Akinobu Taketomi

Variants in IL28B in Liver Recipients and Donors Correlate With Response to Peg-Interferon and Ribavirin Therapy for Recurrent Hepatitis C

BACKGROUND & AIMS Patients with hepatitis C virus (HCV)-related liver disease frequently undergo orthotopic liver transplantation, but recurrent hepatitis C is still a major cause of morbidity. Patients are treated with peg-interferon and ribavirin (PEG-IFN/RBV), which has substantial side effects and is costly. We investigated genetic factors of host, liver donor, and virus that might predict sensitivity of patients with recurrent hepatitis C to PEG-IFN/RBV. METHODS Liver samples were analyzed from 67 HCV-infected recipients and 41 liver donors. Liver recipient and donor DNA samples were screened for single nucleotide polymorphisms near the IL28B genes (rs12980275 and rs8099917) that affect sensitivity to PEG-IFN/RBV. HCV RNA was isolated from patients and analyzed for mutations in the core, the IFN sensitivity-determining region, and IFN/RBV resistance-determining regions in nonstructural protein 5A. RESULTS In liver recipients and donors, the IL28B single nucleotide polymorphism rs8099917 was significantly associated with a sustained viral response (SVR; P = 0.003 and P = .025, respectively). Intrahepatic expression of IL28 messenger RNA was significantly lower in recipients and donors that carried the minor alleles (T/G or T/T) in rs8099917 (P = .010 and .009, respectively). Genetic analyses of IL28B in patients and donors and of the core and nonstructural protein 5A regions encoded by HCV RNA predicted an SVR with 83% sensitivity and 82% specificity; this was more effective than analysis of any single genetic feature. CONCLUSIONS In patients with recurrent HCV infection after orthotopic liver transplantation, combination analyses of single nucleotide polymorphisms of IL28B in recipient and donor tissues and mutations in HCV RNA allow prediction of SVR to PEG-IFN/RBV therapy.

Clinical Significance of Histone Deacetylase 1 Expression in Patients with Hepatocellular Carcinoma

Objective: Histone deacetylases (HDACs) play an important role in chromatin remodeling, gene repression and regulating cell cycle progression and differentiation. This study was designed to clarify the role of HDAC1 expression in hepatocellular carcinoma (HCC). Method: The expression of HDAC1 in 47 patients with surgically resected HCC was immunohistochemically examined and analyzed in relation to their clinicopathological factors. The patients were divided into two groups according to the expression status of HDAC1: a high HDAC1 group (n = 25) with more than 20% of positively stained cells and a low HDAC1 group (n = 22) with 20% or fewer positively stained cells. Results: A high HDAC1 expression indicated a higher incidence of cancer cell invasion into the portal vein, a poorer histological differentiation, and a more advanced TNM stage. The survival rates after a surgical resection in low and high HDAC1 patients at 1, 3, 5 and 10 years were 100, 95.5, 81.8 and 60.8% and 88.0, 60.0, 40.0 and 32.0%, respectively (p = 0.008). A multivariate analysis using the Cox regression analysis showed that a high HDAC1 expression was an independent prognostic factor of HCC in patients after hepatic resection (relative risk: 10.1, p = 0.0018). Conclusions: High HDAC1 expression might have an important role in the aggressiveness and cell dedifferentiation, and its expression status may be a useful biomarker for predicting the outcome of the patients with HCC.

