Takashi Nishizaki

Small Graft for Living Donor Liver Transplantation

ObjectiveTo evaluate the impact of graft size on recipients in living donor liver transplantation (LDLT) to establish a clinical guideline for the minimum requirement. Summary Background DataAlthough the minimum graft size required for LDLT has been reported to be 30% to 40% of graft volume (GV)/standard liver volume (SLV), the safety limit of the graft size was unknown. MethodsA total of 33 cases of LDLT, excluding auxiliary transplantation, were reviewed with a minimum observation period of 4 months. The 33 patients were divided into three groups according to GV/SLV: medium-size graft group, small-size graft group, and extra-small graft group. The effect of GV/SLV on graft function, graft regeneration, and survival was evaluated. ResultsThe overall patient survival rate was 94% at a mean follow-up of 15 months with a minimum observation period of 4 months. There were no statistically significant differences in postoperative bilirubin clearance, alanine aminotransferase, prothrombin time, and frequency of postoperative complications among the three groups. One week after transplantation, the regeneration rate (GV at 1 week/harvested GV) in the extra-small and small groups was significantly higher than that of the medium group. The graft and patient survival rates were both 100% in the extra-small group, 75% and 88% in the small group, and 90% and 95% in the medium group. ConclusionsSmall-for-size grafts less than 30% of SLV can be used with careful intraoperative and postoperative management until the grafts regenerate.

Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene.

Background. Tacrolimus is a substrate of P-glycoprotein (PGP) encoded by the multidrug resistant (MDR)1 gene (ABCB1). PGP, a multidrug efflux pump, restricts the distribution of tacrolimus in the brain. In this study, we investigate the correlation of ABCB1 gene polymorphism with tacrolimus-induced neurotoxicity in patients after liver transplantation. Methods. The genotype of 6 patients with neurotoxic events and 11 patients without neurotoxic events was analyzed by polymerase chain reaction (PCR), and 8 mutations were detected. In addition to laboratory findings and patient characteristics, the contribution of mutations in the ABCB1 gene was evaluated with stepwise discriminant function analysis. Results. High tacrolimus concentration, liver dysfunction, and mutation at position 2677 in exon 21 were demonstrated as positive predictors of tacrolimus-induced neurotoxicity. Conclusion. It is indicated that blood concentrations, liver function, graft weight, and polymorphism in the ABCB1 gene are important factors in tacrolimus-induced neurotoxicity.

Surgical manipulation of VX2 carcinoma in the rabbit liver evokes enhancement of metastasis

To search for possible untoward effects of surgical manipulation of a malignant tumor, a series of experiments was carried out using VX2 carcinoma of rabbits. Fourteen days after inoculation of VX2 carcinoma into the liver, the rabbits were separated into two groups: Group I, manual manipulation during relaparotomy; and Group II, relaparotomy alone without manual manipulation of the tumor. After these procedures, the tumor was surgically removed and histologic examinations were made. The incidence of vascular permeation of liver tumor cells into the hepatic vein was significantly higher in Group I (P less than 0.01). On the 14th day after resection of the tumor, the number of metastatic nodules in the lungs was significantly increased in Group I (P less than 0.01). Survival time of rabbits after resection of tumor was significantly shorter in Group I (P less than 0.01). These results are taken to mean that manual manipulation of a tumor may well enhance metastasis.

Laparoscopic hepatic resection for hepatocellular carcinoma

Despite recent progress in diagnostics for hepatocellular carcinoma, the rate of resectability remains low, mainly because of the advancement of the underlying liver disease. We report a case of a 54-year-old man with a hepatocellular carcinoma and poor liver function that was treated successfully with a laparoscopic hepatic resection. Laparoscopic hepatic resection is considered to be feasible with the aid of an ultrasonic dissector and a microwave coagulator; however, close attention should be paid to the development of air embolism and hepatic vein injury.

The impact of donor age on living donor liver transplantation.

