

The significance of thymidine phosphorylase activity in hepatocellular carcinoma and chronic diseased livers: a special reference to liver fibrosis and multicentric tumor occurrence.

The role of thymidine phosphorylase (TP), an angiogenic factor, in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to clarify the significance of TP in HCC. Thirty-seven patients with HCC, who underwent hepatectomy, were included. The TP activity in both cancerous and non-cancerous parts of livers were measured by an enzyme-linked immunosorbent assay. Another 11 patients without HCC were used to evaluate the TP activity in the non-cancerous parts of livers. Both the cancerous and non-cancerous TP activities were clinico-pathologically investigated with special reference to the multicentric occurrence of HCCs and the degree of liver fibrosis; consisting of normal, fibrosis and cirrhosis. The TP activity in the cancerous part was 94.6 +/- 70.2 U/mg protein, while that in non-cancerous parts of the liver was 80.9 +/- 48.8 U/mg protein. No significant difference was observed. The TP activity in the cancerous part did not correlate with any clinicopathological variables, such as tumor differentiation, portal vein invasion, intrahepatic metastases and prognosis. However, the TP activity in the non-cancerous parts of the liver correlated with the degree of fibrosis (normal/fibrosis/cirrhosis = 34:74:90 U/ mg protein, respectively). Furthermore, regarding the correlation between TP activity in the non-cancerous parts and the simultaneously multicentric occurrence of HCC, the TP activity in the multicentric group (n = 8; 121 U/mg protein) was significantly higher than that in the non-multicentric group (n = 29; 70 U/mg protein). The TP activity in the non-cancerous parts increased in proportion to the degree of liver fibrosis. Furthermore, it is suggested that the higher TP activity in the non-cancerous part is related to the multicentric occurrence of HCCs.

Clinicopathologic features and postoperative prognosis of multicentric small hepatocellular carcinoma.

BACKGROUND: Assessment of clinicopathologic characteristics and postoperative prognoses for patients with multicentric hepatocellular carcinoma (HCC) is important to determine not only a need to operate, but also an appropriate treatment after hepatic resection. STUDY DESIGN: Between May 1990 and April 1998, among 116 patients with an initial hepatectomy for HCC measuring 3 cm or less in maximum diameter, 34 patients had multicentric HCC (MC group), and 82 patients had single nodular HCC (SN group). To clarify the clinicopathologic features of patients in the MC group versus the SN group, we compared both the clinicopathologic parameters and the postoperative prognosis after curative hepatectomy between the two groups. RESULTS: The percentages of patients positive for hepatitis B surface antigen and hepatitis C virus antibody were not significantly different between the two groups. No differences were noted in pathologic characteristics of the main tumor or tumor markers. On the other hand, in the MC group, the percentage of patients evaluated in a Child's classification as either B or C was significantly higher (p < 0.05) than that of patients in the SN group, indicating that patients with multicentric HCC have a poor hepatic functional reserve. Both survival and disease-free survival of patients in the MC group who underwent a curative hepatectomy did not differ statistically from those in the SN group. CONCLUSIONS: Our results indicate that hepatic resection is useful, even for patients with multicentric HCC, if a curative hepatectomy can be performed and liver function can be saved, despite their poor hepatic functional reserve.

[Factors linked to 5-year survival after hepatectomy for hepatocellular carcinoma: univariate and multivariate analyses of 312 patients].

The purpose of this study was to clarify the factors linked to 5-year survival after hepatectomy for hepatocellular carcinoma (HCC). Three hundreds and twelve patients who underwent hepatectomy for HCC between 1985 and 1994 were observed for at least 5 years. These patients were divided into 2 groups: 160 patients who died within 5 years after hepatectomy and 152 patients who did not die within 5 years. Statistical analysis by chi 2 test showed that the favorable factors linked to 5-year survival were (a) diabetes mellitus (-), (b) albumin > 3.7 g/dl, (c) hepaplastin test > 61%, (d) indocyanine green retention test at 15 minutes < 16%, (e) curative resection (+), (f) alpha-fetoprotein < or = 32 ng/ml, (g) portal vein invasion (-), (h) intrahepatic metastasis (-), and (i) stage I and II. Statistical analysis by stepwise regression test showed that the favorable factors linked to 5-year survival were (a) intrahepatic metastasis (-), (b) diabetes mellitus, (c) indocyanine green retention test at 15 minutes < 16%, (d) curative resection (+) and (e) alpha-fetoprotein < or = 32 ng/ml. When patients diagnosed with HCC, patients selection for hepatectomy should be done, based on the total estimation, such as tumor invasiveness, liver functions, and diabetes mellitus.

Evaluation of major hepatic resection for small hepatocellular carcinoma.

BACKGROUND/AIMS: The aim of this study is to clarify the significance of a major hepatectomy for small hepatocellular carcinomas (HCCs). METHODOLOGY: Seventy-eight patients with solitary HCC measuring less than 3 cm in diameter, whose liver function was considered sufficient to tolerate a right hepatic lobectomy, were classified into 2 groups consisting of: a major group (n = 18), who underwent a major hepatectomy (2 segments or more); and, a minor group (n = 60), who underwent a hepatectomy including one segment or less. The early post-operative outcome and the long-term outcomes, comprising patient survival as well as disease-free survival, were compared. In addition, the post-operative long-term changes in liver function tests and esophageal variceal occurrence were also compared. RESULTS: In the post-operative mortality and morbidity, no significant differences were found between the 2 groups. However, 1 patient in the major group unexpectedly died of liver failure 6 months after operation. No significant difference was observed in patient survival and disease-free survival. The platelet count in the major group tended to decline more rapidly than that in the minor group. Furthermore, 1 patient in the major group demonstrated risky esophageal varices 29 months after operation, which had to be treated by endoscopic injection sclerotherapy. CONCLUSIONS: Based on the above findings, a major hepatectomy is therefore not recommended for patients with solitary small HCC measuring 3 cm or less in diameter.