Feasibility of left lobe living donor liver transplantation between adults: An 8-year, single-center experience of 107 cases

Operative mortality for a right lobe (RL) donor in adult living donor liver transplantation (LDLT) is estimated to be as high as 0.5–1%. To minimize the risk to the donor, left lobe (LL)‐LDLT might be an ideal option in adult LDLT. The aim of the study was to assess the feasibility of LL‐LDLT between adults based on a single‐center experience of 107 LL‐LDLTs performed over 8 years. The mean graft weight of LL grafts was 452 g, which amounted to 40.5% of the estimated standard liver volume of the recipients. The overall 1‐, 3‐ and 5‐year patient survival rates in LL‐LDLT were 81.4, 76.9 and 74.7%, respectively, which were comparable to those of RL‐LDLT. Twenty‐six grafts (24.3%) were lost for various reasons with three losses directly attributable to small‐for‐size graft syndrome. Post‐operative liver function and hospital stay in LL donors were significantly better and shorter than that in RL donors, while the incidence of donor morbidity was comparable between LL and RL donors. In conclusion, LL‐LDLT was found to be a feasible option in adult‐to‐adult LDLT. Further utilization of LL grafts should be undertaken to keep the chance of donor morbidity and mortality minimal.

Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma

Background. Liver transplantation is an accepted treatment option for patients with otherwise untreatable hepatocellular carcinoma (HCC). The present study assessed the outcome of living donor liver transplantation (LDLT) under extended selection criteria based on a single-center experience. Methods. A total of 60 patients who underwent LDLT for HCC were included. Our indication for LDLT included HCC without extrahepatic spread or macroscopic vascular invasion. The size and number of HCC nodules were not limited. Recurrence-free survival rates according to various factors were compared to identify risk factors for recurrence. Results. Forty patients (67%) preoperatively exceeded the Milan criteria. The median follow-up was 437 days (range: 23–1,385 days). The overall 1- and 3-year actuarial survival rates were 88.4 and 68.6%, respectively. HCC recurred in eight patients (14.3%) within a mean follow-up of 288 days; all were patients who exceeded the Milan criteria. The 1-, 2- and 3-year recurrence-free survival rates of patients who fulfilled the Milan criteria were 100%, 100%, and 100%, respectively, whereas those of patients who exceeded the criteria were 83.0%, 74.0%, and 74.0%, respectively. Tumor diameter >5 cm was significantly associated with worse prognosis, but the number of tumors was not. A preoperative des-gamma-carboxy prothrombin value >300 mAU/ml was strongly associated with the high recurrence rate. These two variables were significant in multivariate analysis. Conclusions. LDLT was shown to offer acceptable results in patients who exceeded the Milan criteria. The indication for LDLT can therefore be expanded beyond the Milan criteria, especially for patients with small multiple tumors <5 cm.

Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation.

Backgrounds. Because many patients who did not meet the Milan criteria have survived long after undergoing living donor liver transplantation (LDLT), extended criteria for recipient with hepatocellular carcinoma (HCC) are therefore considered to be necessary. Methods and Results. A total of 90 consecutive adult LDLT recipients with HCC between 1996 and 2007 were reviewed. The recurrence-free survival rates of all 90 patients were 86.0%, 81.3%, and 81.3% at 1, 3, and 5 years, respectively. Fourteen of 90 patients developed a recurrence of tumor after the LDLT. The tumor recurrences were diagnosed within 1 year after the LDLT in 11 (78.6%) patients. In a multivariate analysis, both the tumor size of less than 5 cm (P=0.0202) and the des-gamma-carboxy prothrombin (DCP) level of less than 300 mAU/mL (P=0.0001) were found to be favorable independent factors for the recurrence of HCC after LDLT. Therefore, the authors devised new selection criteria for HCC patients (a tumor size of <5 cm or a DCP of <300 mAU/mL). The 1-, 3-, and 5-year overall or recurrence-free survival rates of the 85 patients who met the new criteria were 92.3%, 85.9%, and 82.7%, or 90.5%, 87.0%, and 87.0%, respectively, which were significantly different from those of the five patients who did not meet the new criteria (P<0.0001). Conclusions. A combination of two factors, namely the tumor size and the DCP level, was found to be useful for expanding the selection of LDLT candidates for HCC.