Background. The impact of the age of the donor on the outcome of living related liver transplantation is yet to be clarified. Methods. During October 14, 1996 and December 20, 1999, 34 living related liver transplantations were performed. Of these, 26 cases were performed using the extended left lobe graft, which were classified into three groups; younger donor group (group Y, donor age <30, n=7), middle-aged donor group (group M, 30≤donor age <50, n=13), and older donor group (group O, donor age<50, n=6). Early allograft function and regeneration were compared between these groups. Results. There was no difference in standard liver volume, and predicted or harvested graft size between the three groups. Although serum transaminase and total bilirubin levels within postoperative day 7 were not different between the groups, the prothrombin time on postoperative day 3 was significantly longer in group O than in group Y. One week after transplantation, group Y had significantly greater graft/standard liver volume ratio than group O, and greater graft volume than group M and O. One month after transplantation, however, there was no significant difference in such graft size parameters between the groups. Graft and patient survival were comparable between the three groups. Conclusion. Although function and regeneration of the allografts from older donors in living donor liver transplantation is worse than those of their younger counterparts, the outcome is not affected by the age of the liver.

Postoperative prophylactic lipiodolization reduces the intrahepatic recurrence of hepatocellular carcinoma

BACKGROUND To determine a feasible postoperative adjuvant chemotherapy for patients with hepatocellular carcinoma, orally-administered chemotherapy (OC) and prophylactic lipiodolization (selective regional cancer chemotherapy using lipid contrast medium plus an anticancer drug) (PL) were compared prospectively. PATIENTS AND METHODS Forty-eight patients who had undergone hepatic resection from 1989 to 1992 were divided into three groups: the control group (n = 19), given no chemotherapy; the OC group (n = 12), given 300 to 400 mg/d of 5-FU derivatives (either 1-hexylcarbamoyl-5-fluorouracil or uracil and tegafur, mean total dosage: 188 g, mean administrative duration: 18 months); and the PL group (n = 17), who underwent prophylactic lipiodolization 1.8 times on average using a 44-mg mean dose of epirubicin per treatment. RESULTS No statistical differences were found either in the 25 variables studied as a background analysis, or among the survival curves of the 3 groups. Recurrence was found in 23 remnant livers of the 48 patients. The 3-year, disease-free survival rate was 15%, 50%, and 86% in the control, OC, and PL groups, respectively. The disease-free survival curve of the PL group was significantly higher compared to either the control (P = 0.001) or the OC group (P = 0.025). CONCLUSIONS Prophylactic lipiodolization was found to be an effective treatment for patients with hepatocellular carcinoma for reducing intrahepatic recurrence after resection.

Angiopoietin 2 expression in invasive ductal carcinoma of the breast: its relationship to the VEGF expression and microvessel density

SummaryAngiopoietin (Ang) is a ligand for the endothelium-specific tyrosine kinase receptor Tie-2, while a shift in the Ang-1:Ang-2 expression ratio in favor of Ang-2 was found to be associated with tumor angiogenesis. In the present study, we analyzed the immunohistochemical expression of Ang-2 in a series of 198 breast cancers, in which VEGF expression and microvessel density (MVD) were previously determined. Ang-2 expression was negative in 24 (12%), positive in 50 (25%) and strongly positive in 124 (63%) of 198 cases. A significant correlation was found between Ang-2 and VEGF expressions (p=0.0004) and between Ang-2 expression and MVD (p=0.0006), while a high MVD was found in 10 (77%) of 13 tumors with a strongly positive VEGF and positive Ang-2 expression and in 40 (71%) of 56 tumors with a strongly positive VEGF and strongly positive Ang-2 expression. Although there was no difference in the disease free survival (DFS) stratified according to Ang-2 expression alone, the 69 patients with a strongly positive VEGF and a strongly positive or positive Ang-2 expression had a significantly (p=0.0316) worse DFS than those with other combinations of VEGF and Ang-2 expressions. A multivariate analysis indicated lymph node metastasis and MVD to be independently significant prognostic factors for DFS, while the combination of VEGF and Ang-2 expressions was not a significant factor for DFS. In conclusion, the Ang-2 expression was found to be closely correlated with VEGF expression and MVD in breast cancer, while a high MVD was frequently found in tumors with a high expression of both VEGF and Ang-2. The survival analysis demonstrated a high MVD, which was induced by a high expression of both VEGF and Ang-2, to therefore have a strong prognostic significance in breast cancer.

