Hirofumi Hasegawa

Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume

BACKGROUND Postoperative liver failure is a life-threatening complication after hepatic resection. Because of recent advances in liver surgery technique and a more stringent patient selection, mortality after hepatic resection has steadily decreased, but its incidence still ranges from 10% to 20%. The factors linked to postoperative liver failure in major hepatic resection in the modern era should be reevaluated. STUDY DESIGN Of 80 patients with viral markers (hepatitis C viral antibody or hepatitis B surface antigen) who underwent major hepatic resections (no less than bisegmentectomies) for hepatocellular carcinoma between 1990 and 1996, 7 patients (8.8%) died of postoperative liver failure within 6 months after hepatectomy. The cause of liver failure was analyzed based on both the preoperative data and the intraoperative findings. In addition, since all the patients who died of liver failure underwent a right hepatic lobectomy, a further data analysis was also done in 47 patients who underwent a right lobectomy of the liver. A volumetric analysis by CT was then done to evaluate the remnant liver volume. RESULTS Between the patients with liver failure and those without liver failure who underwent a right lobectomy, there were no significant differences in preoperative data or intraoperative findings. Volumetric analysis revealed that the remnant liver volume of patients who died of liver failure was significantly smaller than that of patients who lived (p = 0.008). The incidence of liver failure in patients with a remnant liver volume of less than 250 mL/m2 was 7 of 20 (38%), while it was 0 of 27 in patients with a liver volume of no less than 250 mL/m2 (p = 0.0012). The only significant risk factor for liver failure in patients with a remnant liver volume of less than 250 mL/m2 was diabetes mellitus (p = 0.0072). CONCLUSIONS The expected remnant liver volume appears to be a good predictor for liver failure in patients who undergo a right lobectomy of the liver. In patients with diabetes mellitus and an expected remnant liver volume of less than 250 mL/m2, a major hepatectomy should be avoided. Careful patient selection based on volumetric analysis in major hepatectomy cases could help prevent the occurrence of postoperative liver failure.

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 Childs 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.

Expression of matrix metalloproteinase-9 in surgically resected intrahepatic cholangiocarcinoma

BACKGROUND Matrix metalloproteinase-9 (MMP-9) has recently been reported to be related to cancer cell invasion. This study was performed to clarify the expression of MMP-9 in surgically resected intrahepatic cholangiocarcinoma (IHCC). METHODS In 37 patients with IHCC who underwent a surgical resection, the expression of MMP-9 and the clinicopathologic characteristics of MMP-9-positive IHCC were investigated. The expression of MMP-9 was immunohistochemically detected in 16 (43%) of 37 IHCC. The patients were divided into MMP-9 (-) IHCC (n = 21), MMP-9 (+) IHCC (n = 12), and MMP-9 (++) IHCC (n = 4). RESULTS The survival rate after surgical resection in patients with MMP-9 (-), (+), and (++) IHCC, was 66%, 39%, and 0% at one year, 50%, 32% and 0% at 3 years, respectively (P = .001). The incidence rate of lymph node metastasis was 6 (28%) of 21 in MMP-9 (-) patients, 7 (58%) of 12 in MMP-9 (+) patients and 4 (100%) of 4 in MMP-9 (++) patients. The incidence rate of lymph node metastasis increased in proportion to an increase in the expression of MMP-9 in IHCC (P = .02). Recurrence in the lymph node was more common in patients with MMP-9 (+) and (++) cancers than in those with MMP-9 (-) cancers. CONCLUSIONS The expression of MMP-9 in IHCC was a prognostic factor related to lymph node metastasis.