Donor Risk in Adult-to-Adult Living Donor Liver Transplantation : Impact of Left Lobe Graft

Background. To ensure donor safety in adult-to-adult living donor liver transplantation, we established a selection criterion for donors in which left lobe (LL) was the first choice of graft. Methods. Two hundred six consecutive donors were retrospectively studied. Donors were divided into two groups according to graft type: LL graft (n=137) and right lobe (RL) graft (n=69). Results. Although mean intraoperative blood loss of LL was significantly increased compared with RL, mean peak postoperative total bilirubin levels and duration of hospital stay after surgery were significantly less for LL than RL (P<0.05). No donor died or suffered a life-threatening complication during the study period. The overall complication rate was 34.0%, including biliary complications in 5.3%. The number of biliary complications was four (2.9%) in LL and seven (10.1%) in RL (P<0.05). Logistic regression analysis revealed that only graft type (LL vs. RL) is significantly related to the occurrence of biliary complications (odds ratio 0.11; P=0.0012). The cumulative overall graft survival rates in the recipients with LL were not significantly different from that in the recipients with RL. Conclusions. LL grafting should be considered favorably when selecting donors for adult-to-adult living donor liver transplantation.

The beneficial role of simultaneous splenectomy in living donor liver transplantation in patients with small-for-size graft

Small‐for‐size (SFS) graft syndrome is one of the major causes of graft loss in living donor liver transplantation (LDLT). We examined whether splenectomy is beneficial for overcoming SFS graft syndrome in LDLT. The patients were classified into two groups: the Sp (−) group (n = 69), in which splenectomy was not performed, and the Sp (+) group (n = 44), in which it was. The incidence of SFS graft syndrome was investigated. Risk factors of SFS graft syndrome were identified by univariate‐ and multivariate analysis. To clarify whether splenectomy is beneficial for patients with a SFS graft, subgroup analysis was performed for patients who had a graft weight‐to‐standard liver weight (GW‐SLW) ratio of 40% or less (n = 50). Thirty‐one of 113 patients developed SFS graft syndrome. A multivariate analysis identified that having a male donor was an independent risk factor of SFS graft syndrome. SFS graft syndrome occurred in 11 of 50 patients with a GW‐SLW ratio <40%, and Sp (−) was an independent risk factor for the occurrence of SFS graft syndrome in patients (P = 0.014). Simultaneous splenectomy is favorable for overcoming SFS graft syndrome in LDLT patients with a GW‐SLW of 40% or less.

Biliary strictures in living donor liver transplantation: Incidence, management, and technical evolution

Biliary complications, biliary strictures (BS) in particular, continue to be a significant cause of morbidity after LDLT despite technical refinement. In this study, we assessed the incidence of BS and their management in living donor liver transplantation (LDLT) with special reference to the type of biliary reconstruction. A total of 182 LDLTs performed at our institution for either adult (n = 157) or pediatric (n = 25) patients were included in the study. The duct‐to‐duct (DD) biliary reconstruction was performed for 106 cases, while the conventional Roux‐en‐Y hepaticojejunostomy (HJ) was utilized for the remaining 76 cases. Overall, BS developed in 46/182 (25.3%) of the cases (DD, 26.4%; HJ, 25.0%). The 1‐ and 3‐year cumulative incidences of BS were 22.9% and 31.9%, respectively, in the DD group, and 15.2% and 29.1%, respectively, in the HJ group (P= not significant). The left‐lobe LDLT was more prone to develop BS. Continuous anastomosis tended to be associated with the high incidence of BS in the DD group. The incidence of anastomotic leak was significantly lower in the DD group. Intervention via either precutaneous or endoscopic approach was successful in the majority of cases, although recurrence could occur in some patients. In conclusion, BS was not associated with the type of reconstruction in LDLT. The primary radiological or endoscopic interventions were satisfactory treatments of choice. Technical refinement is an important factor to reduce the incidence of BS. Liver Transpl 12:979–986, 2006.