A loss of c-kit expression is associated with an advanced stage and poor prognosis in breast cancer

To evaluate the c-kit expression in breast cancer, 217 invasive ductal carcinomas of the breast were immunohistochemically stained for c-kit protein. The c-kit expression was positive in 59 (27%) of 217 tumours, while the c-kit expression was negative in 158 (73%) of 217 tumours. There was a significant correlation between a negative expression of the c-kit protein and lymph node metastasis (P<0.0001), and the incidence of a negative expression of the c-kit protein increased as the number of the metastatic lymph nodes increased (P=0.0003). The c-kit expression did not significantly correlate with the tumour size, nuclear grade, oestrogen receptor status, MIB-1 counts and p53 protein expression. A univariate analysis indicated the patients with the negative c-kit expression to have a worse disease-free survival (DFS) than those with the positive c-kit expression (P=0.0041), while a multivariate analysis determined lymph node metastases and the MIB-1 counts to be independently significant factors for DFS. In conclusion, a loss of the c-kit expression was found in about three-fourth of invasive ductal carcinoma of the breast and was associated with lymph node metastases. The prognostic implications of the c-kit expression seem to be due to fact that a loss of the c-kit expression is associated with an advanced stage of breast cancer.

Surgical treatment strategy for patients with stage IV hepatocellular carcinoma

BACKGROUND This study was conducted to identify the prognostic indicators for patients with stage IV hepatocellular carcinoma (HCC), as well as to clarify the strategy of surgical treatment for those patients. METHODS Forty-six patients with stage IV HCC were included in this study. Prognostic factors were univariately and multivariately analyzed. Furthermore, the significance of intraoperative treatment for residual tumors was investigated in patients with an absolute noncurative operation. RESULTS The poor prognostic factors were as follows: host factors, Childs classification of B and C and immunosuppressive acidic protein level of greater than 400 micrograms/ml; tumor factors, tumor diameter of greater than 5 cm, poorly differentiated histologic features, positive portal vein invasion, and intrahepatic metastases involving more than three segments; others, an absolute noncurative operation and no preoperative treatment. Tumor diameter of more than 5 cm was then suggested to be an independent prognostic indicator. Survival of patients with stage IV-A HCC who underwent a curative operation was similar to that of those with stages III HCC: Furthermore, the survival of patients with Stage IV-A who had an absolute noncurative operation but underwent either intraoperative microwave coagulation or ethanol injection to the residual HCCs was not statistically different from that of those with a curative operation. CONCLUSIONS Therefore for stage IV-A HCC surgical treatment is considered to be both useful and the first choice of treatment when all the tumors in the liver can be removed or when the residual tumors can be treated during operation by either microwave coagulation or ethanol injection as a result of an incomplete removal of the tumors.

Effects of deletion variant of hepatocyte growth factor on reduced-size liver transplantation in rats.

BACKGROUND The deletion variant of hepatocyte growth factor (dHGF) exerts mitogenic and antifibrotic effects. The purpose of this study was to evaluate the effect of dHGF on rats that had undergone syngeneic or allogeneic reduced-size (60%) orthotopic liver transplantation (ROLT). METHODS Starting immediately after the syngeneic (Lewis to Lewis) and allogeneic (Lewis to Brown Norway) ROLT, 500 microg/kg dHGF was administered i.v. twice a day until the day the rats were killed. Its effect on hepatic graft weight, regeneration, and biochemical parameters was evaluated. RESULTS dHGF promoted restoration of the liver volume and liver regeneration as well as protein synthesis in the rats that underwent syngeneic ROLT. In the rats that underwent allogeneic ROLT, dHGF reduced the level of serum cytosolic enzymes related to acute cellular rejection, but a significant improvement in liver regeneration and protein synthesis was not seen. When tacrolimus was administered to prevent rejection of the allogeneic grafts, the beneficial effect of dHGF was apparent, and was as beneficial as in syngeneic ROLT. CONCLUSIONS Administering dHGF after liver transplantation augments the regeneration and functional recovery of partial liver grafts and reduces hepatocyte injury in acute cellular rejection.