The role of telomerase activity in hepatocellular carcinoma

OBJECTIVE:The aim of this study was to clarify the role of telomerase activity in hepatocellular carcinoma (HCC).METHODS:Specimens from both HCC and noncancerous liver were obtained from 39 patients with HCC using a 14-gauge biopsy needle immediately after laparotomy. Telomerase activity was determined using a telomeric repeat amplification protocol assay. The 3+ of telomerase activity in HCC was defined as a high telomerase group, and 2+ or less of HCC telomerase activity was defined as a low telomerase group. In noncancerous liver, 2+ or more of telomerase activity was defined as an increased telomerase group, and 1+ or less of telomerase activity was defined as a nonincreased telomerase group. The correlation between telomerase activity in HCC or noncancerous liver and clinicopathological factors, including prognosis, was investigated.RESULTS:Telomerase activities in HCCs were 0 in one patient, 1+ in two, 2+ in seven, and 3+ in 29 patients. The disease-free survival rate in the high telomerase group was significantly worse than that in the low telomerase group. The des-γ-carboxy prothrombin level in a high telomerase group (median, 330 mAU/ml) was significantly higher than that in the low telomerase group (median, 150 mAU/ml). A multivariate analysis revealed that higher TNM stage, high telomerase activity in HCC, female gender, and high α-fetoprotein value were independent significant factors related to be early recurrence. The incidence of multicentric HCC occurrence in the increased telomerase group (53.3%) tended to be higher than that in the nonincreased telomerase group (27.3%).CONCLUSION:A high telomerase activity in HCC correlated with the potential of HCC to be more malignant, which was expressed as both a high level of des-γ-carboxy prothrombin and an earlier recurrence after hepatectomy than that of HCC with a low telomerase activity.

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

We aimed to clarify the clinical significance of des-γ-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 77 735 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.

Modulation of immunologic reactions between cultured porcine hepatocytes and human sera.

In the clinical application of a hybrid artificial liver system using porcine hepatocytes, some immunologic reactions occur between human serum and porcine hepatocytes. In this study, we investigated the immunologic mechanisms of the cytotoxic reactions, and we tried to inactivate the human serum cytotoxicity by heating the serum or the addition of nafamostat mesilate (NM). Immunologic reaction between human serum and porcine hepatocytes by evaluating the immunochemical response against human IgM, IgG, and C3 was investigated. The immunochemical analysis of inactivation by heated human serum (56 degrees C, 30 min) and adding NM were performed. The evaluation of serum cytotoxicity was as follows: when porcine hepatocytes were cultured with heating the human serum or the addition of NM, the survival ratio was observed. Immunochemical reactions against human C3 were all positive, but positive reaction against human IgM occurred in only one case (5%); those against human IgG were all negative. Both heating the serum and adding NM inhibited the immunochemical reaction of human C3. The inhibition of human C3 with NM was dependent on that concentration. Both heating of the serum and adding NM to the medium decreased damage of porcine hepatocytes. An immunologic reaction between human serum and porcine hepatocytes in a porcine bioartificial liver clearly occurred, and this reaction was controlled by heating the serum and adding NM. We believe that NM is useful in the clinical application of our hybrid artificial liver system.

Preclinical and therapeutic utility of HVJ liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex virus thymidine kinase

Although gene therapy has been suggested to be a novel strategy to treat hepatocellular carcinoma (HCC), no study showing the clinical feasibility of vectors to treat HCC has been reported. In this preclinical study, we show evidence indicating that hemagglutinating virus of Japan (HVJ) liposomes are a feasible vector to treat HCC in a clinical setting using ganciclovir (GCV) and herpes simplex virus thymidine kinase (HSV-tk), which is driven by the cytomegalovirus immediate early enhancer/promoter (plasmid pcDNA3/HSV-tk). In in vitro experiments, almost complete tumor cell regression was achieved with the optimal GCV concentration (100 μg/mL) and more than 1/3 regression was seen even with a 20% transduction ratio using HuH7 HCC cells stably transformed by HSV-tk. HVJ liposomes showed a 19.7% (mean) transduction rate of the lacZ gene in a relatively large mass of more than 300 mm3 in vivo, which is a clinically detectable size, implanted into SCID mice. Moreover, a single HSV-tk injection of HVJ liposomes followed by GCV treatment inhibited tumor growth at least within a week, and repeat administration was more effective. Furthermore, subcutaneous injection of an HVJ liposomes vehicle induced no apparent inflammatory response in C3H/HeN mice, whereas lacZ gene transfection resulted in inflammatory pathology, suggesting a lower immunogenicity of the HVJ envelope protein than those of bacteria-derived plasmid DNA or the β-galactosidase gene product. From these findings, we conclude that HVJ liposomes are a clinically safe and effective gene transfer vector to treat HCC. Cancer Gene Therapy (2001) 8, 252–258