Validity of preoperative volumetric analysis of congestion volume in living donor liver transplantation using three-dimensional computed tomography

Reconstruction of middle hepatic vein (MHV) tributaries is controversial in right‐lobe living donor liver transplantation (LDLT). This study aimed to evaluate the appropriateness of reconstructing MHV tributaries by volumetry using 3‐dimensional computed tomography (3D‐CT). Between November 2003 and January 2005, 42 donor livers (right‐lobe graft, n = 25; left‐lobe graft, n = 17) were evaluated using this software. The total congestion volume (CV) associated with the MHV tributaries and the inferior right hepatic vein (IRHV), and graft volume (GV) were calculated. In recipients with right‐lobe grafts, CV/(right liver volume [RLV]) and (GV − CV)/(standard liver volume [SLV]) were compared between 2 groups: with reconstruction (n = 16) and without reconstruction (n = 9). To evaluate the influence of CV on the remnant right lobe in donors, total bilirubin was compared between 2 groups: high CV (CV > 20%, n = 13) or low CV (CV ≤ 20%, n = 4). The mean CV/RLV ratio was 32.3 ± 17.1% (V5, 15.2 ± 9.9%; V8, 9.2 ± 4.1%; and IRHV, 8.5 ± 11.4%) and the maximum ratio was as high as 80.8%. The mean (GV − CV)/SLV ratio before reconstruction in patients with or without reconstruction resulted in 33.5 ± 12.8% and 55.4 ± 12.9%, respectively (P < 0.01). In donors, total bilirubin was significantly high in the high CV group on postoperative day 1 compared with the low CV group (P < 0.05). In conclusion, calculation of CV using 3D‐CT software proved to be very useful. We concluded that this evaluation should be an integral part of procedure planning, especially for right‐lobe LDLT. (Liver Transpl 2005;11:1556–1562.)

Hepatocellular carcinoma with a pseudocapsule on gadolinium-enhanced MR images: correlation with histopathologic findings.

PURPOSE To evaluate the characteristics of hepatocellular carcinoma (HCC) with a pseudocapsule on dynamic magnetic resonance (MR) images. MATERIALS AND METHODS The institutional review board approval was obtained, and the requirements for informed consent were waived for this retrospective study. Dynamic MR studies of surgically resected 106 HCCs in 93 patients were retrospectively reviewed. A false-positive fibrous capsule (FC) on dynamic MR images was considered to be a pseudocapsule. Pathologic specimens of HCCs with a pseudocapsule were reviewed. The differences in size, tumor grade, the degree of liver fibrosis and background liver diseases, and the incidence of vascular invasion were compared between HCCs with a pseudocapsule on MR images and those with FC at histologic examination by using Student t, Kruskal-Wallis, and chi(2) tests. RESULTS The sensitivity, specificity, and accuracy of dynamic MR in the diagnosis of histologic FC were 94.0% (47 of 50), 73.2% (41 of 56), and 83.0% (88 of 106), respectively. There were 15 (14.2%) HCCs with a pseudocapsule. The pathologic specimens suggested possible causes of the pseudocapsule that included prominent sinusoids (n = 6), peritumoral fibrosis mimicking bridging fibrosis (n = 3), and both (n = 5). In one case, the capsulated HCC was surrounded by a well-differentiated HCC component. The mean size of a HCC with a pseudocapsule tended to be smaller than that with histologic FC, although it was not significant (mean +/- standard deviation: 2.8 cm +/- 1.0 vs 3.5 cm +/- 2.0, P = .09). Liver cirrhosis was less frequent in HCCs with a pseudocapsule than in those with a histologic FC (one of 14 [7.1%] vs 20 of 49 [40.8%], P < .05). The tumor grades were not significantly different, and the incidence of vascular invasion after standardizing the tumor size (<or=4 cm) was similar (five of 14 [35.7%] vs 12 of 37 [32.4%]). CONCLUSION Dynamic MR imaging is accurate in depicting FC in HCCs. HCC with a pseudocapsule at MR possibly consists of peritumoral sinusoids and/or fibrosis. The pseudocapsule may be similar to histologic FC in terms of tumor invasiveness.