Role of Adhesion Molecule Expression and Soluble Fractions in Hepatic Resection

BACKGROUND Little has so far been documented about the relationship between liver injury and adhesion molecules. The aim of this study is to clarify the role of adhesion molecules in hepatic resection by studying both the expression of such adhesion molecules and the measurement of their soluble fractions in the blood. STUDY DESIGN To study adhesion molecule expression in the liver, liver biopsies were obtained before and after hepatectomy in 14 patients. Using frozen sections, immunochemical staining for intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was then performed. To study the soluble fractions of adhesion molecules in the hepatic venous blood, the serum soluble fractions of ICAM-1 and VCAM-1 from another 17 patients were measured using an enzyme-linked immunosorbent assay. The plasma levels of polymorphonuclear leukocyte (PMN) elastase were also measured using an enzyme immunoassay. Both the preoperative and postoperative values of the serum soluble fractions of ICAM-1, VCAM-1, and PMN elastase were then compared. The correlation between their values and the perioperative variables was also investigated. RESULTS Either ICAM-1 or VCAM-1 was stained on the sinusoidal endothelial cells and Kupffer cells or circulating PMNs in the sinusoid. The positive rate of either ICAM-1 or VCAM-1 staining in livers with more than 40 minutes of total ischemic time (80%) was significantly higher than that in livers with less than 40 minutes of total ischemic time (0%; p < 0.05). The incidence of postoperative complications in the ICAM-1 positive staining group tended to be higher than that in the ICAM-1 negative group. Both soluble fractions of ICAM-1 and VCAM-1 in patients with cirrhotic liver disease were also significantly higher than those in patients with a normal liver. The soluble VCAM-1 level in patients with a chronic active hepatitic liver tended to be higher than that in those with a nonactive hepatitic liver. The preoperative level of soluble ICAM-1 correlated with that ofVCAM- 1, PMN elastase, albumin, aspartate aminotransferease (AST), and the indocyanine green dye retention test at 15 minutes (ICG R15), while the preoperative level of VCAM-1 correlated with albumin, the hepaplastin test, AST, and ICG R15. Both the serum soluble ICAM-1 and VCAM-1 levels after hepatectomy were significantly lower than those before hepatectomy. By contrast, the posthepatectomy level of PMN elastase was significantly higher than its prehepatectomy level. The difference between the postoperative and preoperative values of soluble ICAM-1 correlated with the postoperative AST level, postoperative alanine aminotransferase level, and total ischemic time. CONCLUSIONS Adhesion molecules were expressed in the liver after hepatic resection, and such expression correlated with a total ischemic time during hepatectomy. In addition, judging from the soluble forms of such molecules, these adhesion molecules play an important role in hepatic resection.

Ileal perforation in diffuse intestinal Behçet disease: Report of a case

Abstract Intestinal ulcers in Behçet disease tend to cause perforation, and postoperative recurrence is common with a high mortality rate. The optimal therapeutic strategy has yet to be elucidated, particularly in cases of diffuse intestinal involvement. We herein present a case of diffuse intestinal Behçet disease with ileal perforation. A 57-year-old Japanese woman was referred to our institution with complaints of intractable oral ulcers and abdominal pain. The patient underwent an emergency laparotomy for perforated peritonitis in spite of the intravenous administration of prednisolone (1.5 mg/kg) under total parenteral nutrition. Macroscopically, an inflamed ileum measuring 1.6 m in length was resected, including a 1-cm perforated ulceration. Innumerable small and deep ulcers were also observed, consisting of nonspecific inflammation. The patient has been free from any recurrence of intestinal ulcers while being treated with prednisolone, colchicine, and a low-residue diet for 1.5 years.

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.